Genes involved in the pathogenesis of hearing disorders grouped according to the type of inheritance—examples.
Etiology of hearing impairment (HI) is complex and comprises genetic and environmental factors. Currently, the background of genetic hearing impairment is an area of intensive research and we are witnessing fast progress in this field. The story has begun in 1997 when the DFNB1 locus was discovered with GJB2 and GJB6 genes causative for almost 50% of cases of recessive, profound, prelingual hearing loss. Nowadays, we have much more possibilities for dissecting the reason of HI, but proper assessment of clinical symptoms is essential for selecting the most optimal diagnostic pathway. In the first stage, the detailed characteristic of hearing loss including its level established by pure tone audiometry (PTA) or auditory brainstem responses (ABR), age of onset, and other helpful features as progressive or no progressive type should be provided. Subsequently, the presence or absence of accompanying symptoms should be established and followed by a detailed analysis of pedigree. In addition, modern assistive algorithms such as AudioGene, Face2Gene, and POSSUM are also discussed. Taking into account the variety of causative genes and pathogenic variants underling hearing loss, searching for causative genes, after exclusion of the DFNB1 variants, should be performed with multigenic panels based on next-generation sequencing technology.
- pathogenic variant
- next-generation sequencing
The dynamic development of new DNA sequencing technologies in recent years has given us unprecedented insight into the information encoded in the human genome. Introduction of these techniques into a clinical practice has put the diagnosis of genetic disorders to a much more advanced level with a very high detection rate of pathogenic variants. Hearing loss (HL) has also greatly benefited from the technological revolution as it is a genetically heterogeneous condition with more than 100 different genes being involved in its pathogenesis, and novel genes are still being discovered (www.herediataryhearingloss.org; accessed 10/2017). As compared to the strategy of sequential analysis of single genes, the application of high-throughput DNA sequencing has increased the diagnostic yield of genetic causes of HL by approximately four times .
At the same time, the technological advancements have brought us to a higher level of complexity. Searching for HL-causing variants, often hundreds of genes have to be analyzed and we are flooded by huge amounts of information that are difficult to interpret . It is partially overcome by still-improving computational tools and growing data from population studies, but an indispensable part of better planning of genetic testing and understanding its results is the information gathered from a thorough clinical examination and family history. Sometimes, the primary clinical data collected prior to genetic testing do not completely match the phenotypic features that could be expected from molecular findings. In such cases, clinical reevaluation is needed to better delineate the phenotype and verify whether the identified genetic variants are indeed responsible for the observed clinical features [3, 4].
2. Pedigree construction and analysis
The fundamental and basic element of genetic evaluation in the consultation room is the creation of a precise and accurate family pedigree based on the detailed medical interview. A genetic pedigree is a diagram of genetic relationship enriched with an information about health history, which allows to easily trace the transmission of symptoms, estimate whether symptoms may be caused by genetic reason, and evaluate the risk for other family members (including unborn) of an inherited disorder. Although in the archival literature, readers may encounter many different systems of constructing pedigrees , the current, uniform, and precise guidelines in this area should be followed and applied in both clinical practice and publications. Taking into account the dynamic rise of genetic knowledge within the last years, triggered by new technologies such as next-generation sequencing (NGS), clinicians and scientists should be familiar with preparation and interpretation of a pedigree. This allows a proper interpretation of medical and genetic information of the studied family. At the time of writing, an authority dealing with the standardization of the terminology used to describe a pedigree is the National Society of Genetic Counselors (NSGC, http://www.nsgc.org) established in 1979 in the United States of America (USA), with its two official journals: “Journal of Genetic Counseling” and “Perspectives in Genetic Counseling.” The Pedigree Standardization Work Group (PSWG) operating within the NSGC established unified recommendations for standardized human pedigree in 1995 [6, 7], and updated it in 2008 . Regarding the fact that no alternative comprehensive, analogous recommendations have been proposed, along with lack of critical comments on the proposed system, the PSWG established rules have become an accepted and international symbolic language of human genetic clinicians and researchers.
The most commonly used pedigree symbols, definitions, and abbreviations in compliance with the PSWG revised recommendations are presented in Figure 1.
