Clinical manifestations and locus of known genes causing ADNSHL. Adapted from [10, 14]
\r\n\tUnstoppable progress in the technologies of synthesis of diamond, graphene, and its compounds with stable parameters will provide materials for the industry of devices for integrated, radio, Opto- and quantum electronics and photonics.
\r\n\tIn most electronic and optical properties, diamond and graphene are superior to traditional and perspective semiconductors. It is safe to say that silicon and gallium arsenide are materials for electronics and optoelectronics of the past, gallium nitride and silicon carbide are high-tech today, and diamond and graphene are the future of electronics and photonics.
Genetic hearing loss has diverse etiologies and approximately 1% of all human genes are involved in the hearing process [1]. It is estimated that at least two-thirds of cases of childhood-onset hearing loss have a genetic cause [2], with the remaining one-third caused by environmental factors, e.g., cytomegalovirus infection, meningitis, acquired conductive loss, and the impact of extracorporeal membrane oxygenation [3]. Many cases of later onset progressive hearing loss are genetic in origin, and genes also play an important role in progressive hearing loss associated with ageing. This chapter will deal with the ability to identify genetic problems or suspected genetic causes in hearing disorders, different types of gene mutation that causes deafness, genetic evaluation of hearing loss, special aspects of genetic tests such as next-generation sequencing, limitation of genetic testing, the development and evaluation of genetic treatment, management, prevention and genetic counseling, benefits of genetic research in deafness, and research needs/anticipating changes. It will conclude by the direction of possible future technological development in these aspects.
The majority of hearing loss is caused by mutations in the DNA (deoxyribonucleic acid) sequence of genes. There are four "bases" in a strand of DNA: adenine (A), guanine (G), thymine (T), and cytosine (C). The DNA also contains a monosaccharide sugar called deoxyribose and a phosphate group. According to base pairing rules (A with T, and C with G), hydrogen bonds bind bases of the two separate strands to make double-stranded DNA. Humans have approximately 30,000 genes. The DNA sequence of these genes provides the code for producing proteins (which consist of amino acids). The gene is located within a designated region on the chromosome and is composed of the different base pairs. The specific location on the chromosome where the gene is found is known as locus. For example, autosomal recessive deafness 1A (DFNB1A) is caused by mutation in the
There are two types of hearing loss caused by genetics. About 30% of people with a genetic type of hearing loss are classified as syndromic, which involves other presenting abnormalities along with hearing impairment. Non-syndromic hearing loss occurs when there are no other problems associated with an individual other than hearing loss. From a genetic standpoint, this accounts for the other 70% of people, which attributes to the vast majority of genetic hearing loss.
The genetic basis is highly complex. There are many different ways that the DNA sequence of a gene can be changed, resulting in different types of mutation. The types of gene mutations include missence, nonsense, substitution, insertion, deletion, duplication, frameshifts, repeat expansion, splice site, and translocation. The chances of developing deafness caused by a mutated gene depend on whether the mutation is dominant or recessive. Dominant and recessive hearing loss results from the allelic mutation in some genes, syndromic and non-syndromic hearing loss is caused by mutations in the same gene, and recessive hearing loss may be caused by a combination of two mutations in different genes from the same functional group [4].
The different gene loci for non-syndromic deafness are designated DFN (for DeaFNess). Based on the mode of inheritance, loci are named as A, B, X, and Y for autosomal dominant (DFNA), autosomal recessive (DFNB), X-linked (DFNX), and Y-linked (DFNY), respectively. The order in which the loci have been described is denoted by a number after these letters, e.g., DFNB1 is the first identified locus causing autosomal recessive HL [5, 6]. Earlier research reports that two-thirds of prelingual-onset sensorineural hearing loss (SNHL) is estimated to have a genetic etiology in developed countries, of which 70% is non-syndromic hearing loss (NSHL). However, 80% of NSHL is autosomal recessive non-syndromic hearing loss (ARNSHL), 20% is autosomal dominant (AD), and the remainder is composed of X-linked and mitochondrial forms [7-9]. NSHL demonstrates extreme genetic heterogeneity, with more than 55 autosomal dominant (deafness, neurosensory, DFNA), 80 autosomal recessive (deafness, neurosensory, DFNB), and 5 X-linked (deafness, neurosensory, DFNX) loci with 30, 55, and 4 causative genes, respectively, identified to date [10]. A fraction of these genes have been associated with both dominant and recessive HL. Furthermore, mitochondrial mutations can also underlie NSHL.
Autosomal dominant non-syndromic hearing loss (ADNSHL) is represented by heterogeneity of genetic and clinical features. ADNSHL is passed directly through generations. It is often possible to identify an autosomal dominant pattern through simple inspection of the family tree. Autosomal dominant traits usually affect males and females equally. ADNSHL associated with
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPostlingual/1st | \n\t\t\tLow frequency progressive | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPostlingual/2nd | \n\t\t\tHigh frequency progressive | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPostlingual/4th | \n\t\t\tHigh frequency progressive | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPrelingual | \n\t\t\tHigh frequency progressive | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPrelingual | \n\t\t\tHigh frequency progressive | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPostlingual | \n\t\t\tFlat/gently downsloping | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPostlingual/1st | \n\t\t\tHigh frequency progressive | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPrelingual | \n\t\t\tLow frequency progressive | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPrelingual | \n\t\t\tMid-frequency loss | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPostlingual/2nd | \n\t\t\tHigh frequency progressive | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPostlingual/3rd, 4th | \n\t\t\tFlat/gently downsloping | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPostlingual/1st | \n\t\t\tFlat/gently downsloping | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPostlingual/2nd | \n\t\t\tMid-frequency loss | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPostlingual | \n\t\t\tHigh frequency progressive | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPostlingual | \n\t\t\tHigh frequency progressive | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPostlingual | \n\t\t\tHigh frequency progressive | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPostlingual | \n\t\t\tHigh frequency progressive | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPrelingual | \n\t\t\tDownsloping | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPostlingual/2nd-6th decades | \n\t\t\tHigh frequency progressive | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPostlingual | \n\t\t\tFlat/gently downsloping | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPostlingual | \n\t\t\tFlat/gently downsloping | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPostlingual | \n\t\t\tHigh frequency progressive | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPostlingual | \n\t\t\tFlat progressive | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPostlingual | \n\t\t\tLow to mild frequencies progressive | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPostlingual | \n\t\t\tProgressive | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPostlingual/2nd | \n\t\t\tFlat progressive | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPostlingual/4th | \n\t\t\tHigh frequency progressive | \n\t\t
Autosomal recessive non-syndromic hearing loss at the
Mutations in the
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPrelingual 1\n\t\t\t | \n\t\t\tUsually stable | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPrelingual 1\n\t\t\t | \n\t\t\tUsually stable | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPrelingual, postlingual | \n\t\t\tUnspecified | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPrelingual | \n\t\t\tSevere to profound; stable | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPrelingual, postlingual | \n\t\t\tStable, progressive | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPrelinqual | \n\t\t\tSevere to profound; stable | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPrelinqual | \n\t\t\tSevere to profound; stable | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPostlingual 2, prelingual | \n\t\t\tProgressive; stable | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPrelingual | \n\t\t\tUsually severe to profound; stable | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPrelingual | \n\t\t\tSevere to profound; stable | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPrelingual | \n\t\t\tSevere to profound; stable | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPrelingual | \n\t\t\tSevere to profound; stable | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPrelingual | \n\t\t\tSevere to profound; stable | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPrelingual | \n\t\t\tSevere to profound; stable | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPrelingual | \n\t\t\tSevere to profound; stable | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPrelingual | \n\t\t\tSevere to profound; stable | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPrelingual | \n\t\t\tModerate to profound; progressive | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPrelingual | \n\t\t\tSevere to profound; stable | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPrelingual | \n\t\t\tSevere to profound; stable | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPrelingual | \n\t\t\tSevere to profound; stable | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPrelingual | \n\t\t\t— | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPrelingual | \n\t\t\tSevere to profound; stable | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tUnknown | \n\t\t\tSevere to profound | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPrelingual | \n\t\t\t— | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPrelingual | \n\t\t\t— | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPrelingual | \n\t\t\tSevere to profound; downsloping | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPrelingual | \n\t\t\tModerate to profound; stable | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPrelingual | \n\t\t\tSevere to profound; stable | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPrelingual | \n\t\t\tSevere to profound; stable | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPrelingual | \n\t\t\tSevere to profound; stable | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPrelingual | \n\t\t\tSevere to profound; stable | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPrelingual | \n\t\t\tSevere to profound; stable | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPrelingual | \n\t\t\tSevere to profound; stable | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPrelingual | \n\t\t\tHigh frequency; progressive | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPostlingual | \n\t\t\tModerate to profound; progressive | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPrelingual | \n\t\t\tSevere to profound; stable | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPrelingual | \n\t\t\tModerate to profound; progressive | \n\t\t
X-linked non-syndromic hearing loss is much rarer, accounting for 1-3% of hereditary deafness [19]. So far, there are only four genes that have been associated with X-linked non-syndromic hearing loss. These are:
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPostlingual | \n\t\t\tProgressive sensorineural; severe to profound | \n\t\t\tAll | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPrelingual | \n\t\t\tProgressive, mixed; variable, but progresses to profound | \n\t\t\tAll | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPostlingual | \n\t\t\tProgressive sensorineural; mild to profound | \n\t\t\tAll | \n\t\t
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\tPostlingual | \n\t\t\tProgressive Sensorinueral, mixed; mild to severe | \n\t\t\tAll | \n\t\t
Mitochondrial DNA (mtDNA) mutations account for at least 5% of cases of postlingual, non-syndromic hearing impairment [21]. MtDNA mutations are classified as either large-scale rearrangements (partial deletions or duplications) that are usually sporadic or point mutations, which are usually maternally inherited, and concern genes responsible for protein synthesis (rRNAs or tRNAs), or genes encoding subunits of the electron transport chain (ETC) [22, 23]. Tang et al. reported that mitochondrial mutations by themselves are not sufficient to produce a deafness phenotype. Modifier factors such as nuclear and mitochondrial genes, or environmental factors such as exposure to aminoglycosides, appear to modulate the phenotypic manifestations [24].
The mutation most commonly associated with maternal inheritance is A1555G on gene
The use of streptomycin, and to a lesser extent other aminoglycoside antibiotics, can cause hearing loss in genetically susceptible individuals. These drugs are known to exert their antibacterial effects at the level of the decoding site of the small ribosomal subunit, causing miscoding or premature termination of protein synthesis [28-30]. The hearing loss is primarily high frequency and may be unilateral. Mitochondrial non-syndromic sensory neural hearing loss (SNHL) is also associated with the A7445G, 7472insC, T7510C, and T7511C mutations in the tRNASer (UCN) gene,
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
\n\t\t\t\t (12S rRNA) | \n\t\t\t1555A->G | \n\t\t\tAminoglycoside induced/worsened | \n\t\t
1494C->T | \n\t\t\tAminoglycoside induced/worsened | \n\t\t|
961(mutations) | \n\t\t\tAminoglycoside induced/worsened | \n\t\t|
827A>G | \n\t\t\tAminoglycoside induced | \n\t\t|
\n\t\t\t\t \n\t\t\t\t(tRNASer(UCN))\n\t\t\t | \n\t\t\t7445A->G | \n\t\t\tPalmoplantar keratoderma | \n\t\t
7472insC | \n\t\t\tNeurological dysfunction, including ataxia, dysarthria, and myoclonus | \n\t\t|
7510T->C | \n\t\t\tNo additional symptoms | \n\t\t|
7511T->C | \n\t\t\tNo additional symptoms | \n\t\t|
\n\t\t\t\t | \n\t\t\t7444G>A | \n\t\t\tAminoglycoside associated; associated with | \n\t\t
\n\t\t\t\t | \n\t\t\t12201T-C | \n\t\t\tNo additional symptoms | \n\t\t
\n\t\t\t\t | \n\t\t\t3388C-A | \n\t\t\tTinnitus and BPPV associated | \n\t\t
\n\t\t\t\t | \n\t\t\t4295A-G | \n\t\t\tHypertrophic cardiomyopathy | \n\t\t
Identified mitochondrial DNA mutations in hearing loss. Modified from [10].
Syndromic forms of hearing loss are less common than non-syndromic forms. To date, more than 400 genes responsible for syndromic hearing loss have been identified [32]. These can include syndromes transmitted in Mendelian or monogenic, syndromes due to chromosomal anomalies, syndromes due to multi-factorial influences, or syndromes due to a combination of these. Syndromic hearing loss can be conductive, sensorineural, or mixed.
Many of the syndromes associated with SNHL do not usually demonstrate gross inner ear anomalies. However, inner ear malformations are common in numerous syndromes. In some cases, the existence of specific inner ear anomalies may be characteristic of certain syndromes such as in BOR syndrome, Waardenburg syndrome, or X-linked deafness with stapes gusher or CHARGE syndrome. SNHL presenting later in life is often related to inner ear infections or inflammatory conditions, trauma, or tumor [33].
Mutations in the same gene may cause syndromic hearing loss in one individual and non-syndromic hearing loss in another. The most common autosomal dominant form is Waardenburg syndrome. The most common autosomal recessive forms are Pendred syndrome and Usher syndrome. Syndromic hearing loss may be transmitted as an autosomal recessive, autosomal dominant, X-linked, or matrilineal trait. Some of the genetics forms of syndromic hearing loss and their main clinical features are given in Table 5 [34].