With the symbols listed in Figure 1, a family tree should be created according to the following rules:
At the beginning, a shaded symbol (square for male, circle for female) denoting the proband (an affected person from a family who came for a medical consultation as first) should be placed. In the bottom left corner, an arrow and letter “P” should be placed to uniquely mark that this individual is the proband.
Above the symbols for proband’s, ancestors starting with parents should be placed. The symbol denoting male partner should be placed to the left of the female’s one if possible. Furthermore, symbols denoting both parents should be connected by a horizontal line (relationship line) and doubled if the parents are consanguineous. The line of descent should be placed in the middle of the horizontal line, which connects parents with the offspring (sibship line).
All symbols representing siblings should be placed in the birth order starting from the left side, at the same height as the proband’s symbol. Vertical lines (individual’s line), linking symbols to the horizontal line (sibship line) above the symbols, must be placed for all siblings’ symbols.
According to the above-described rules, symbols representing all remaining family members should be placed and joined with the appropriate lines.
Some additional, useful information such as disease, age, age at death, initials, or the first name may be placed below appropriate symbols.
The pedigree line definitions and rules of placing them within the pedigree are presented in Figure 2.
Additional most common symbols, rules, and family situations are gathered in Figure 3.
Since drawing pedigrees, especially for large families, is complicated and time consuming, it is worth to use computer programs that facilitate and accelerate this task. There are many professional and public tools, which are useful in the process of creating accurate family diagrams for both, clinical and educational purposes, e.g., Genial Pedigree Draw (http://www.pedigreedraw.com/), Progeny Online Pedigree Tool (http://www.progenygenetics.com/online-pedigree/), and CeGaT Pedigree Chart Designer (http://www.cegat.de/en/for-physicians/pedigree-chart-designer/).
Understanding the elementary rules of inheritance is the key to appreciate how traits or diseases are passed on within a family. It should be reminded here that every individual has two copies of almost every gene localized on chromosome (autosome), one of them derives from biological mother and the second one from biological father. The situation is different in case of sex chromosomes—every male has only one X (inherited from mother) and Y chromosome (inherited from father). The Y chromosome is transmitted in its entirety exclusively from father to son. In contrast, every female has two X chromosomes (inherited from both parents) . Another derogation from basic inheritance rules is mitochondrial inheritance, in which the entire independent small genome is passed only from mother to offspring . Typically, there are four most common inheritance patterns, depending on the genomic localization and influence on the protein function of pathogenic variants or genes i.e., autosomal dominant (AD), autosomal recessive (AR), sex-linked, and mitochondrial . Diseases caused by pathogenic variants localized in a single gene are mostly inherited in an AD or AR pattern and are referred to as Mendelian inheritance (tribute to Gregor Mendel, who first noted this pattern in pea plants).
The AD mode of inheritance occurs when a single copy of the disrupted (mutated) gene is causative of the disease. It should be emphasized that for AD disorders, a variety of inter and intrafamilial variability of symptoms may occur. Nevertheless, there are few substantial features, which make this mode of inheritance rather simple to distinguish. Dominantly inherited genetic diseases tend to occur in every generation of a family, they affect males and females equally; furthermore, the disorder may be transmitted from males and females. The risk for offspring to inherit the pathogenic variant is 50%. Due to the variability of symptoms severity, characteristic for this type of inheritance, the risk of becoming symptomatic may be less than 50%. A typical family tree representing the AD mode of inheritance is shown in Figure 4.
The AR type of inheritance requires two disrupted copies of a gene for a disease to occur. Thus, both parents of an affected individual are obligatory asymptomatic carriers (due to an assumption that heterozygotes do not manifest a disease). Furthermore, the symptoms are not typically seen in every generation. AR diseases are much more common in offspring of consanguineous pairs (which is evident within small, isolated populations e.g., Icelanders, Bedouins, or Amish . In contrast to the AD inheritance mode, affected individuals present more consistent clinical picture. The risk for offspring to inherit both pathogenic variants is 25%, whereas the risk to inherit one heterozygous variant is 50%. It should be also noted that all children of an affected parent and a noncarrier partner, regardless of their gender, will be obligate carriers. A typical family pedigree illustrating the AR mode of inheritance is shown in Figure 5.