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
\n\t\t\t\t | \n\t\t\t⋅ Type 1: dystopia canthorum, iris heterochromy, brilliant blue eyes, broad nasal root, premature, graying of hair, white forelock, and vestibular dysfunction | \n\t\t\t\n\t\t\t\t | \n\t\t\tSensorineural hearing loss | \n\t\t
\n\t\t\t | \n\t\t\t | \n\t\t | |
\n\t\t\t | ⋅ Type 2: similar phenotype except dystopia canthorum | \n\t\t\tMITF, SNAI2 | \n\t\t\t\n\t\t |
\n\t\t\t | ⋅ Type 3 (Klein-Waardenburg syndrome ): upper extremity abnormalities other Type 1 clinical features | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t |
\n\t\t\t | ⋅ Type 4 (Waardenburg-Shah syndrome): pigmentation abnormalities and Hirschsprung’s disease other Type 2 clinical features | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t |
\n\t\t\t\t | \n\t\t\t⋅ Choanal atresia | \n\t\t\tMutations in | \n\t\t\tSevere-to- | \n\t\t
\n\t\t\t\t | \n\t\t\t⋅ Coloboma | \n\t\t\t\n\t\t\t\t | \n\t\t\tprofound | \n\t\t
(AD) | \n\t\t\t⋅ Characteristic ears | \n\t\t\tdetected in | \n\t\t\tasymmetrical | \n\t\t
\n\t\t\t | ⋅ Cranial nerve anomalie | \n\t\t\tmore than 75% | \n\t\t\tmixed losses | \n\t\t
\n\t\t\t | ⋅ Cardiovascular malformations | \n\t\t\tof CHARGE | \n\t\t\t\n\t\t |
\n\t\t\t | ⋅ Genital hypoplasia | \n\t\t\tpatients | \n\t\t\t\n\t\t |
\n\t\t\t | ⋅ Cleft lip/palate | \n\t\t\tSEMA3E | \n\t\t\t\n\t\t |
\n\t\t\t | ⋅ Tracheoesophageal fistula | \n\t\t\t\n\t\t\t | \n\t\t |
\n\t\t\t | ⋅ Growth deficiency | \n\t\t\t\n\t\t\t | \n\t\t |
\n\t\t\t | ⋅ Developmental delay | \n\t\t\t\n\t\t\t | \n\t\t |
\n\t\t\t\t | \n\t\t\t⋅ Micrognathia | \n\t\t\tGenetic | \n\t\t\tTypically | \n\t\t
\n\t\t\t\t | \n\t\t\t⋅ Glossoptosis | \n\t\t\theterogeneity | \n\t\t\tconductive and | \n\t\t
(AD) | \n\t\t\t⋅ Cleft palate | \n\t\t\t\n\t\t\t | bilateral | \n\t\t
\n\t\t\t\t | \n\t\t\t⋅ Long and flat face | \n\t\t\tMutations in | \n\t\t\tBoth | \n\t\t
\n\t\t\t\t | \n\t\t\t⋅ Malar and mandibular hypoplasia | \n\t\t\t\n\t\t\t\t | \n\t\t\tsensorineural and | \n\t\t
(AD) | \n\t\t\t⋅ Small nose with a depressed nasal bridge | \n\t\t\t\n\t\t\t\t | \n\t\t\tconductive | \n\t\t
\n\t\t\t | and anteverted nares | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t |
\n\t\t\t | ⋅ Altered vision | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t |
\n\t\t\t | ⋅ Joint problems | \n\t\t\t\n\t\t\t | \n\t\t |
\n\t\t\t\t | \n\t\t\t⋅ Branchial cleft, cysts, or fistulae | \n\t\t\t\n\t\t\t\t | \n\t\t\tSensorineural, | \n\t\t
(AD) | \n\t\t\t⋅ Ear abnormalities | \n\t\t\tmutations | \n\t\t\tconductive, or | \n\t\t
\n\t\t\t | ⋅ Kidney abnormalities | \n\t\t\t\n\t\t\t | mixed hearing loss | \n\t\t
\n\t\t\t\t | \n\t\t\t⋅ Zygomatic arches hypoplasia | \n\t\t\tGenetic | \n\t\t\tAbout 40-50% of | \n\t\t
\n\t\t\t\t | \n\t\t\t⋅ Hypoplasia of supraorbital rims | \n\t\t\theterogeneity: | \n\t\t\tpatients with | \n\t\t
(AD) | \n\t\t\t⋅ Micrognathia | \n\t\t\tTCS-1, TCS-2 | \n\t\t\tTreacher Collins | \n\t\t
\n\t\t\t | ⋅ Narrow face | \n\t\t\tand TCS- 3 | \n\t\t\thave conductive | \n\t\t
\n\t\t\t | ⋅ Antimongoloid slant of the eyes and | \n\t\t\thave been | \n\t\t\thearing loss. Few | \n\t\t
\n\t\t\t | hypertelorism | \n\t\t\trelated to | \n\t\t\tcases of mixed | \n\t\t
\n\t\t\t | ⋅ Coloboma of the lower lid with | \n\t\t\tmutations in | \n\t\t\thearing loss have | \n\t\t
\n\t\t\t | deficiency of cilia medial to the coloboma | \n\t\t\t\n\t\t\t\t | \n\t\t\tbeen described. | \n\t\t
\n\t\t\t | ⋅ Large nose is with hypoplastic alae | \n\t\t\tand | \n\t\t\t\n\t\t |
\n\t\t\t | ⋅ Down-turning mouth | \n\t\t\trespectively | \n\t\t\t\n\t\t |
\n\t\t\t | ⋅ Cleft palate | \n\t\t\t\n\t\t\t | \n\t\t |
\n\t\t\t | ⋅ External ear abnormalities | \n\t\t\t\n\t\t\t | \n\t\t |
\n\t\t\t\t | \n\t\t\t⋅ Craniosynostosis | \n\t\t\t\n\t\t\t\t | \n\t\t\tMild to moderate | \n\t\t
(AD) | \n\t\t\t⋅ Frontal bossing | \n\t\t\t\n\t\t\t | conductive | \n\t\t
\n\t\t\t | ⋅ Wide set eyes | \n\t\t\t\n\t\t\t | hearing loss | \n\t\t
\n\t\t\t | ⋅ Hypoplastic midface | \n\t\t\t\n\t\t\t | \n\t\t |
\n\t\t\t | ⋅ Proptosis | \n\t\t\t\n\t\t\t | \n\t\t |
\n\t\t\t | ⋅ Small upper jaw | \n\t\t\t\n\t\t\t | \n\t\t |
\n\t\t\t | ⋅ Syndactyly | \n\t\t\t\n\t\t\t | \n\t\t |
\n\t\t\t\t | \n\t\t\t⋅ Synostosis | \n\t\t\t\n\t\t\t\t | \n\t\t\tConductive | \n\t\t
\n\t\t\t\t | \n\t\t\t⋅ High forehead | \n\t\t\t\n\t\t\t | hearing loss | \n\t\t
(AD) | \n\t\t\t⋅ Proptosis | \n\t\t\t\n\t\t\t | \n\t\t |
\n\t\t\t | ⋅ External strabismus | \n\t\t\t\n\t\t\t | \n\t\t |
\n\t\t\t | ⋅ Hypertelorism | \n\t\t\t\n\t\t\t | \n\t\t |
\n\t\t\t | ⋅ Prognathism | \n\t\t\t\n\t\t\t | \n\t\t |
\n\t\t\t | ⋅ Hypoplastic upper jaw | \n\t\t\t\n\t\t\t | \n\t\t |
\n\t\t\t\t | \n\t\t\t⋅ Brachycephaly | \n\t\t\t\n\t\t\t\t | \n\t\t\tConductive or mixed | \n\t\t
\n\t\t\t\t | \n\t\t\t⋅ Low frontal hair line | \n\t\t\t\n\t\t\t | \n\t\t |
(AD) | \n\t\t\t⋅ Flattened nasofrontal angle | \n\t\t\t\n\t\t\t | \n\t\t |
\n\t\t\t | ⋅ Widely spaced eyes | \n\t\t\t\n\t\t\t | \n\t\t |
\n\t\t\t | ⋅ Ptosis | \n\t\t\t\n\t\t\t | \n\t\t |
\n\t\t\t | ⋅ Facial asymmetry | \n\t\t\t\n\t\t\t | \n\t\t |
\n\t\t\t | ⋅ Syndactyly | \n\t\t\t\n\t\t\t | \n\t\t |
\n\t\t\t | ⋅ Broad or duplicated thumb or hallux | \n\t\t\t\n\t\t\t | \n\t\t |
\n\t\t\t\t | \n\t\t\t⋅ Broad face is midface hypoplasia | \n\t\t\t\n\t\t\t\t | \n\t\t\tConductive | \n\t\t
(AD) | \n\t\t\t⋅ Prognatism | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t |
\n\t\t\t | ⋅ High forehead, flat occiput, hypertelorism | \n\t\t\t\n\t\t\t | \n\t\t |
\n\t\t\t | ⋅ Swallowing orbits which cause proptosis | \n\t\t\t\n\t\t\t | \n\t\t |
\n\t\t\t | ⋅ Skull malformation | \n\t\t\t\n\t\t\t | \n\t\t |
\n\t\t\t | ⋅ Limb abnormalities | \n\t\t\t\n\t\t\t | \n\t\t |
\n\t\t\t\t | \n\t\t\t⋅ Anus imperforatus | \n\t\t\tIt is caused by | \n\t\t\tSensorineural or | \n\t\t
\n\t\t\t\t | \n\t\t\t⋅ Rectovaginal | \n\t\t\tmutations in | \n\t\t\tconductive | \n\t\t
(AD) | \n\t\t\t⋅ Rectoperineal fistula | \n\t\t\t\n\t\t\t\t | \n\t\t\thearing loss | \n\t\t
\n\t\t\t | ⋅ External ear anomalies | \n\t\t\t\n\t\t\t | \n\t\t |
\n\t\t\t | ⋅ Thumbs malformation | \n\t\t\t\n\t\t\t | \n\t\t |
\n\t\t\t\t | \n\t\t\t⋅ Malar hypoplasia | \n\t\t\t\n\t\t\t\t | \n\t\t\tConductive | \n\t\t
(AR** or AD) | \n\t\t\t⋅ Micrognathia | \n\t\t\t\n\t\t\t | hearing loss- | \n\t\t
\n\t\t\t | ⋅ Down-slanting eyes | \n\t\t\t\n\t\t\t | mainly due to | \n\t\t
\n\t\t\t | ⋅ Coloboma | \n\t\t\t\n\t\t\t | anomalies of | \n\t\t
\n\t\t\t | ⋅ Cleft palate | \n\t\t\t\n\t\t\t | middle ear | \n\t\t
\n\t\t\t | ⋅ Limb defects | \n\t\t\t\n\t\t\t | \n\t\t |
\n\t\t\t\t | \n\t\t\t⋅ Limbs abnormalities | \n\t\t\tNot known | \n\t\t\tConductive or | \n\t\t
(Sporadic, AD or | \n\t\t\t⋅ Maxillar hypoplasia | \n\t\t\t\n\t\t\t | mixed hearing | \n\t\t
AR) | \n\t\t\t⋅ Micrognatia | \n\t\t\t\n\t\t\t | Loss | \n\t\t
\n\t\t\t\t | \n\t\t\t⋅ Hemifacial microsomia | \n\t\t\tGenetic | \n\t\t\tRanges from | \n\t\t
\n\t\t\t\t | \n\t\t\t⋅ Auricular malformations | \n\t\t\theterogeneity | \n\t\t\tmild to moderate | \n\t\t
(Sporadic, AR or | \n\t\t\t⋅ Vertebrae abnormalities | \n\t\t\t\n\t\t\t | conductive | \n\t\t
AD) | \n\t\t\t⋅ Facial cleft | \n\t\t\t\n\t\t\t | impairment and | \n\t\t
\n\t\t\t | ⋅ Ocular abnormalities | \n\t\t\t\n\t\t\t | severe to profound | \n\t\t
\n\t\t\t | ⋅ Congenital heart diseases | \n\t\t\t\n\t\t\t | sensorineural hearing loss | \n\t\t
\n\t\t\t\t | \n\t\t\t⋅ Type 1: vestibular dysfunction onset | \n\t\t\t\n\t\t\t\t | \n\t\t\tProfound hearing | \n\t\t
(AR) | \n\t\t\tof retinitis pigmentosa in childhood | \n\t\t\t\n\t\t\t\t | \n\t\t\tLoss | \n\t\t
\n\t\t\t | ⋅ Type 2: normal vestibular response | \n\t\t\t\n\t\t\t\t | \n\t\t\tMild to moderate | \n\t\t
\n\t\t\t | retinitis pigmentosa begins in the second decade of life | \n\t\t\t\n\t\t\t\t | \n\t\t\thearing loss | \n\t\t
\n\t\t\t | ⋅ Type 3: variable vestibular response, | \n\t\t\t\n\t\t\t\t | \n\t\t\tProgressive hearing loss | \n\t\t
\n\t\t\t | variable onset of retinitis pigmentosa | \n\t\t\t\n\t\t\t | \n\t\t |
\n\t\t\t\t | \n\t\t\t⋅ Abnormal iodine metabolism (goiter) | \n\t\t\t\n\t\t\t\t | \n\t\t\tUsually bilateral, severe to | \n\t\t
(AR) | \n\t\t\t\n\t\t\t | \n\t\t\t | profound | \n\t\t
\n\t\t\t\t | \n\t\t\t⋅ SIDS, syncopal episodes prolongation of | \n\t\t\tKCNQ1, KCNE1 | \n\t\t\tSensorineural hearing loss | \n\t\t
(AR) | \n\t\t\tthe QT interval | \n\t\t\t\n\t\t\t | \n\t\t |
\n\t\t\t\t | \n\t\t\t⋅ Ovarian dysfunction in females, | \n\t\t\tHSD17B4, HARS2, LARS2 | \n\t\t\tSensorineural hearing loss | \n\t\t
(AR) | \n\t\t\t⋅ Intellectual disability, | \n\t\t\t\n\t\t\t | \n\t\t |
\n\t\t\t | ⋅ Loss of sensation and weakness in the limbs | \n\t\t\t\n\t\t\t | \n\t\t |
\n\t\t\t\t (AR,AD, X-Linked) | \n\t\t\t⋅ Renal abnormalities including glomerulonephritis, hematuria, and renal failure | \n\t\t\tCOL4A3, COL4A4 and COL4A5 | \n\t\t\tProgressive sensorineural hearing loss | \n\t\t
\n\t\t\t | ⋅ Hearing loss usually begins in the adolescent years | \n\t\t\t\n\t\t\t | \n\t\t |
\n\t\t\t\t (X-Linked) | \n\t\t\t⋅ Visual disability ⋅ Dystonia, fractures ⋅ Intellectual disability | \n\t\t\t\n\t\t\t\t | \n\t\t\tProgressive hearing loss | \n\t\t
\n\t\t\t\t (X-Linked) | \n\t\t\t⋅ Eye disorder ⋅ Developmental delays in motor skills ⋅ Mild to moderate intellectual disability | \n\t\t\tNDP | \n\t\t\tSensorineural Progressive HL | \n\t\t
Syndromic hearing loss and their clinical features. Modified from [34].