A sex-linked mode of inheritance consists of three subtypes: X-linked dominant (XLD), X-linked recessive (XLR), and Y-linked. Whereas the Y chromosome contains very limited number of genes and there are only few Y-linked disorders, none of them related to hearing and speech disorders, this type of inheritance will not be described here. The XLD and XLR type of inheritance relate to genes located on the X chromosome, and for the occurrence of XLD symptoms, only one copy of a disrupted X-linked gene is required. XLD diseases usually manifest very severely in males, which may lead to spontaneous abortion or neonatal death. The characteristic feature for this type of inheritance is that there is no transmission of the disease from male to male, and all of the female offspring of affected male will inherit the pathogenic variant and the disease. A characteristic family tree for the XLD mode of inheritance is shown in Figure 6.
For an XLR disease to occur in females, both copies of a gene must be impaired. Characteristic features for an XLR inheritance mode are affected males, but an extremely low number or no affected females, in every generation. A distinct feature of the XLR inheritance pattern is that the pedigree tree shows no male to male transmission of the disease. All males harboring a pathogenic variant in an X-linked gene present severe symptoms of the disease, whereas carrier females are in general unaffected or present significantly less severe symptoms. A typical family tree representing the XLR mode of inheritance is shown in Figure 7.
Although within small families, which currently are very common, especially in European countries, the recognition of an X-linked inheritance pattern is rather challenging and remains unknown until the results of genetic testing .
The mitochondrial mode of inheritance has distinctive features differentiating it from others. Briefly, this unique features come directly from mitochondrial DNA (mtDNA) specificity: mtDNA is a small, independent, circular genome; furthermore, an average human cell contains up to 1000 mitochondria and in every mitochondrion several copies of the mtDNA genome may be present. If all mitochondria in a given individual contain an mtDNA variant it is defined as homoplasmy. In contrast, heteroplasmy indicates the coexistence of more than one mtDNA type within an individual. As all mitochondria of offspring are of maternal origin, the pathogenic variants localized within mtDNA are exclusively passed from mother to children and they may affect males and females equally. Consistently, males do not transmit the mtDNA disorders to their offspring. A representative family tree demonstrating mitochondrial mode of inheritance is shown in Figure 8.
It should be emphasized that in many cases distinction between the mitochondrial and AD inheritance is a difficult task based only on the family tree analysis.
3. Nonsyndromic hearing loss
It has to be stressed that all patients with a positive family history of HL should be referred for genetic counseling. Over generations, an inherited disorder automatically raises a suspicion of a genetic underlying cause. A careful analysis of a family pedigree enables to identify or to presume the mode in which hearing impairment is inherited. This in turn is an important step in directing genetic testing at specific genes that are causally involved in the pathogenesis of autosomal dominant, recessive, X-linked, or mitochondrial HL. In case of marriages between individuals with hearing impairment or between individuals coming from families with hearing impairment, the family pedigrees should be analyzed especially carefully. In the offspring of such couples, different HL causative variants of different genes may be found. Interestingly, in a study of 80 deafness genes, the DNA samples of HL patients were significantly enriched in potentially pathogenic variants . One possible explanation of the phenomenon may the above-mentioned marriages between hearing impaired individuals. Attention should also be paid to the consanguinity between parents, which is common in certain populations. Looking for a genetic cause of HL in offspring of a consanguineous couple, the autosomal recessive mode of inheritance with pathogenic variants in a homozygous state is primarily expected.
A diagnostic challenge represents an HL patient without other affected family members, also referred to as a sporadic case. Here, a family history of HL is negative and a genetic cause is strongly suspected after exclusion of environmental factors, such as prenatal infection (with toxoplasmosis, rubella, cytomegalovirus, and herpesvirus—“TORCH” organisms), postnatal infections (mainly bacterial meningitis, mumps), prematurity, traumatic injury, blood vessels or autoimmune disease, Meniere’s disease, acoustic neuroma, exposure to chemical agents, or noise that may be responsible for HL development. While describing HL, four major terms related to its presentation such as (I) the age of onset, (II) the type, (III) the degree of HL, and (IV) stability are usually used. The onset of HL can be congenital, prelingual (before a child develops speech), postlingual (after the acquisition of speech and language, usually after the age of six), adult-onset or age-related late-onset (presbyacusis). The different types of HL (conductive, sensorineural, or mixed) indicate which part of the ear is affected. Genetically determined HL is usually bilateral although families with asymmetric and unilateral HL are also reported [14, 15].