*AD- Autosomal dominant inheritance, **AR- Autosomal recessive inheritance
Despite the significant advances in understanding the molecular basis of hearing loss, precise identification of genetic cause still presents some difficulties due to phenotypical variation. Gene discovery efforts for hearing disorders are complicated by the extreme heterogeneity. Usher syndrome or Jervell and Lange-Nielsen syndrome, which can be mistaken for nonsyndromic hearing loss, where Usher syndrome can be caused by mutations in several different genes. We must therefore have a clear understanding of the different types of diagnostic tests available to patients, including karyotyping, RFLP, FISH, microarray, clinical exome sequencing, preimplantation genetic diagnosis, and newborn genetic screening. Establishing a genetic diagnosis of hearing loss is a critical component of the clinical evaluation of hearing impaired persons and their families. If a genetic cause of hearing loss is determined, it is possible to provide families with prognostic information, recurrence risks, and improved habilitation options [9].
The identification of genes or genetic cause for hearing loss is a breakthrough approach. First we have to rule out non-genetic causes, then syndromic causes, and then look for non-syndromic causes. Mutations in some of these genes, such as
With the fast development and wide applications of next-generation sequencing (NGS) technologies, genomic sequence information is within reach to aid the achievement of goals to decode life mysteries and improve life qualities. Today, NGS-based tests are rapidly replacing traditional tests, which include many single gene-sequencing tests for hearing loss. These tests use disease-targeted exon capture, whole-exome sequencing (WES), or whole-genome sequencing (WGS) strategies. The main advantage of these tests is that they address the problem of genetic heterogeneity, where many different genes result in phenotypes that cannot be easily distinguished clinically [36-39]. NGS also offers sequencing of very large gene or in presence of substantial locus heterogeneity, where it may be difficult to analyze the same gene by comprehensive Sanger sequencing.
NGS systems are typically represented by SOLiD/Ion Torrent PGM from Life Technologies, Genome Analyzer/HiSeq/MiSeq/NextSeq from Illumina, and GS FLX Titanium/GS Junior from Roche. Today, Illumina dominates the genome sequencing market, where instrument versatility, high throughput and accuracy, turnaround speed, faster and simpler sample preparation, and supportive data analysis software make it a driving force and the clear winner as of now. Their technology creates new applications and also decipher many existing genetic research and clinical diagnostic markets.
Targeted genomic capture and massively parallel sequencing technologies are revolutionizing genomics by making it possible to sequence complete genomes of model organisms. However, the cost and capacity required are still high, especially considering that the functional significance of intronic and intergenic noncoding DNA sequences is still largely unknown. One application that these technologies are well suited for is the re-sequencing of many selected parts of a genome, such as all exons, from a large set of genes. This requires that the targeted parts of the genome are highly enriched in the sample. Recent technological changes, such as genome capture, genome enrichment, and genome partitioning, have successfully been used to enrich large parts of the genome [40-42]. The targeted fragments can subsequently be captured using solid- or liquid-phase hybridization assays [43, 44].
Clinical exome sequencing or whole-exome sequencing is a highly complex molecular test that analyzes the exons or coding regions of thousands of genes simultaneously from a small sample of blood, using NGS techniques. Exome sequencing is especially valuable when a patient’s symptoms suggest numerous possible genetic causes. The whole-exome sequencing test sequences base by base with the required depth of coverage to achieve accurate consensus sequence rather than limiting the testing to a single gene or panel of genes and incurring diagnostic delays and escalating costs. It is possible to identify point mutations, insertions, deletions, inversions, and rearrange the exome.
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
Nonsyndromic Recessive | \n\t\t\tDFNB79 | \n\t\t\t\n\t\t\t\t | \n\t\t\tTargeted enrichment of genomic locus | \n\t\t\t[48] | \n\t\t
DFNB82 | \n\t\t\t\n\t\t\t\t | \n\t\t\tWhole exome | \n\t\t\t[49] | \n\t\t|
DFNB84 | \n\t\t\t\n\t\t\t\t | \n\t\t\tWhole exome | \n\t\t\t[50] | \n\t\t|
Dominant | \n\t\t\tDFNA4 | \n\t\t\t\n\t\t\t\t | \n\t\t\tWhole exome | \n\t\t\t[51] | \n\t\t
DFNA41 | \n\t\t\t\n\t\t\t\t | \n\t\t\tTargeted enrichment of genomic locus | \n\t\t\t[52] | \n\t\t|
X-Linked | \n\t\t\tDFNX4 | \n\t\t\tSMPX | \n\t\t\tTargeted enrichment of genomic locus | \n\t\t\t[53] | \n\t\t
Syndromic | \n\t\t\tPerrault syndrome | \n\t\t\t\n\t\t\t\t | \n\t\t\tWhole exome | \n\t\t\t[54] | \n\t\t
Perrault syndrome | \n\t\t\t\n\t\t\t\t | \n\t\t\tTargeted enrichment of genomic locus | \n\t\t\t[55] | \n\t\t|
Carnevale, Malpuech, Michels, and oculo-skeletal-abdominal syndromes | \n\t\t\t\n\t\t\t\t | \n\t\t\tWhole exome | \n\t\t\t[56] | \n\t\t|
Hereditary sensory and autonomic neuropathy type 1 (HSAN1) with dementia and hearing loss | \n\t\t\t\n\t\t\t\t | \n\t\t\tWhole exome | \n\t\t\t[57] | \n\t\t
Deafness genes identified using genomic capture and massively parallel sequencing.
Among NGS applications, whole-exome sequencing is a cost-effective alternative to whole-genome sequencing. The total size of the human exome is ~30 Mb, which comprises ~180,000 exons that are arranged in about 22,000 genes and constitute about 2-3% of the entire human genome, but contains ~85% of known disease-causing variants. The exome refers to the portion of the human genome that contains functionally important sequences of DNA that direct the body to make proteins essential for the body to function properly. Research revealed that most of the errors that occur in DNA sequences are usually located in the exons that lead to genetic disorders. Consequently, sequencing human exome is considered to be an efficient method to discover the genetic cause of hearing disorders. Currently, sequencing whole genomes is still a substantial undertaking, which is not a routine procedure that can be done on hundreds of samples. At present, exome sequencing represents an alternative in which, approximately 30-70 Mb sequences encompassing exons and splice sites are targeted, enriched, and sequenced using commercially available sequence capture methods. Several Human Exome Sequence Capture kits are now commercially available. These include the Agilent SureSelect Human All Exon Kit, the Illumina Nextera Rapid Capture Exome and Nextera Rapid Capture Expanded Exome Kit, the TargetSeq In-solution Target Enrichment Kit from Life Tech/Applied Biosystems, and SeqCap EZ Exome from Roche NimbleGen. Clinical exome sequencing should be considered in the diagnostic assessment of a phenotype individual when a genetic disorder is suspected clinically, but limited genetic testing is available clinically, the patient’s features are unclear or atypical, there are multiple genetic conditions as part of the differential diagnosis, and a novel or candidate gene is suspected but has yet to be discovered.
Hundreds of syndromic forms of deafness have been described, and for many of them, the underlying genes still await discovery. Since the introduction of the first NGS technology in 2004, more than 1,000 NGS-related manuscripts have been published. Until now, approximately a dozen of genes for HL have been successfully determined using NGS [45-47] (Table 6).
Consider a case where there is an interest in a large but limited subset of particular genes, not the whole genome, or even the whole exome, but more than just one or two genes. This sort of situation frequently arises in the context of oncology, where the characterization of a set of oncogenes on a set of pathways can help stratify cases and select the best therapeutic options. These may consist of 30-150 particular target genes, with a desire to have high throughput by analyzing multiple different specimens within a single NGS run. Generally referred to as “NGS panels,” this is a third form of library which, depending on design, may start with extracting genomic DNA from a test sample where selection of targets of interest is performed. This can be by gene-specific PCR, leading to a pool of amplicons (already of the desired length, although in this case with defined endpoints), by hybridization capture, or by selective genomic DNA coding only for particular genes. This genetic material is then a very focused subset of the source genome from which to prepare the library material for dispersion and sequencing, following either of the paths above as appropriate to the sample type (note that for a direct PCR amplified genomic DNA panel type, the size shearing and adapter ligation steps may be dispensed with as these are effectively carried out in the PCR step).
A particularly clever aspect of NGS panels is that it is possible, either in the direct PCR stage for genomic DNA-based panels or in the adapter ligation step for exome-based panels, to use PCR primers or adapters, respectively, which contain an internal sequence element (commonly referred to as a “barcode”) that is distinct to each sample prepared. This then allows multiple panel libraries from different samples to be mixed together prior to the dispersion and actual sequencing steps. By doing this, each individual sequence read will start with a sample-unique “barcode,” allowing it to be associated back to the sample of origin. This allows many different unrelated panel sample libraries to be mixed together in one dispersion and sequencing run, thereby taking full advantage of the massively parallel nature of NGS technology and allowing for high throughput with respect to the number of samples per run. This makes panels highly cost-effective and of relatively low labor input on a per-sample basis. Depending on the type of research or clinical question being addressed in an NGS assay, the choice of the best method helps to make results cost-effective and most directly meaningful.
Different panels designed to diagnose hearing loss include:
Hearing Loss Panel Tier 1—testing for mutations in
OtoGenomeTM Test Panel offered by Partners Healthcare. This test panel simultaneously screens 87 genes known to cause both non-syndromic hearing loss and syndromes that can present as isolated hearing loss, such as Usher, Pendred, Jervell and Lange-Nielsen (JLNS), Branchio-Oto-Renal (BOR), Deafness and Male Infertility (DIS), Perrault, and Waardenburg syndromes.
The large amount of data derived from NGS platforms imposes increasing demands on statistical methods and bioinformatic tools for the analysis. Although the NGS platforms rely on different principles and differ in how the array is made, their work flows are conceptually very similar. All of them generate millions or billions of short sequencing reads simultaneously. Several layers of analysis are necessary to convert these raw sequence data into understanding of functional biology. These include alignment of sequence reads to a reference, base-calling and/or polymorphism detection, de novo assembly from paired or unpaired reads, and structural variant detection (Figure 1). To date, a variety of software tools are available for analyzing NGS data. Although tremendous progress has been achieved over the last several years in the development of computational methods for the analysis of high-throughput sequencing data, there are still many algorithmic and informatics challenges remaining. For example, even if a plethora of alignment tools have been adapted or developed for the reconstruction of full human genotypes from short reads, this task remains an extremely challenging problem. Also, when a high-throughput technology is used to sequence an individual (the donor), any genetic difference between the sequenced genomes and a reference human genome—typically the genome maintained at NCBI—is called the variant. Although this reference genome was built as a mosaic of several individuals, it is haploid, and may not contain a number of genomic segments present in other individuals. By simply mapping reads to the reference genome, it is impossible to identify these segments. Thus, de novo assembly procedures should be used instead. Nonetheless, NGS technologies continue to change the landscape of human genetics. The resulting information has both enhanced our knowledge and expanded the impact of the genome on biomedical research, medical diagnostics, and treatment, and has accelerated the pace of gene discovery [47].
Next-generation sequencing: An approach from sample to analysis.
Clinical diagnostic using NGS technologies may be applicable in such cases where clinicians consider a non-syndromic hearing disorder, especially after negative results on tests for mutations in the autosomal recessive
Cytogenetic tests are a diagnostic tool for a number of clinical syndromes associated with hearing loss. They proved the causal association between specific chromosomal abnormalities and clinical features observed in patients. Although cytogenetics is not the first technique to be considered when evaluating a child with non-syndromic deafness, this form of testing could be valuable in cases of deafness of unknown etiology, particularly if there were accompanying congenital anomalies, or a family history of multiple spontaneous abortions. When all other causes of deafness are eliminated, cytogenetics could be used to determine if the hearing loss may be due to a chromosome rearrangement, such as a balanced translocation. The advantage would be that, if such a chromosome rearrangement were found, it would immediately suggest the location of the deafness gene [59].
Cytogenetic or molecular cytogenetic tests such as karyotyping, fluorescent in situ hybridization (FISH), or chromosomal microarray analysis (CMA) may provide diagnostic information when syndromes characterized by chromosomal aneuploidies, structural rearrangements, or deletions or duplications are suspected. Genetic testing of specific individual genes (PAX3 for Waardenburg syndromes types I and III), or small panels of genes related to a specific clinical finding (FGFR-related craniosynostosis panel) may be appropriate, depending on the suspected diagnosis [60].
Prenatal diagnosis of chromosomal aberrations requires cytogenetic analysis of amniotic fetal cells. Amniocentesis is an invasive, well-established, safe, and reliable test during pregnancy that removes a small amount of fluid from the sac around the baby to look for birth defects and chromosomal problems. Amniocentesis is done from 12 to 15 weeks of gestation for chromosomal analysis. When the amniotic sample is received in the laboratory, it is centrifuged at 750 rpm for 10 minutes. The amniotic fluid is then carefully decanted from the cell pellet into a sterile test tube, and then the cell pellet is re-suspended in amniotic fluid. Then, suitable medium supplemented with fetal bovine serum, L-glutamine, and antibiotics are added and the cultures are incubated at 37ºC in 5% CO2 incubator. The cells are harvested at 8-10 days after culture, subjected to routine hypotonic and fixative treatments as for whole blood culture, and then the chromosomes are analyzed [61].
Genetic screening for a specific mitochondrial mutation during pregnancy could offer a strategy of minimizing hearing loss in babies from exposure to avoidable risk factors such as neonatal use of aminoglycoside antibiotics [3]. Genetic counseling should ideally be offered to all pregnant women who have a family history of any condition that might be tested by either amniocentesis or chorionic villus sampling (CVS). It is important to offer genetic counseling before and after prenatal diagnostic testing. The important aspects should be considered such as presentation of the background risk of congenital disease and anomaly, and individual increased risks (such as increased maternal age), options and limitations for prenatal genetic diagnosis, possible diseases that can be detected, risks associated with the relevant tests, and conflictual areas in relation to prenatal diagnosis and alternatives. [62]. Different techniques used in genetic analysis and their applications are summarized in Table 7.
\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t\t\n\t\t\t\t | \n\t\t
\n\t\t\t\t | \n\t\t\tSequencing of targeted genes to analyze variations | \n\t\t\t1975, Frederick Sanger | \n\t\t\t[63] | \n\t\t
\n\t\t\t\t | \n\t\t\tDetect and localize the presence or absence of specific DNA sequences on chromosomes | \n\t\t\t1980, Bauman et al. | \n\t\t\t[64] | \n\t\t
\n\t\t\t\t | \n\t\t\tVariations in homologous DNA sequences | \n\t\t\t1984, Sir Alec Jeffreys | \n\t\t\t[65] | \n\t\t
\n\t\t\t\t | \n\t\t\tCopy number variation of numbers of genes involved in disease | \n\t\t\t1995, Schena et al. | \n\t\t\t[66] | \n\t\t
\n\t\t\t\t | \n\t\t\tCopy number variations of targeted genes | \n\t\t\t1996, Heid et al. | \n\t\t\t[67] | \n\t\t
\n\t\t\t\t | \n\t\t\tDetects variations of entire genome and/or coding regions, genome resequencing, transcriptome profiling, DNA-protein interactions, maximum read length >40,000 bases | \n\t\t\t2003, Levene et al. | \n\t\t\t[68] | \n\t\t
\n\t\t\t\t | \n\t\t\tAnalyzes the exons or coding regions of thousands of genes simultaneously | \n\t\t\t2009, Sarah B Ng et al. | \n\t\t\t[69] | \n\t\t
Different techniques used in genetic analysis and applications.
Molecular genetic testing can be helpful because an etiology cannot be otherwise established in the majority of individuals with genetic hearing loss. Molecular analysis is essentially non-invasive and may reduce the need for more extensive and expensive testing; it sometimes requires sedation or general anesthesia of infants and children. Molecular analysis can be beneficial for the diagnosis of syndromic hearing loss before additional features emerge (e.g., in Pendred syndrome or Jervell and Lange-Nielsen syndrome), and can distinguish individuals with mitochondrial mutations who are at risk for iatrogenic hearing loss when treated with aminoglycosides [4]. There are other benefits of molecular analysis, which include associated knowledge of the pattern of inheritance and more accurate genetic counseling. Recently developed high-throughput techniques reduce the burden of the costs of sequencing. For example, sequencing costs have massively reduced from $5,292.39/Mb in 2001 to $0.06/Mb by April 2013 [70]. It is estimated that the sequencing costs will further reduce with precipitous dropping per-base cost with advancing techniques.
Despite the significant advantages of genetic testing, there are also several limitations and challenges. These limitations and challenges are briefly discussed below:
The spectrum of DNA variation in a human genome comprises small base changes (substitutions), insertions and deletions of DNA, large genomic deletions of exons or whole genes, and rearrangements such as inversions and translocations. Traditional Sanger sequencing is restricted to the discovery of substitutions and small insertions and deletions [71].
Although NGS promises a personalized approach to complex diseases, it has limitations. NGS cannot detect large deletions or duplications of DNA or nucleotide repeats that can cause disease. These limitations of NGS technologies may necessitate use of alternative or complementary genetic testing strategies in some cases.
Not all regions of the genome are efficiently captured and analyzed by current exon-capture or WGS approaches, and large deletions and duplications, in addition to copy-number and structural variations, may not be efficiently detected [72].
It is possible to determine with recent technology if an asymptomatic newborn has a mutation in the genes known to be implicated to hearing loss, although there is no certainty that all of these genes will be responsible for the incidence of hearing loss in the future.
Current methods of DNA analysis require 2-5 mls of blood, which would be unacceptable for a newborn screen. However, It is anticipated that sufficient DNA could be extracted from a drop of blood collected for newborn bloodspot metabolic screen, with improved sequence techniques (the Guthrie test) [3].
Genetic testing for deafness is not collectively perceived to be advantageous. Deafness is not usually considered to be negative or limiting especially by the deaf community. Many deaf individuals consider themselves to be part of their own linguistic (sign language) and cultural group, where they have their own values, identity, and traditions. It is not perceived to be a medical condition or disability. As a result, advances in hearing loss research and genetic testing might be perceived as harmful. Genetic services may be considered; however, some individuals prefer to have deaf children [4, 73].
A positive genetic test can also lead to an increased level of anxiety and individuals may feel guilty for having potentially passed a gene alteration on to their children.
Despite recent developments in medicine, there is still no cure for most types of hearing loss. The development of a biological method for the repair, regeneration, and replacement of hair cells of the damaged cochlea has the potential to restore normal hearing. At present, gene therapy and stem cells are two promising therapeutic applications for hearing disorders.
Gene therapy involves using specific sequences of DNA to treat human disease. It is an experimental form of treatment that is still being developed, but it has a unique application for hearing loss. Two main gene therapy approaches have been considered: replacing a mutated gene that causes disorder with a healthy copy of the gene, or inactivating a mutated gene that is functioning improperly. Gene therapy technology has improved in recent years, making it a promising technique for treating hearing disorders. The gene vector, the route of gene administration, the therapeutic gene, and the target cells are four major elements of gene therapy. With the recent developments in the field, a wide variety of viral and non-viral vectors have emerged that can deliver genetic payloads to target cells in the inner ear. There are three viral vectors commonly utilized for gene therapy (targeted at the inner ear): adenoviral vectors, adeno-associated viral vectors, and lentiviral vectors. Several promising clinical trials have been reported using gene therapy.
The first study of gene therapy for hearing disorders was reported in 1994 by Fujiyoshi and colleagues. They developed the myelin basic protein (MBP) transgenic mice by microinjecting an MBP cosmid clone into the pronucleus of fertilized eggs of shiverer mice to replace the autosomal recessive mutation (deletion) gene by the transgene for MBP. The MBP transgenic mice were found to recover up to 25% of normal levels of MBP, and significantly higher myelinated axons were present in the transgenic mice compare to control mice [74, 75]. In 1996, other studies reported that foreign genes were successfully transfected into the inner ear using replication-deficient viral vectors [75-77].
The discovery of RNA interference (RNAi)-mediated gene inactivation has introduced a new mechanism for targeted therapy of the inner ear at the molecular level [78]. RNAi is an intracellular two-step process that converts precursor double-stranded RNA molecules into functional small interfering RNAs (siRNAs). Synthetic double-stranded RNAs can be introduced as siRNA mimics and used to trigger RNAi and intentionally reduce the expression of targeted genes for therapeutic applications. A few allele variants of
Bacterial artificial chromosome (BAC) mediated transgenesis has proven to be a highly reliable way to obtain accurate transgene expression for in vivo studies of gene expression and function. BAC transgenes direct gene expression at physiological levels with the same developmental timing and expression patterns as endogenous genes in transgenic animal models. Recently, transgene expression through the germline was demonstrated to maintain normal inner ear morphology and stable hearing function in a mouse model of human non-syndromic deafness DFNB3 caused by a missense mutation in the
Neurotrophic factors are essential in the development of the inner ear and are able to protect inner ear hair cells and spiral ganglion neurons from the damage caused by various pathogenic factors and promote the recovery from cochlear injury. Up to now, more than 20 neurotrophic factors have been revealed with protective effects on inner ear cells [75]. Neurotrophin gene therapy is promising both in the protection against exogenous damage and the regeneration after endogenous and exogenous damage. It has been reported that neurotrophic factors, such as BDNF (brain-derived neurotrophic factor), NT-3 (neurotrophins 3), TGF (transforming growth factor), GDNF (glial cell line-derived neurotrophic factor), FGF (fibroblast growth factor), CNTF (ciliary neurotrophic factor), and HGF (hepatocyte growth factor) have protective effects of different extents on inner ear hair cells and neurons [82-86].
The discovery of new therapies for the treatment of hereditary hearing loss will depend on a better understanding of gene function in the survival and differentiation of existing neurons, and encourages the growth and differentiation of new neurons and synapses, bonding nerves to cochlear hair cells to form synaptic connections as well as in maintaining the unique inner ear ion balance.
There is no ideal gene delivery system for gene therapy so far. Three kinds of vectors (bacterial vector, multiplex gene vector, labeled gene vector) may have great prospects. Long-term human gene therapy will not be feasible until there is substantial improvement in transduction efficiencies into human tissues. The combination of more efficient gene transfers, targeted vector systems, and effective and relatively nontoxic selection systems to maintain gene expression may make the long-term correction of hearing disorders feasible and safe. Some practices of inner ear gene therapy may need to be carried out at the embryonic stage for the treatment of hereditary hearing loss in the future.
The recent developments in stem cell technologies are opening novel therapeutic possibilities for the treatment of hearing disorders. Stem cell therapy is a relatively new technique used to treat many forms of human disease in which exogenous stem cells are used to replace dead or damaged endogenous cell types. In recent years, researchers have undertaken a number of successful animal studies in the area of developing stem cell therapies for hearing loss and able to turn stem cells into many of the cell types in the inner ear whose damage and death leads to hearing loss, such as hair cells and auditory nerve cells.
Stem cells are a group of cells in our bodies with the capacity to self-renew and differentiate to various types of cells, thus to construct tissues and organs. When a stem cell divides, each new cell has the potential either to remain undifferentiated (self-renewal) or become a specialized (differentiation) type of cell with a specific function. Stem cells can be classified into different types, based on their source of origin, the time of derivation, and the potential to produce different lineages. The primordial master stem cell is the zygote. The zygote and early blastomeres are totipotent and can generate any and all human cells type in the body, such as the brain, liver, blood, or heart cells. It can even give rise to a whole functional organism including extraembryonic tissues. Pluripotent stem cells have a slightly more limited potential. They have the ability to produce cell types from all three embryonic germ layers (endoderm, mesoderm, and ectoderm), including all the somatic lineages as well as germ cells; but infrequently, if ever, can produce extraembroynic lineages such as those from the placenta. It cannot form an entire functional organism. Lastly, multipotent stem cells such as hematopoietic stem cells have a more limited ability, producing cell types usually restricted to a single organ or germ layer. Multipotent stem cells have the ability to differentiate into a closely related family of cells. Pluripotent stem cells have the widest range of potential applications. They can generally be classified as embryonic or adult, depending on their developmental stage of derivation.