It has been estimated that about 80% of prelingual HL results from genetic factors. It is most often inherited as an autosomal recessive feature without other accompanying medical problems The second most common inheritance pattern of prelingual HL is autosomal dominant (20%), while X-linked and mitochondrial constitute together approximately 1–1.5% . Most of the reported families with nonsyndromic postlingual HL present an autosomal dominant pattern of inheritance. Currently, 36 different genes causally involved in autosomal dominant HL have been identified (www.herediataryhearingloss.org; accessed 10/2017) and only a few of them are associated with prelingual HL .
If hearing impairment represents an isolated finding that can be associated with abnormalities of the middle and/or inner ear but is not accompanied by visible abnormalities of the outer ear or any other medical problems, it is referred to as nonsyndromic or isolated. The major cause of prelingual severe-to-profound autosomal recessive nonsyndromic HL in many populations are pathogenic variants of the
Discussing the genetic causes underlying partial deafness, defined as normal or slightly deteriorated thresholds involving low frequencies combined with profound HL in high frequencies , pathogenic variants localized within mtDNA and
Considering the significant contribution of genetic factors to HL and the recent guideline for clinical evaluation and etiologic diagnosis of HL, one may conclude that single-gene testing is justified if a specific genetic etiology of HL is suspected. If there are no specific clinical indications, testing for the DFNB1-related HL should be performed. If the investigations do not provide conclusive results, HL genes may be analyzed by the NGS approaches such as multigene panels, whole exome or whole genome sequencing . All known nonsyndromic deafness loci (locus denotes the position in the genome linked with the disease) are labeled as DFN (DeaFNess) and classified according to the type of inheritance (DFNA: autosomal dominant; DFNB: autosomal recessive; DFNX: X-linked) followed by a number indicating the order of locus discovery. In Table 1, some of the most common HL causative loci are gathered.
|Inheritance pattern||Genes and loci involved|
As it was previously stated, HL is a genetically heterogenous disease; nevertheless, there are some common, characteristic features, which may be a valuable asset in the process of dissecting the genetic reason of HL. Examples of pedigrees, characteristic audiometric features, and additional remarks for some common HL genes are shown in Table 2.
Despite quite a large number of genes causative for HL, the first step in the diagnostic approach should be the analysis of the DFNB1 locus, as the testing is inexpensive and fast . Apart from obvious clinical indications, such as IP3 malformation for the
4. Syndromic hearing loss
In contrast to the nonsyndromic hearing impairment, the syndromic hearing impairment is defined as a part of a syndrome, and it is associated with malformations of the external ear, malformations of other organs or other medical problems. HL is identified in more than 400 different syndromes . The most common type of autosomal dominant syndrome with sensorineural HL is
The two following autosomal recessive syndromic forms of HL represent rare metabolic disorders that, however, should not be missed out as their symptoms may resolve by appropriate treatment and dietary modifications. The
Syndromic X-linked HL is represented by the
In the Mohr-Tranebjaerg syndrome, also known as progressive deafness syndrome with blindness, dystonia, fractures and mental deficiency, progressive pre- or postlingual sensorineural deafness occurs in the early childhood and is a presenting symptom. MTS is caused by recessive variants of the
Mutations in the
5. Assistive algorithms
Regarding the heterogeneity of genetically related HL, the precise evaluation of its cause is a challenging task. Apart from some, rather rare, unquestionable phenotypic manifestations, many of the cases of possibly genetically related HL (syndromic and nonsyndromic) are hard to distinguish. It should be noted that there is a group of useful, assistive algorithms, which are helpful for both: establishing the diagnosis and targeting a diagnostic approach.