Embryonic and adult stem cells differ primarily in the number of different cells each can produce. Embryonic stem cells are derived from a four- or five-day-old embryo that is in the blastocyst phase of development. It can develop into any cell type of the body. In contrast, adult stem cells reside in many organs of the adult human body and can generate a range of cell types from the originating organ or even regenerate the entire original organ. Adult stem cells can be found in a great number of organs and tissues including the brain, bone marrow, peripheral blood, blood vessels, skeletal muscle, skin, teeth, heart, gut, liver, ovarian epithelium, and testis [91]. A relatively recent breakthrough in stem cell research is the discovery that specialized adult (somatic) cells can be ‘reprogrammed’ into cells that behave like embryonic stem cells, termed induced pluripotent stem cells (iPSCs) [92]. Like human embryonic stem cells, the iPS (induced pluripotent stem cells) cells are immortal, pluripotent, and express genes characteristic of all three embryonic germ cell layers (endoderm, ectoderm, and mesoderm) when induced to differentiate.
A number of criteria must be satisfied to achieve functional restoration, including generation of an adequate number of cells to invert the defects, differentiation of the cells to the correct phenotype, formation of appropriate three-dimensional tissue structures, and production of cells/tissues that are mechanically and structurally complaint with the native tissue without immunological rejection [80, 93]. The generation of neural stem cells and control of neural differentiation from human embryonic stem cells have opened new doors for therapy of hearing disorders. Several studies have demonstrated successful delivery of embryonic and adult stem cells to normal and damaged tissues in vivo, and in some cases a therapeutic effect has been observed.
One of the first reports of stem cell delivery to the inner ear was a study by Ito and colleagues (2001) that demonstrated survival and migration of adult rat hippocampus-derived neural stem cells (NSCs) implanted into the rat cochlea. Within 2-4 weeks of grafting to the cochlea, some NSCs survived in the cochlear cavity. Some of them had adopted the morphologies and positions of hair cells [94]. Following this study was a report about the potential of NSC transplantation to the damaged mouse cochlea. The majority of transplanted cells integrated in the vestibular sensory epithelia and expressed specific markers (myosin VIIa) for hair cells in vivo. The result of this study suggests that transplanted NSCs have the potential to differentiate and restore inner ear hair cells. However, a small number of hair cell marker-positive grafted cells and no evidence of synaptic connections between transplants and host spiral ganglion neurons hampered well-established methods for functional recovery [95]. The principal differences between human and mouse NSCs seem to be the length of the cell cycle (up to 4 days in humans) and the predilection of human cells to senesce (after ~100 cell divisions) [96]. NSCs can achieve therapeutic efficacy in human clinical applications, although many limitations remain to be overcome.
Several studies reported on the transplantation of embryonic stem (ES) cells into the inner ear. ES cells have the ability to differentiate into neuronal cell types when transplanted into the spiral ganglion of cochlea. ES cells that have been transplanted into the spiral ganglion of the cochlea were found to express neural markers [97, 98] and develop cellular processes similar to axons that extend towards the organ of Corti [99-102]. Some of these stem cell-derived neurons were shown to establish synaptic contacts with sensory hair cells, the peripheral target for spiral ganglion neurons (SGNs) in vitro (Matsumoto et al., 2008) and to survive in animals with selective loss of SGNs [99, 103].
For a cell therapy approach aiming at restoring impaired function, implanted cells need to be able to convey auditory information from the periphery to more centrally located nuclei. Recent studies have shown that dorsal root ganglion cells or ES cells are transplanted to the transected auditory nerve migrated along the nerve fibers in the internal auditory meatus and, in some cases, even reach proximate to the ventral cochlear nucleus in the brainstem [104, 105]. Interestingly, Ito et al. (2001) reported that embryonic brain tissue transplanted to the acutely transected ventral cochlear tract resulted in not only regeneration but additionally functional recovery [105, 106]. However, there are many chemical factors that produce a barrier between the peripheral and central nervous system and could impede the ability of central processes of replacement neurons to make a connection in the cochlear nucleus.
A number of studies have shown that adult bone marrow-derived stem cells (MSCs) can also have therapeutic potential in the damaged inner ear. MSCs have shown plasticity with a capacity to differentiate into a variety of specialized cells. MSCs have been delivered both systemically and by direct injection through the scala tympani into the mouse and gerbil cochlea respectively [107, 108]. Matsuoka and colleagues investigated the potential of MSCs to adopt properties of SGNs in vivo [108]. Identification of stem cells in the human fetal cochlea [109] contributes to the study stem cell biology of the auditory organ in humans, while advances in identification of stem cells have been made in rodents [110].
Umbilical cord blood (UCB) is the most recently identified useful source of hematopoietic stem cells (HSCs) for treatment of a wide variety of disorders. UCB has potential applications in hearing disorders. A study provided the first evidence of positive engraftment of intravenously transplanted human umbilical cord blood CD133+ HSCs into the inner ear of NOD-SCID mice rendered deaf with kanamycin and noise in vivo [111]. In another study, the researchers have demonstrated that hematopoietic stem cell transplantation (HSCT) may provide improvement in mucopolysaccharidosis-associated sensorineural hearing loss [112]. Recently, an FDA-approved clinical trial involving stem cells derived from UCB has been initiated for treatment of children with sensorineural hearing loss [113].
Mammalian cochlear hair cells do not regenerate spontaneously, although vestibular hair cells in adult mammals regenerate at levels so low as to rule out any significant functional recovery [114, 115]. The discovery of stem cells has opened the possibility of devising strategies to recruit these cells to repair damaged or lost cochlear hair cells. Stem cells are important tools for hearing disorder research and offer great potential for use in the clinic. Certain types of stem cells, such as neural stem cells, are more capable than others of replacing lost or damaged hair cells, although they have limitations. There is a great challenge in identifying more effective ways of directing stem cells to develop into inner ear hair cells. The field of auditory stem cell research is still in its infancy, although important advances are already taking place. Stem cell therapy for hearing loss is some years away from being clinically feasible.
Gene therapy and stem cell treatment have still a long way to go before these treatments will be available to use in humans. Therefore, existing measures must focus on the prevention of hearing loss to decrease the frequency of genetic hearing loss. There is a need of improved implementation of genetic counseling and awareness in populations that are at high risk of hereditary hearing loss.
Early detection and intervention of hearing loss is the most important factor in minimizing the impact of hearing loss on a child’s development and educational achievements. At least, all children with a risk for hereditary hearing loss need to be given screening audiometry. The hearing loss can be progressive in nature for a person with autosomal recessive non-syndromic hearing loss caused by mutations in
Knowledge of the genetic cause is helpful in determining the kind of damage to the auditory system that caused deafness. Identification of the underlying cause in terms of how the inner ear is damaged may assist in choosing rehabilitation strategies, such as hearing aid or cochlear implant. In children with congenital severe-to-profound autosomal recessive non-syndromic hearing loss who are positive for mutations in
Genetic counseling is an important part of evaluation and management of hearing disorders. The process of genetic counseling is intended to inform patients and their families of the medical, psychological, and familial implications of genetic hearing disorders, as well as the risks, benefits, and limitations of genetic testing. In the United States, genetics professionals recommend "non-directive" counseling. It is meant to be informative and supportive rather than advise people what to do or whether or not to have children. Genetic information can help predict whether the hearing loss will remain the same or whether it will worsen over time. In addition, genetic testing can help determine if problems besides hearing loss may be present or may develop in the future. It can also help patients and families who may be at risk for conditions that can be passed down in families (inherited conditions). There are a number of people who may have quite different attitudes about deafness in their family. Some hearing parents might be concerned about having another deaf child, while others may believe that the hearing loss would not cause a problem, but they would want to know if any other associated medical problems might be involved. Likewise, deaf parents may feel comfortable about their own abilities, but would have a better opinion of not to have a deaf child, in view of the fact that other deaf parents may be more worried about the challenges of raising a hearing child [117]. In such case, the genetic counselor should be very cautious in providing information concerning the nature of the disease, the implications of being carriers (mutation carriers of genes associated with hearing loss), and the reproductive choices. Genetic counseling services for families with deafness can only be effective and appropriate if the social values of the deaf community are taken into consideration.
Advances in genetic testing are already directly impacting people’s lives. The demand for molecular tests is by now increasing with the discovery of the varied molecular defects underlying hearing loss. Genetic testing has now reached a stage where it is becoming increasingly applicable for precise diagnosis of hearing disorders. The development of NGS technology has made DNA sequencing not only rapid and cost-effective, but also highly accurate and reproducible. In the near future, it is expected that there will be more enhancements in the speed and cost of DNA sequencing. We are already in the modern DNA sequencing era, where aims of third- and fourth-generation DNA sequencing additionally boost the speed of sequencing and reduce costs. Although sequencing the whole genome seems exhaustive, it could be more cost-effective than having to select the genes of interest [118]. Once genome sequencing becomes more cost-effective and fast, it will accelerate the pace of gene discovery for deafness and clinical application of this discovery will be realized. Over the next few years, most molecular genetic testing will be performed on automated instruments and some genetic tests for hearing disorders will be available as at-home kits on a large scale.
One of the roles of genetic testing is to identify presently known genetic causes of hearing loss in failed hearing screening of newborns and children who are identified with childhood-onset hearing loss. Furthermore, it increases our knowledge of the genetic causes of hearing loss. The potential for increased usage of aminoglycoside antibiotics also supports the case for a genetic screening program of pregnant women for the
Molecular diagnostic results should always be interpreted with caution, as our knowledge of the molecular basis of hearing loss is still evolving. Keeping pace with emerging clinical genetic technologies requires specialized genetic training as well as broad genetic literacy for patients and clinicians ordering and receiving genetics test results. Genetic information that is shared by the patient and patient\'s family is unique. The application of genetic tests has appropriately generated substantial debate in the community with regard to the delivery and impact of the information on clinicians, patients, and society in general. The potential for misuse of genetic information is enormous and requires action to protect the privacy of genetic information and protect individuals from discrimination based on genetic information. The ethical, legal, and social issues surrounding genetic testing for hearing loss need to be addressed. In the near future, more studies of the ethical and social aspects of genetic testing for hearing disorders should be done. It is hoped that the potential for misuse of genetic information in the future will be limited.
Some of the novel rehabilitation options under development to slow down the progression of hearing loss are gene and even mutation specific [80], suggesting that comprehensive genetic testing will be an integral part of the care of deaf and hard-of-hearing patients in the future [9]. Over time, the genetic diagnostic tests will become available faster, followed by targeted gene therapy or various permutations of progenitor cell transplantation, and eventually, the preventive interventions for a wider range of hearing impaired patients.
Cancer is a complex, severe class of diseases that involves a group of cells that exhibit abnormal and uncontrolled division and proliferation. It is one of the primary health concerns which accounts for the second major cause of death globally. As per the recent statistics of the world health organization (WHO), in 2020, around 10 million people succumbed to death due to cancer. However, every year the number of incidences is increasing day by day. According to WHO, around 0.3 million new cases are diagnosed each year among the age group of 0–19 years. Cancer can affect a person of any age; however, with age, the risk increases. Globally, steady increases in cancer cases every year are taking a toll on the health care system [1, 2, 3, 4, 5]. To combat cancer, identification of potential drugs and potential drugs combination is essential. Potential research has been carried out to counter such problems by addressing novel drug design and discovery approaches. In medicinal chemistry, heterocyclic rings have played a significant role in the search for potential therapeutic agents. Various drugs are currently in use and in development that widely addresses such problems. However, due to changes in cancer forms and mutations, current therapy faces challenges of poor selectivity and specificity towards certain types of cancer cells, which narrows down their effectiveness. Generally, cancer cells act by disrupting and disturbing the cell signaling pathways; therefore, it is crucial to design novel target-based heterocyclic anticancer compounds with high efficacy and fewer side effects, which will provide a solid backup to the present chemotherapeutic regime [6, 7, 8, 9, 10].
Benzimidazole is a bicyclic nitrogen bearing aromatic heterocyclic ring, structurally it consists of benzene ring fused with imidazole ring at the 4th and 5th position of the ring. Chemically it appears as white crystals, amphoteric in nature, resembles the structure of purine. It is synthesized by different reported methods. However, condensation of 1,2-diamino benzene with carbonyl compounds to give benzimidazole is the conventional method which was used widely for its preparation. In 1858, it was synthesized by Heinrich Debus, a German chemist from glyoxal, ammonia and formaldehyde, that’s why it was also known as glyoxalin. Benzimidazole ring is one of bioactive heterocyclic scaffold exhibiting wide range of biological activities. The ▬NH group present at second position of the ring is both highly acidic and weak base in nature, it also has ability to form stable salts [11, 12, 13, 14, 15, 16].
With time benzimidazole ring emerged as an important multifaceted heterocyclic system due to its wide range of pharmacological activity such as antibacterial [17], antiparasitic [18], antifungal [19], anti-inflammatory [20], analgesics [21], antiviral [22], antitubercular [23], anticoagulant [24], antihistaminic [25], antioxidant [26], antiulcer [27] and anticancer [28, 29, 30, 31]. Some of the benzimidazole based marketed drugs are listed in with their indication and marketed name in Figure 1. Adding to this benzimidazole scaffold have also displayed a significant role in synthesis of organic intermediates. In light of the application of benzimidazole earlier various authors have reported many review articles. Due to the diverse therapeutic potential, benzimidazole have attracted lot of researchers to explore more in the field of drug discovery to synthesize novel and potent compounds with a broad spectrum of biological activities. Owing to this, with time efforts have been made to create libraries of these potent compounds. In cancer treatment benzimidazole based drugs played a significant role, various targeted therapies are designed and developed as Kinase inhibitors such as EGFR, VEGFR and PI3K inhibitors here, in this chapter we have included some potent benzimidazole based kinase inhibitors.