The Face2Gene (http://suite.face2gene.com/) is a collection of phenotyping applications, which enable accurate and comprehensive assessment of a patient based on characteristic dysmorphic facial features. As the variations in the face and skull are very common and are present in about 40% of genetic disorders, they are very useful in identification of the disorder. Briefly, the picture of patient face is uploaded to an application, than the quantification of the similarity is calculated with the usage of the algorithm database. The result is the list of syndromes with analogous morphology. The algorithm Face2Gene is accessible free of charge to all healthcare specialists.
The AudioGene (http://audiogene.eng.uiowa.edu/) predicts the genes underling autosomal dominant nonsyndromic hearing loss (ADNSHL) based on the audiometric data. This algorithm also takes into account the age of the patient, which is essential in the ADNSHL study due to characteristic deterioration of hearing during patient’s life. The algorithm is based on the computational analysis of specific audiometric data deposited in the database. Furthermore, the machine-learning method is applied to select and prioritize possibly causative genes for pathogenic variant screening [36, 37].
The Pictures of Standard Syndromes and Undiagnosed Malformations (POSSUM) (https://www.possum.net.au/) is a comprehensive dysmorphology database designed for the diagnosis of multiple malformations, metabolic, teratogenic, chromosomal, and skeletal syndromes as well as their images. This database consists of information on over 4000 different syndromes and searching is based on the selected features and results in a specific list of possible diagnoses .
6. Next-generation sequencing technology in dissecting the background of hearing loss
In almost all genetically related diseases (included hearing impairment), there is a need for tailored diagnostic strategies in searching for their molecular background. The milestone in this research area was the development of the method for the DNA sequencing by Frederick Sanger in 1975 . Whereas the direct sequencing (called also Sanger sequencing—tribute to its inventor) allows to debunk the molecular cause of disease in a limited number of genes, e.g., when HL background analyses were limited to the
An undisputable advantage of the WES is the possibility of simultaneous sequencing of the whole coding DNA sequence (protein coding part within all human genes ~20,000) regardless of the disease studied. This makes WES a universal test for almost all known genetic diseases. The multigene panel sequencing is a more economical solution, especially dedicated for the diagnostic purpose. It should be noted that with the panel sequencing, only already known genes associated with a given disease are analyzed. Although the targeted NGS has many advantages, whole-genome sequencing (WGS) is still the state of art approach with its high cost representing a main drawback. The application of high-throughput DNA sequencing methods generates a vast amount of information, which accelerated the discovery of new, causative genes for many diseases. Also in the field of genetically related HL, with the NGS technology, novel genes have been discovered for all modes of inheritance described above. The important, newly discovered genes causative of recessive HL are:
For the clinical diagnostic purpose, there are many commercial tests based on NGS, which differ in technologies and numbers of genes included. Heretofore, at least 20 commercially available tests, based on the NGS technology, focused on genetically related HL may be applied . Due to the constant reduction of costs and availability, diagnostic approach based on the NGS technology in the nearest future will become a standard, which will significantly improve the level of patient care.
Index of technical terms
Ołdak M. Chapter 8—Next generation sequencing in vision and hearing impairment. Clinical Applications for Next-Generation Sequencing. Boston: Academic Press; 2016. p. 153-170