Examples of benzimidazole based drugs in clinical use.
Benzimidazole based compounds have got much attention due to exhibiting significant cytotoxic activity. In last one decade a lot of benzimidazole based anticancer drugs have received status of US FDA global approval. Recently, Binimetinib, Selumetinib and Abemaciclib got approval for treatment of various mutated forms of cancer. Here, we have discussed some of benzimidazole based anticancer drugs which are recently approved, under development and in pipeline.
Binimetinib (
Benzimidazole based clinically approved anticancer agents.
Drug | Clinical trial number | Clinical trial study | Date of study | Current status and study phase |
---|---|---|---|---|
Binimetinib | NCT04965818 | Phase 1b/2 study of Futibatinib in combination with Binimetinib in patients with advanced KRAS mutant cancer | Last update on September 27, 2021 | Recruiting Phase 1b/2 |
NCT03170206 | Study of CDK4/6 inhibitor Palbociclib in combination with the Binimetinib for patients with advanced KRAS mutant NSCLC | Last update on June 10, 2021 | Recruiting Phase 1 | |
Bendamustine | NCT04217317 | CPI-613 in combination with Bendamustine in patients with relapsed or refractory T-cell Non-Hodgkin lymphoma | Last update on August 30,2021 | Recruiting Phase 2 |
NCT04510636 | Study of Pembrolizumab with Bendamustine in Hodgkin lymphoma | Last update on August 30,2021 | Not yet Recruiting Phase 2 | |
Selumetinib | NCT02768766 | Intermittent Selumetinib for uveal melanoma | Last update on March 19, 2021 | Recruiting Phase 1 |
NCT05101148 | Phase I study to assess the effect of food on the PK and gastrointestinal toxicity of Selumetinib in adolescent children with Neurofibromatosis Type 1 related plexiform neurofibromas | Last update on November 1, 2021 | Recruiting Phase 1 | |
Abemaciclib | NCT04003896 | A study to evaluate Abemaciclib in advanced biliary tract carcinoma who failed prior first line therapy. | Last update on | Active, Not recruiting Phase 2 |
NCT04040205 | Abemaciclib for bone and soft tissue sarcoma with cyclin dependent kinase (CDK) pathway attention | February 15, 2021 | Recruiting Phase 2 | |
Veliparib | NCT02723864 | Veliparib and VX-970 in combination with cisplatin in people with refractory solid tumors | Last update on February 5, 2021 | Active, Not recruiting Phase 1 |
NCT01434316 | Veliparib and Dinaciclib in treating patients with advanced solid tumors | July 20, 2021 | Recruiting Phase 1 | |
Dovitinib | NCT01635907 | Dovitinib in neuroendocrine tumors | Last update on April 14, 2020 | Completed Phase 2 |
Pracinostat | NCT03848754 | Pracinostat and Gemtuzumab ozogamicin in patients with relapsed or refractory acute myeloid leukemia | Last update on October 18, 2021 | Active, not recruiting Phase 1 |
Galeterone | NCT04098081 | Galeterone with Gemcitabine for patients with metastatic pancreatic adenocarcinoma | Last update on March 10, 2021 | Recruiting Phase 2 |
Nazartinib | NCT02335944 | Study and safety and efficacy of Nazartinib in combination with cMET inhibitor INC280 in NSCLC patients with EGFR mutation | Last update on October 4, 2021 | Active, not recruiting Phase 1/2 |
NCT02108964 | A phase I/II, multicentre, open label study of Nazartinib, administered orally in adult patients with EGFR mutated solid malignancies | Last update on August 13, 2021 | Active, Not recruiting Phase 1/2 |
Benzimidazole based anticancer drugs in clinical development.
Bendamustine (
Selumetinib (
Abemaciclib (
Veliparib (
Dovitinib (
Pracinostat (7) is chemically (E)-3-(2-butyl-1-(2-(diethyl amino) ethyl)-1H-benzoimidazol-5-yl)-N-hydroxyacrylamide, it is orally available, investigational drug exhibiting potential antitumor activity [49, 50]. Pracinostat is a small molecule next generation histone diacetylases (HDAC) inhibitor indicated acute myeloid leukemia [51]. In some recent study Pracinostat was found to suppresses growth and metastasis of breast cancer by inactivating the IL-6/STAT3 signaling pathway [52].
Galeterone (
Nazartinib (
Commonly the mechanism behind action of anticancer agents involve DNA intercalation, gene regulation, microtubule inhibition, transcription regulation, DNA synthesis inhibition, enzyme inhibition and so on. Nowadays in cancer treatment, target therapy emerged as one of the acknowledged strategies. Most of the available anticancer drugs acts by targeting structural proteins, tyrosine kinases, phosphoinositide 3 kinase and protein kinases for example Binimetinib acts by inhibiting mitogen activated kinase as discussed in earlier section. In this section we have included some recent examples of benzimidazole based enzyme inhibitors as potent anticancer agents.
Akhter et al. have reported a novel series of benzimidazole based oxadiazole derivatives as potential EGFR inhibitors. The target compound
Srour et al. have reported a novel series of thiazole benzimidazole derivatives as potent inhibitor of EGFR tyrosine kinase. Target compound
Akhter et al. have reported as series of pyrazole benzimidazole derivatives as potential inhibitors of EGFR. Target compound
Examples of benzimidazole derivatives as potent EGFR inhibitors.
Abdullaziz et al. have reported a novel series of 2-furybenzimidazole derivatives as potent inhibitors of VEGFR-2 kinase. Target compound
Lien et al. have reported novel 2-aminobenzimidazole derivative
Recently Yuan et al. have designed and synthesized a new series of benzimidazole derivatives as potent and selective inhibitor of VEGFR-2 kinase. Target compound
Examples of benzimidazole derivatives as potent VEGFR-2 inhibitors.
Meguid et al. have reported a novel series of benzimidazole derivatives as potent dual inhibitors of EGFR and VEGFR-2 kinases. Target compound
Kassab et al. have reported novel quinazoline bearing benzimidazole derivatives as potential inhibitors of EGFR and VEGFR-2 kinases. Target compound 22 displayed excellent inhibitory activity against EGFR kinase with an IC50 value of 127.4 μM, whereas it displayed an IC50 value of 185.7 μM against VEGFR-2 kinase. Further, cytotoxicity study of compound against MCF7 cancer cell line demonstrated good potency with IC50 value of 12.0 μM [66] (Figure 5).
Examples of benzimidazole derivatives as potent EGFR/VEGFR dual inhibitors.
GSK2636771 (
Jin et al. have reported novel benzimidazole derivatives as potent PI3K inhibitor. Target compound 24 was found most potent against PI3Kα with 36% and 86% inhibition compare to reference drug Alpelisib, which showed an inhibition of 110% and 109% at 50 nM and 500 nM respectively. Further, molecular docking analysis of target compound 24 demonstrated strong binding with six strong hydrogen bond with GLN-859, SER-854 and VAL-851 amino acid residues. Further, HUMO-LUMO calculation which is studied by using Gaussian 09 software target compound 24 showed presence of thiazole core and amide bonds which played an important role in its biological activity [69].
Recently a novel series of benzimidazole based dehydroabietic acid derivatives were reported Yang et al. as potent PI3Kα inhibitors. Target compound
Chanrasekhar et al. have reported a novel series of benzimidazole derivatives as potent PI3K inhibitors Target compound
Wu et al. have reported a novel series of triazine substituted benzimidazole derivatives a potent dual inhibitor of PI3K and mTOR, most of the compounds from the series displayed potent inhibitory activity with IC50 below 33 nM. Target compound
Shin et al. have reported a novel series of benzimidazole derivatives a potent inhibitor of PI3Kδ. Target compound
He et al. has reported benzimidazole-isoquinolinone derivatives which inhibits the cell growth via inhibiting PI3K/mTOR/Akt pathway. Target compound
Wu et al. have reported triazine bearing benzimidazole derivatives a potent inhibitor of PI3K and mTOR. Target compound
Examples of benzimidazole derivatives as potent PI3K inhibitors.
Ibrahim et al. have reported a novel series of flavopiridol-benzimidazole as potent inhibitor potent inhibitor of CDK2 and CDK9 kinase. Target compound
Examples of benzimidazole derivative as potent CDK inhibitor.
Pankaj et al. have reported a novel hybrid derivatives of benzimidazole-thiazolidinedione as potent cytotoxic agents. Target compound
Sivaramakarthikeyan et al. have reported novel hybrid derivatives of benzimidazole and pyrazole as potent anticancer agents. Compound 35 and 36 have demonstrated potent anticancer activity against selected human pancreatic cancer cell lines namely SW1990 and AsPC1 with an IC50 value in range of 30.9–61.8 μM respectively. Molecular docking study of both compound showed significant binding with the active site of B-cell lymphoma [78].
Mantu et al. have reported a novel series of benzimidazole-quinoline hybrid derivatives as potent anticancer agent. Target compound 37 exhibited potent antitumor activity against renal cancer cell line A498 and breast cancer cell line MDA-MB-468 with percentage growth inhibition of 52.92% and 56.54% respectively. Compound 37 also exhibited potent antitumor activity against leukemia cell line RPMI-8226 and non-small cell lung cancer cell line NCI-H23 with total growth inhibition of 35% [79].
Sharma et al. have reported benzimidazole-thiazolidinedione hybrid derivatives as potent anticancer agents. Target compound 38 and 39 displayed potent anticancer activity against cancer cell line with an IC50 value of in range of 0.13-10.24 μM against prostate cancer cell line PC-3, breast cancer (MDAMB-231), cervical cancer (HeLa), lung cancer (A549), and bone cancer (HT1080) cell lines. Both hybrid derivative 38 and 39 demonstrated significant inhibition of A549 cells migration through disruption of F-actin assembly, further treatment with 38 and 39 also showed increase in level of ROS in A549 cells by collapsing the mitochondrial membrane potential [80].
Bistrovic et al. have reported novel hybrid derivatives of benzimidazole-1,2,3-triazole as potent anticancer agents. Target compound 40 and 41 demonstrated excellent inhibitory activity with IC50 value of 0.05 and 6.18 against A549 cancer cell line and an IC50 value of 17.53 and 8.80 against HeLa cancer cell line respectively. Furthermore, apoptosis detection study by annexin assay of compound
Examples of benzimidazole containing hybrid derivatives as potent anticancer agents.
Many benzimidazole-containing compounds as anticancer agents are studied and available, involving various mechanisms in inhibiting mutated cancerous cells, in which kinases inhibitors play a significant role. However, in targeted therapy, benzimidazole-based derivatives are still widely explored. Due to the challenge of target specificity and poor selectivity, very few compounds have been approved to treat mutated cancers. The search for a novel benzimidazole-based next generation kinase inhibitor is going to subside such challenges. Benzimidazole-based target therapies such as enzyme inhibitors have gained a lot of attraction; owing to this, recently US FDA has approved EGFR inhibitor Abemaciclib and MEK inhibitor Binimetinib and Selumetinib as potent anticancer compounds against mutated forms of cancer. Apart from this, many benzimidazole-containing compounds are in the developmental phase as EGFR, VEGFR-2, CDK and PI3K inhibitors. However, some of the compounds demonstrated excellent kinase inhibitory activity but failed to provide a strong safety profile; these compounds will pave a path as lead compounds; further modifications, designing, and developing such compounds will give potent compounds with maximum efficiency and minimal side effects. The presented chapter mainly focuses on benzimidazole-based kinase inhibitors and their advances; the pivotal information catered here can be regarded as noteworthy and crucial by medicinal chemists for drug design, discovery and development of novel, potent and safe, target-based anticancer agents.
Authors wishes to acknowledge Jamia Hamdard (deemed-to-be-University) for providing support for conducting this study.
Authors declare “no conflict of interest.”
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In this chapter, we have presented a brief comprehensive survey of cultural heritage using augmented reality systems. This survey describes the main objectives and characteristics of marker-less augmented reality systems through presenting up-to-date research results in this area. We describe the marker-less technologies in the area of AR, indoor marker-less AR, outdoor marker-less AR, real-time solutions to the tracking problem, real-time registration, cultural heritage in AR, 3D remonstration techniques, as well as presenting the problems in each research.",book:{id:"7699",slug:"advanced-methods-and-new-materials-for-cultural-heritage-preservation",title:"Advanced Methods and New Materials for Cultural Heritage Preservation",fullTitle:"Advanced Methods and New Materials for Cultural Heritage Preservation"},signatures:"Hoshang Kolivand, Abdennour El Rhalibi, Mostafa Tajdini, Sarmad Abdulazeez\nand Pisit Praiwattana",authors:[{id:"151219",title:"Prof.",name:"Abdennour",middleName:null,surname:"El Rhalibi",slug:"abdennour-el-rhalibi",fullName:"Abdennour El Rhalibi"},{id:"225824",title:"Dr.",name:"Hoshang",middleName:null,surname:"Kolivand",slug:"hoshang-kolivand",fullName:"Hoshang Kolivand"},{id:"256916",title:"Dr.",name:"Sarmad",middleName:null,surname:"Abdulazeez",slug:"sarmad-abdulazeez",fullName:"Sarmad Abdulazeez"},{id:"256917",title:"Dr.",name:"Pisit",middleName:null,surname:"Praiwattana",slug:"pisit-praiwattana",fullName:"Pisit Praiwattana"},{id:"289071",title:"Dr.",name:"Mostafa",middleName:null,surname:"Tajdini",slug:"mostafa-tajdini",fullName:"Mostafa Tajdini"}]},{id:"36570",doi:"10.5772/45619",title:"Archaeological Geophysics - From Basics to New Perspectives",slug:"archaeological-geophysics-from-basics-to-new-perspectives",totalDownloads:6548,totalCrossrefCites:4,totalDimensionsCites:8,abstract:null,book:{id:"1999",slug:"archaeology-new-approaches-in-theory-and-techniques",title:"Archaeology",fullTitle:"Archaeology, New Approaches in Theory and Techniques"},signatures:"Roger Sala, Ekhine Garcia and Robert Tamba",authors:[{id:"131865",title:"Dr.",name:"Roger",middleName:null,surname:"Sala",slug:"roger-sala",fullName:"Roger Sala"}]},{id:"36574",doi:"10.5772/37679",title:"The Study of Shell Object Manufacturing Techniques from the Perspective of Experimental Archaeology and Work Traces",slug:"the-study-of-shell-object-manufacturing-techniques-from-the-perspective-of-experimental-archaeology-",totalDownloads:3116,totalCrossrefCites:1,totalDimensionsCites:5,abstract:null,book:{id:"1999",slug:"archaeology-new-approaches-in-theory-and-techniques",title:"Archaeology",fullTitle:"Archaeology, New Approaches in Theory and Techniques"},signatures:"Adrián Velázquez-Castro",authors:[{id:"113840",title:"Dr.",name:"Adrian",middleName:null,surname:"Velazquez",slug:"adrian-velazquez",fullName:"Adrian Velazquez"}]},{id:"70612",doi:"10.5772/intechopen.89154",title:"The Technological Diversity of Lithic Industries in Eastern South America during the Late Pleistocene-Holocene Transition",slug:"the-technological-diversity-of-lithic-industries-in-eastern-south-america-during-the-late-pleistocen",totalDownloads:683,totalCrossrefCites:1,totalDimensionsCites:4,abstract:"Brazilian archaeological literature has insisted for decades upon associating hunter-gatherer sites dated to the Pleistocene–Holocene transition either to the Itaparica tradition, if located in central or northeastern Brazil, or to the Umbu tradition and Humaitá tradition, if located in southern Brazil, Uruguay, or any other adjacent part of Paraguay and Argentina. These associations have been based almost entirely on the presence or absence of lesmas and “projectile points,” regardless of their morphological and technological features. In the Uruguayan archaeological literature, three other cultures are recognised: Fell industry, Catalanense industry, and Tigre tradition, all in the Uruguayan region. However, the last 10 years of systematic studies on the lithic assemblages from these sites have shown that Paleoindian societies from Eastern South America are more culturally diverse than expected and that previously defined archaeological cultures present several issues in their definition, suggesting that many of these “traditions” are not valid and should no longer be used. Instead, new lithic industries and archaeological cultures should be defined only when cultural patterns are observable through systematic analyses.",book:{id:"9251",slug:"pleistocene-archaeology-migration-technology-and-adaptation",title:"Pleistocene Archaeology",fullTitle:"Pleistocene Archaeology - Migration, Technology, and Adaptation"},signatures:"João Carlos Moreno De Sousa",authors:[{id:"303361",title:"Dr.",name:"João Carlos",middleName:null,surname:"Moreno De Sousa",slug:"joao-carlos-moreno-de-sousa",fullName:"João Carlos Moreno De Sousa"}]}],mostDownloadedChaptersLast30Days:[{id:"36570",title:"Archaeological Geophysics - From Basics to New Perspectives",slug:"archaeological-geophysics-from-basics-to-new-perspectives",totalDownloads:6552,totalCrossrefCites:4,totalDimensionsCites:8,abstract:null,book:{id:"1999",slug:"archaeology-new-approaches-in-theory-and-techniques",title:"Archaeology",fullTitle:"Archaeology, New Approaches in Theory and Techniques"},signatures:"Roger Sala, Ekhine Garcia and Robert Tamba",authors:[{id:"131865",title:"Dr.",name:"Roger",middleName:null,surname:"Sala",slug:"roger-sala",fullName:"Roger Sala"}]},{id:"36576",title:"Homage to Marcel Proust - Aspects of Dissemination and Didactic in a Museum and a Science Centre: Science Communication Visions for the Third Generation Museums",slug:"generations-of-ancient-history-dissemination-towards-the-public-at-the-university-museum-in-trondhei",totalDownloads:2644,totalCrossrefCites:1,totalDimensionsCites:1,abstract:null,book:{id:"1999",slug:"archaeology-new-approaches-in-theory-and-techniques",title:"Archaeology",fullTitle:"Archaeology, New Approaches in Theory and Techniques"},signatures:"Kistian Overskaug",authors:[{id:"117119",title:"Dr.",name:"Kristian",middleName:null,surname:"Overskaug",slug:"kristian-overskaug",fullName:"Kristian Overskaug"}]},{id:"63772",title:"Cultural Heritage in Marker-Less Augmented Reality: A Survey",slug:"cultural-heritage-in-marker-less-augmented-reality-a-survey",totalDownloads:1628,totalCrossrefCites:6,totalDimensionsCites:9,abstract:"Augmented reality (AR) is considered as one of the most significant technologies in the field of computer graphics and is utilised in many applications. In this chapter, we have presented a brief comprehensive survey of cultural heritage using augmented reality systems. This survey describes the main objectives and characteristics of marker-less augmented reality systems through presenting up-to-date research results in this area. We describe the marker-less technologies in the area of AR, indoor marker-less AR, outdoor marker-less AR, real-time solutions to the tracking problem, real-time registration, cultural heritage in AR, 3D remonstration techniques, as well as presenting the problems in each research.",book:{id:"7699",slug:"advanced-methods-and-new-materials-for-cultural-heritage-preservation",title:"Advanced Methods and New Materials for Cultural Heritage Preservation",fullTitle:"Advanced Methods and New Materials for Cultural Heritage Preservation"},signatures:"Hoshang Kolivand, Abdennour El Rhalibi, Mostafa Tajdini, Sarmad Abdulazeez\nand Pisit Praiwattana",authors:[{id:"151219",title:"Prof.",name:"Abdennour",middleName:null,surname:"El Rhalibi",slug:"abdennour-el-rhalibi",fullName:"Abdennour El Rhalibi"},{id:"225824",title:"Dr.",name:"Hoshang",middleName:null,surname:"Kolivand",slug:"hoshang-kolivand",fullName:"Hoshang Kolivand"},{id:"256916",title:"Dr.",name:"Sarmad",middleName:null,surname:"Abdulazeez",slug:"sarmad-abdulazeez",fullName:"Sarmad Abdulazeez"},{id:"256917",title:"Dr.",name:"Pisit",middleName:null,surname:"Praiwattana",slug:"pisit-praiwattana",fullName:"Pisit Praiwattana"},{id:"289071",title:"Dr.",name:"Mostafa",middleName:null,surname:"Tajdini",slug:"mostafa-tajdini",fullName:"Mostafa Tajdini"}]},{id:"73769",title:"Human Evolution in the Center of the Old World: An Updated Review of the South Asian Paleolithic",slug:"human-evolution-in-the-center-of-the-old-world-an-updated-review-of-the-south-asian-paleolithic",totalDownloads:847,totalCrossrefCites:0,totalDimensionsCites:1,abstract:"The Indian Subcontinent was an important geographic region for faunal and hominin evolution in Asia. While the Oldowan as the earliest technocomplex continues to be elusive, the oldest Acheulean is dated to ~1.5 Ma and the early Middle Paleolithic is ~385 ka (from the same site). New Late Pleistocene dates have been reported for the Middle Paleolithic which continues up to 38 Ka in southern India. The Upper Paleolithic remains ambiguous and requires critically multidisciplinary investigations. The microlithic evidence appears to spread rapidly across the subcontinent soon after its emergence at ~48 Ka (though its origin is debated) and continues into the Iron Age. The timeline of the initial arrival of Homo sapiens continues to be debated based on the archaeology (advanced Middle Paleolithic vs. microlithic) and genetic studies on indigenous groups. Other issues that need consideration are: interactions between archaics and arriving moderns, the marginal occurrence of symbolic behavior, the absolute dating of rock art and the potential role of hominins in specific animal extinctions and ecological marginalization. The region does not appear to have been a corridor for dispersals towards Southeast Asia (although gene flow may have occurred). Instead, once various prehistoric technologies appeared in the Subcontinent, they possibly followed complex trajectories within relative isolation.",book:{id:"9251",slug:"pleistocene-archaeology-migration-technology-and-adaptation",title:"Pleistocene Archaeology",fullTitle:"Pleistocene Archaeology - Migration, Technology, and Adaptation"},signatures:"Parth R. Chauhan",authors:[{id:"307040",title:"Dr.",name:"Parth",middleName:null,surname:"Chauhan",slug:"parth-chauhan",fullName:"Parth Chauhan"}]},{id:"73386",title:"Island Migration, Resource Use, and Lithic Technology by Anatomically Modern Humans in Wallacea",slug:"island-migration-resource-use-and-lithic-technology-by-anatomically-modern-humans-in-wallacea",totalDownloads:725,totalCrossrefCites:1,totalDimensionsCites:3,abstract:"Island migration and adaptation including both marine and terrestrial resource use and technological development by anatomically modern humans (AMH) are among the most significant issues for Pleistocene archaeology in Southeast Asia and Oceania, and directly related to the behavioral and technological advancements by AMH. This paper discusses such cases in the Wallacean islands, located between the past Sundaland and the Sahul continent during the Pleistocene. The Pleistocene open sea gaps between the Wallacean islands and both landmasses are very likely the major factor for the relative scarcity of animal species originating from Asia and Oceania and the high diversity of endemic species in Wallacea. They were also a barrier for hominin migration into the Wallacean islands and Sahul continent. We summarize three recent excavation results on the Talaud Islands, Sulawesi Island and Mindoro Island in Wallacea region and discuss the evidence and timeline for migrations of early modern humans into the Wallacean islands and their adaptation to island environments during the Pleistocene.",book:{id:"9251",slug:"pleistocene-archaeology-migration-technology-and-adaptation",title:"Pleistocene Archaeology",fullTitle:"Pleistocene Archaeology - Migration, Technology, and Adaptation"},signatures:"Rintaro Ono, Alfred Pawlik and Riczar Fuentes",authors:[{id:"177123",title:"Dr.",name:"Rintaro",middleName:null,surname:"Ono",slug:"rintaro-ono",fullName:"Rintaro Ono"},{id:"300616",title:"Dr.",name:"Alfred",middleName:null,surname:"Pawlik",slug:"alfred-pawlik",fullName:"Alfred Pawlik"},{id:"330591",title:"Dr.",name:"Riczar",middleName:null,surname:"Fuentes",slug:"riczar-fuentes",fullName:"Riczar Fuentes"}]}],onlineFirstChaptersFilter:{topicId:"263",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:8,numberOfPublishedChapters:87,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:98,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:27,numberOfPublishedChapters:285,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:139,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:0,numberOfUpcomingTopics:2,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!1},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:105,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:9,numberOfPublishedChapters:101,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:11,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:0,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!1},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"14",title:"Artificial Intelligence",doi:"10.5772/intechopen.79920",issn:"2633-1403",scope:"Artificial Intelligence (AI) is a rapidly developing multidisciplinary research area that aims to solve increasingly complex problems. In today's highly integrated world, AI promises to become a robust and powerful means for obtaining solutions to previously unsolvable problems. This Series is intended for researchers and students alike interested in this fascinating field and its many applications.",coverUrl:"https://cdn.intechopen.com/series/covers/14.jpg",latestPublicationDate:"May 14th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:8,editor:{id:"218714",title:"Prof.",name:"Andries",middleName:null,surname:"Engelbrecht",slug:"andries-engelbrecht",fullName:"Andries Engelbrecht",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRNR8QAO/Profile_Picture_1622640468300",biography:"Andries Engelbrecht received the Masters and PhD degrees in Computer Science from the University of Stellenbosch, South Africa, in 1994 and 1999 respectively. He is currently appointed as the Voigt Chair in Data Science in the Department of Industrial Engineering, with a joint appointment as Professor in the Computer Science Division, Stellenbosch University. Prior to his appointment at Stellenbosch University, he has been at the University of Pretoria, Department of Computer Science (1998-2018), where he was appointed as South Africa Research Chair in Artifical Intelligence (2007-2018), the head of the Department of Computer Science (2008-2017), and Director of the Institute for Big Data and Data Science (2017-2018). In addition to a number of research articles, he has written two books, Computational Intelligence: An Introduction and Fundamentals of Computational Swarm Intelligence.",institutionString:null,institution:{name:"Stellenbosch University",institutionURL:null,country:{name:"South Africa"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:4,paginationItems:[{id:"14",title:"Cell and Molecular Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",isOpenForSubmission:!0,editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",slug:"rosa-maria-martinez-espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",biography:"Dr. Rosa María Martínez-Espinosa has been a Spanish Full Professor since 2020 (Biochemistry and Molecular Biology) and is currently Vice-President of International Relations and Cooperation development and leader of the research group 'Applied Biochemistry” (University of Alicante, Spain). Other positions she has held at the university include Vice-Dean of Master Programs, Vice-Dean of the Degree in Biology and Vice-Dean for Mobility and Enterprise and Engagement at the Faculty of Science (University of Alicante). She received her Bachelor in Biology in 1998 (University of Alicante) and her PhD in 2003 (Biochemistry, University of Alicante). She undertook post-doctoral research at the University of East Anglia (Norwich, U.K. 2004-2005; 2007-2008).