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics in Medicine. 2015; 17(5):405-424
Oldak M, Ozieblo D, Pollak A, Stepniak I, Lazniewski M, Lechowicz U, et al. Novel neuro-audiological findings and further evidence for TWNK involvement in Perrault syndrome. Journal of Translational Medicine. 2017; 15(1):25
Pollak A, Lechowicz U, Kedra A, Stawinski P, Rydzanicz M, Furmanek M, et al. Novel and de novo mutations extend association of POU3F4 with distinct clinical and radiological phenotype of hearing loss. PLoS One. 2016; 11(12):e0166618
Resta RG. The crane’s foot: The rise of the pedigree in human genetics. Journal of Genetic Counseling. 1993; 2(4):235-260
Bennett RL, Steinhaus KA, Uhrich SB, O’Sullivan CK, Resta RG, Lochner-Doyle D, et al. Recommendations for standardized human pedigree nomenclature. Journal of Genetic Counseling. 1995; 4(4):267-279
Bennett RL, Steinhaus KA, Uhrich SB, O’Sullivan CK, Resta RG, Lochner-Doyle D, et al. Recommendations for standardized human pedigree nomenclature. Pedigree standardization task force of the National Society of genetic Counselors. American Journal of Human Genetics. 1995; 56(3):745-752
Bennett RL, French KS, Resta RG, Doyle DL. Standardized human pedigree nomenclature: Update and assessment of the recommendations of the National Society of genetic Counselors. Journal of Genetic Counseling. 2008; 17(5):424-433
Charlesworth B. The evolution of sex chromosomes. Science. 1991; 251(4997):1030-1033
Taylor RW, Turnbull DM. Mitochondrial DNA mutations in human disease. Nature Reviews. Genetics. 2005; 6(5):389-402
Oxford Desk DABIRT. Reference: Clinical genetics. The Ulster Medical Journal. 2006; 75(3):235
Chakraborty R, Deka R. Isolated populations. Encyclopedia of Biostatistics. USA: John Wiley & Sons, Ltd. 2005
Vona B, Muller T, Nanda I, Neuner C, Hofrichter MA, Schroder J, et al. Targeted next-generation sequencing of deafness genes in hearing-impaired individuals uncovers informative mutations. Genetics in Medicine. 2014; 16(12):945-953
Kim SH, Kim AR, Choi HS, Kim MY, Chun EH, Oh SH, et al. Molecular etiology of hereditary single-side deafness: Its association with pigmentary disorders and Waardenburg syndrome. Medicine (Baltimore). 2015; 94(43):e1817
Zazo Seco C, Serrao de Castro L, van Nierop JW, Morin M, Jhangiani S, Verver EJ, et al. Allelic mutations of KITLG, encoding KIT ligand, cause asymmetric and unilateral hearing loss and Waardenburg syndrome type 2. American Journal of Human Genetics 2015; 97(5):647-660
Alford RL, Arnos KS, Fox M, Lin JW, Palmer CG, Pandya A, et al. American College of Medical Genetics and Genomics guideline for the clinical evaluation and etiologic diagnosis of hearing loss. Genetics in Medicine. 2014; 16(4):347-355
Smith RJH, Jones MKN. Nonsyndromic Hearing Loss and Deafness, DFNB1. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mefford HC, et al., editors. Seattle (WA): GeneReviews(R); 1993
Hoefsloot LH, Roux AF, Bitner-Glindzicz M, contributors to EDbpm. EMQN best practice guidelines for diagnostic testing of mutations causing non-syndromic hearing impairment at the DFNB1 locus. European Journal of Human Genetics. 2013; 21(11):1325-1329
Sloan-Heggen CM, Bierer AO, Shearer AE, Kolbe DL, Nishimura CJ, Frees KL, et al. Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss. Human Genetics. 2016; 135(4):441-450
Skarzynski H, Lorens A, Piotrowska A. A new method of partial deafness treatment. Medical Science Monitor. 2003; 9(4):CS20-CS24
Lechowicz U, Gambin T, Pollak A, Podgorska A, Stawinski P, Franke A, et al. Iterative sequencing and variant screening (ISVS) as a novel pathogenic mutations search strategy - application for TMPRSS3 mutations screen. Scientific Reports. 2017; 7(1):2543
Iwanicka-Pronicka K, Pollak A, Skorka A, Lechowicz U, Korniszewski L, Westfal P, et al. Audio profiles in mitochondrial deafness m.1555A>G and m.3243A>G show distinct differences. Medical Science Monitor 2015; 21:694-700