\nHer multidisciplinary research focuses on investigating archaea and their potential applications in biotechnology. She has an H-index of 21. She has authored one patent and has published more than 70 indexed papers and around 60 book chapters.\nShe has contributed to more than 150 national and international meetings during the last 15 years. Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",isOpenForSubmission:!0,editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. He performed post-doctoral studies at Max-Planck Institute, Germany, and University of Florence, Italy in addition to making several scientific visits abroad. He currently works as a Full Professor of Biochemistry in the Faculty of Pharmacy, Anadolu University, Turkey. Dr. Beydemir has published over a hundred scientific papers spanning protein biochemistry, enzymology and medicinal chemistry, reviews, book chapters and presented several conferences to scientists worldwide. He has received numerous publication awards from various international scientific councils. He serves in the Editorial Board of several international journals. Dr. Beydemir is also Rector of Bilecik Şeyh Edebali University, Turkey.",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",slug:"deniz-ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",biography:"Dr. Deniz Ekinci obtained a BSc in Chemistry in 2004, MSc in Biochemistry in 2006, and PhD in Biochemistry in 2009 from Atatürk University, Turkey. He studied at Stetson University, USA, in 2007-2008 and at the Max Planck Institute of Molecular Cell Biology and Genetics, Germany, in 2009-2010. Dr. Ekinci currently works as a Full Professor of Biochemistry in the Faculty of Agriculture and is the Head of the Enzyme and Microbial Biotechnology Division, Ondokuz Mayıs University, Turkey. He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. Dr. Ekinci serves as the Editor in Chief of four international books and is involved in the Editorial Board of several international journals.",institutionString:null,institution:{name:"Ondokuz Mayıs University",institutionURL:null,country:{name:"Turkey"}}},editorThree:null},{id:"17",title:"Metabolism",coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",isOpenForSubmission:!0,editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",slug:"yannis-karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",biography:"Yannis Karamanos, born in Greece in 1953, completed his pre-graduate studies at the Université Pierre et Marie Curie, Paris, then his Masters and Doctoral degree at the Université de Lille (1983). He was associate professor at the University of Limoges (1987) before becoming full professor of biochemistry at the Université d’Artois (1996). He worked on the structure-function relationships of glycoconjugates and his main project was the investigations on the biological roles of the de-N-glycosylation enzymes (Endo-N-acetyl-β-D-glucosaminidase and peptide-N4-(N-acetyl-β-glucosaminyl) asparagine amidase). From 2002 he contributes to the understanding of the Blood-brain barrier functioning using proteomics approaches. He has published more than 70 papers. His teaching areas are energy metabolism and regulation, integration and organ specialization and metabolic adaptation.",institutionString:null,institution:{name:"Artois University",institutionURL:null,country:{name:"France"}}},editorTwo:null,editorThree:null},{id:"18",title:"Proteomics",coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",isOpenForSubmission:!0,editor:{id:"200689",title:"Prof.",name:"Paolo",middleName:null,surname:"Iadarola",slug:"paolo-iadarola",fullName:"Paolo Iadarola",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCl8QAG/Profile_Picture_1623568118342",biography:"Paolo Iadarola graduated with a degree in Chemistry from the University of Pavia (Italy) in July 1972. He then worked as an Assistant Professor at the Faculty of Science of the same University until 1984. In 1985, Prof. Iadarola became Associate Professor at the Department of Biology and Biotechnologies of the University of Pavia and retired in October 2017. Since then, he has been working as an Adjunct Professor in the same Department at the University of Pavia. His research activity during the first years was primarily focused on the purification and structural characterization of enzymes from animal and plant sources. During this period, Prof. Iadarola familiarized himself with the conventional techniques used in column chromatography, spectrophotometry, manual Edman degradation, and electrophoresis). Since 1995, he has been working on: i) the determination in biological fluids (serum, urine, bronchoalveolar lavage, sputum) of proteolytic activities involved in the degradation processes of connective tissue matrix, and ii) on the identification of biological markers of lung diseases. In this context, he has developed and validated new methodologies (e.g., Capillary Electrophoresis coupled to Laser-Induced Fluorescence, CE-LIF) whose application enabled him to determine both the amounts of biochemical markers (Desmosines) in urine/serum of patients affected by Chronic Obstructive Pulmonary Disease (COPD) and the activity of proteolytic enzymes (Human Neutrophil Elastase, Cathepsin G, Pseudomonas aeruginosa elastase) in sputa of these patients. More recently, Prof. Iadarola was involved in developing techniques such as two-dimensional electrophoresis coupled to liquid chromatography/mass spectrometry (2DE-LC/MS) for the proteomic analysis of biological fluids aimed at the identification of potential biomarkers of different lung diseases. He is the author of about 150 publications (According to Scopus: H-Index: 23; Total citations: 1568- According to WOS: H-Index: 20; Total Citations: 1296) of peer-reviewed international journals. He is a Consultant Reviewer for several journals, including the Journal of Chromatography A, Journal of Chromatography B, Plos ONE, Proteomes, International Journal of Molecular Science, Biotech, Electrophoresis, and others. He is also Associate Editor of Biotech.",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",slug:"simona-viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",biography:"Simona Viglio is an Associate Professor of Biochemistry at the Department of Molecular Medicine at the University of Pavia. She has been working since 1995 on the determination of proteolytic enzymes involved in the degradation process of connective tissue matrix and on the identification of biological markers of lung diseases. She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. 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This group of bio-inspired metaheuristics solves multiple optimization problems by applying the metaphor of natural selection. It so far has solved problems such as resource allocation, routing, schedule planning, and engineering design. Moreover, in the field of machine learning, evolutionary computation has carved out a significant niche both in the generation of learning models and in the automatic design and optimization of hyperparameters in deep learning models. This collection aims to include quality volumes on various topics related to evolutionary algorithms and, alternatively, other metaheuristics of interest inspired by nature. For example, some of the issues of interest could be the following: Advances in evolutionary computation (Genetic algorithms, Genetic programming, Bio-inspired metaheuristics, Hybrid metaheuristics, Parallel ECs); Applications of evolutionary algorithms (Machine learning and Data Mining with EAs, Search-Based Software Engineering, Scheduling, and Planning Applications, Smart Transport Applications, Applications to Games, Image Analysis, Signal Processing and Pattern Recognition, Applications to Sustainability).",annualVolume:11421,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/25.jpg",editor:{id:"136112",title:"Dr.",name:"Sebastian",middleName:null,surname:"Ventura Soto",fullName:"Sebastian Ventura Soto",profilePictureURL:"https://mts.intechopen.com/storage/users/136112/images/system/136112.png",institutionString:null,institution:{name:"University of Córdoba",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"111683",title:"Prof.",name:"Elmer",middleName:"P.",surname:"Dadios",fullName:"Elmer Dadios",profilePictureURL:"https://mts.intechopen.com/storage/users/111683/images/system/111683.jpg",institutionString:"De La Salle University",institution:{name:"De La Salle University",institutionURL:null,country:{name:"Philippines"}}},{id:"106873",title:"Prof.",name:"Hongwei",middleName:null,surname:"Ge",fullName:"Hongwei Ge",profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institutionString:null,institution:{name:"Dalian University of Technology",institutionURL:null,country:{name:"China"}}},{id:"171056",title:"Dr.",name:"Sotirios",middleName:null,surname:"Goudos",fullName:"Sotirios Goudos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bS9IuQAK/Profile_Picture_1622623673666",institutionString:null,institution:{name:"Aristotle University of Thessaloniki",institutionURL:null,country:{name:"Greece"}}},{id:"15895",title:"Assistant Prof.",name:"Takashi",middleName:null,surname:"Kuremoto",fullName:"Takashi Kuremoto",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLrqQAG/Profile_Picture_1625656196038",institutionString:null,institution:{name:"Nippon Institute of Technology",institutionURL:null,country:{name:"Japan"}}},{id:"125844",title:"Prof.",name:"Wellington",middleName:"Pinheiro Dos",surname:"Santos",fullName:"Wellington Santos",profilePictureURL:"https://mts.intechopen.com/storage/users/125844/images/4878_n.jpg",institutionString:null,institution:{name:"Federal University of Pernambuco",institutionURL:null,country:{name:"Brazil"}}}]},{id:"26",title:"Machine Learning and Data Mining",keywords:"Intelligent Systems, Machine Learning, Data Science, Data Mining, Artificial Intelligence",scope:"The scope of machine learning and data mining is immense and is growing every day. It has become a massive part of our daily lives, making predictions based on experience, making this a fascinating area that solves problems that otherwise would not be possible or easy to solve. This topic aims to encompass algorithms that learn from experience (supervised and unsupervised), improve their performance over time and enable machines to make data-driven decisions. It is not limited to any particular applications, but contributions are encouraged from all disciplines.",annualVolume:11422,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/26.jpg",editor:{id:"24555",title:"Dr.",name:"Marco Antonio",middleName:null,surname:"Aceves Fernandez",fullName:"Marco Antonio Aceves Fernandez",profilePictureURL:"https://mts.intechopen.com/storage/users/24555/images/system/24555.jpg",institutionString:null,institution:{name:"Autonomous University of Queretaro",institutionURL:null,country:{name:"Mexico"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"43680",title:"Prof.",name:"Ciza",middleName:null,surname:"Thomas",fullName:"Ciza Thomas",profilePictureURL:"https://mts.intechopen.com/storage/users/43680/images/system/43680.jpeg",institutionString:null,institution:{name:"Government of Kerala",institutionURL:null,country:{name:"India"}}},{id:"16614",title:"Prof.",name:"Juan Ignacio",middleName:null,surname:"Guerrero Alonso",fullName:"Juan Ignacio Guerrero Alonso",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6HB8QAM/Profile_Picture_1627901127555",institutionString:null,institution:{name:"University of Seville",institutionURL:null,country:{name:"Spain"}}},{id:"3095",title:"Prof.",name:"Kenji",middleName:null,surname:"Suzuki",fullName:"Kenji Suzuki",profilePictureURL:"https://mts.intechopen.com/storage/users/3095/images/1592_n.jpg",institutionString:null,institution:{name:"University of Chicago",institutionURL:null,country:{name:"United States of America"}}},{id:"214067",title:"Dr.",name:"W. 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The area covers many techniques that offer solutions to emerging problems in robotics and enterprise-level software systems. Collaborative intelligence is highly and effectively achieved with multi-agent systems. Areas of application include swarms of robots, flocks of UAVs, collaborative software management. Given the level of technological enhancements, the popularity of machine learning in use has opened a new chapter in multi-agent studies alongside the practical challenges and long-lasting collaboration issues in the field. It has increased the urgency and the need for further studies in this field. We welcome chapters presenting research on the many applications of multi-agent studies including, but not limited to, the following key areas: machine learning for multi-agent systems; modeling swarms robots and flocks of UAVs with multi-agent systems; decision science and multi-agent systems; software engineering for and with multi-agent systems; tools and technologies of multi-agent systems.",annualVolume:11423,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/27.jpg",editor:{id:"148497",title:"Dr.",name:"Mehmet",middleName:"Emin",surname:"Aydin",fullName:"Mehmet Aydin",profilePictureURL:"https://mts.intechopen.com/storage/users/148497/images/system/148497.jpg",institutionString:null,institution:{name:"University of the West of England",institutionURL:null,country:{name:"United Kingdom"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"275140",title:"Dr.",name:"Dinh Hoa",middleName:null,surname:"Nguyen",fullName:"Dinh Hoa Nguyen",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRbnKQAS/Profile_Picture_1622204093453",institutionString:null,institution:{name:"Kyushu University",institutionURL:null,country:{name:"Japan"}}},{id:"20259",title:"Dr.",name:"Hongbin",middleName:null,surname:"Ma",fullName:"Hongbin Ma",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRhDJQA0/Profile_Picture_2022-05-02T08:25:21.jpg",institutionString:null,institution:{name:"Beijing Institute of Technology",institutionURL:null,country:{name:"China"}}},{id:"28640",title:"Prof.",name:"Yasushi",middleName:null,surname:"Kambayashi",fullName:"Yasushi Kambayashi",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYOQxQAO/Profile_Picture_1625660525470",institutionString:null,institution:{name:"Nippon Institute of Technology",institutionURL:null,country:{name:"Japan"}}}]}]}},libraryRecommendation:{success:null,errors:{},institutions:[]},route:{name:"profile.detail",path:"/profiles/99961",hash:"",query:{},params:{id:"99961"},fullPath:"/profiles/99961",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()