Snoeckx RL, Huygen PL, Feldmann D, Marlin S, Denoyelle F, Waligora J, et al. GJB2 mutations and degree of hearing loss: A multicenter study. American Journal of Human Genetics. 2005; 77(6):945-957
Pollak A, Skorka A, Mueller-Malesinska M, Kostrzewa G, Kisiel B, Waligora J, et al. M34T and V37I mutations in GJB2 associated hearing impairment: Evidence for pathogenicity and reduced penetrance. American Journal of Medical Genetics. Part A. 2007; 143A(21):2534-2543
Alasti F, Van Camp G, Smith RJH. Pendred Syndrome/DFNB4. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mefford HC, et al., editors. Seattle (WA): GeneReviews(R); 1993
Gurtler N, Kim Y, Mhatre A, Schlegel C, Mathis A, Daniels R, et al. Two families with nonsyndromic low-frequency hearing loss harbor novel mutations in Wolfram syndrome gene 1. Journal of Molecular Medicine (Berl). 2005; 83(7):553-560
Lechowicz U, Pollak A, Frączak A, Rydzanicz M, Stawiński P, Lorens A, et al. Application of nextgeneration sequencing to identify mitochondrial mutations: Study on m.7511T>C in patients with hearing loss. Molecular Medicine Reports. 2018; 17(1):1782-1790
Pollak A, Prevalence SH. Of DFNB1 hearing loss among cochlear implant users established with the 3-step DFNB1 approach. Journal of Hearing Science. 2017; 7(1):33-40
Gorlin RJ, Toriello HV, Cohen MM. Hereditary Hearing Loss and its Syndromes: Oxford University Press, USA; 1995
Baser ME, Friedman JM, Aeschliman D, Joe H, Wallace AJ, Ramsden RT, et al. Predictors of the risk of mortality in neurofibromatosis 2. American Journal of Human Genetics. 2002; 71(4):715-723
Baker S, Booth C, Fillman C, Shapiro M, Blair MP, Hyland JC, et al. A loss of function mutation in the COL9A2 gene causes autosomal recessive stickler syndrome. American Journal of Medical Genetics. Part A. 2011; 155A(7):1668-1672
Jacoszek A, Pollak A, Ploski R, Oldak M. Advances in genetic hearing loss: CIB2 gene. European Archives of Oto-Rhino-Laryngology. 2017; 274(4):1791-1795
Van Camp G, Maternally SRJ. Inherited hearing impairment. Clinical Genetics. 2000; 57(6):409-414
Pandya A. Nonsyndromic Hearing Loss and Deafness, Mitochondrial. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mefford HC, et al, editors. Seattle (WA): GeneReviews(R); 1993
Iwanicka-Pronicka K, Pollak A, Skorka A, Lechowicz U, Pajdowska M, Furmanek M, et al. Postlingual hearing loss as a mitochondrial 3243A>G mutation phenotype. PLoS One 2012; 7(10):e44054
Taylor KR, Booth KT, Azaiez H, Sloan CM, Kolbe DL, Glanz EN, et al. Audioprofile surfaces: The 21st century audiogram. The Annals of Otology, Rhinology, and Laryngology. 2016; 125(5):361-368
Hildebrand MS, DeLuca AP, Taylor KR, Hoskinson DP, Hur IA, Tack D, et al. A contemporary review of AudioGene audioprofiling: A machine-based candidate gene prediction tool for autosomal dominant nonsyndromic hearing loss. The Laryngoscope. 2009; 119(11):2211-2215
Stromme P. The diagnosis of syndromes by use of a dysmorphology database. Acta Paediatrica Scandinavica. 1991; 80(1):106-109
Sanger F, Coulson AR. A rapid method for determining sequences in DNA by primed synthesis with DNA polymerase. Journal of Molecular Biology. 1975; 94(3):441-448
Demkow U, Ploski R. Clinical Applications for Next-Generation Sequencing. USA: Academic Press; 2015
Oldak M, Ruszkowska E, Pollak A, Sobczyk-Kopciol A, Kowalewski C, Piwonska A, et al. A note of caution on the diagnosis of Martin-Probst syndrome by the detection of the p.D59G mutation in the RAB40AL gene. European Journal of Pediatrics. 2015; 174(5):693-696
Oldak M, Sciezynska A, Mlynarski W, Borowiec M, Ruszkowska E, Szulborski K, et al. Evidence against RAB40AL being the locus for Martin-Probst X-linked deafness-intellectual disability syndrome. Human Mutation. 2014; 35(10):1171-1174
Eisenberger T, Di Donato N, Baig SM, Neuhaus C, Beyer A, Decker E, et al. Targeted and genomewide NGS data disqualify mutations in MYO1A, the “DFNA48 gene”, as a cause of deafness. Human Mutation. 2014; 35(5):565-570