Introductory Chapter: Down Syndrome and Other Chromosome Abnormalities

1. Introduction

Down syndrome (DS) is one of the most frequent autosomal disorders in humans and is also known as trisomy 21. Its incidence at birth is approximately 1 in 700 [1, 2, 3]. Down syndrome is associated with mental retardation, typical facial appearance, congenital heart disease, leukemia, gastrointestinal malformation, Alzheimer’s disease, and several other congenital abnormalities with varying degree of severity [4]. Investigation on DS karyotype revealed a diploid chromosome number of 2n = 47, XX/XY, +21 in 95% cases, while mosaicism was found in approximately 2% of cases. On the other hand, Robertsonian translocations involving 13q21q or 14q21q or 21q21q account for approximately 3% of all DS cases [5].

Mental retardation is one of the most important clinical features of Down syndrome. Interests were generated to understand the cause of mental retardation among DS live births and to explore the etiology of Down syndrome. Genotyping using polymorphic microsatellite markers had enabled the investigators [6, 7] to study the maternal meiotic errors and also to look into the candidate genes responsible for DS pathophysiology. Two established risk factors for the birth of DS babies are advanced maternal age [8] and altered recombination [9]. Study of parental origin of extra chromosome 21, stage of meiotic nondisjunction, and recombination pattern revealed the overall reduction in meiotic recombination irrespective of maternal age [3, 10].

Human chromosome 21 (HC21) is one of the smallest acrocentric chromosomes. Investigation revealed that 21q22 contains genes in triplicated condition, which are responsible for DS phenotype. This segment was regarded as Down Syndrome Critical Region (DSCR) [4, 11]. After the completion of sequencing of HC21, several genes and their prospective functions had been identified. Triplication and overexpression of which significantly contributed toward the development of DS phenotype [12, 13].

Besides advanced maternal age, environmental risk factors for the birth of DS babies have also been identified, which include smokeless chewing tobacco, oral contraceptives [14], and cigarette smoking [15]. However, there was lack of convincing evidence regarding risk of maternal drinking during gestational period for DS births [16].

Though advanced maternal age is one of the most important risk factors for the meiotic nondisjunction of chromosome 21 in DS individuals, investigation of this association at the genetic level, involving telomere length measurement, is still limited [17]. Measurement of telomere length in older mothers with DS babies revealed shorter telomere than age-matched control mothers without DS babies. It has been suggested that older mothers with DS babies are genetically older than control euploid mother, and telomere length attrition or genetic aging may be associated with nondisjunction of chromosome 21 during first and second meiotic divisions [10].

Mouse has been used extensively for genetic experiment and also to study any human chromosomal alterations. The rapid development of genetic engineering provided the impetus for the generation of multiple Down syndrome mouse models in order to better understand the pathophysiology and also to correlate genotype with the phenotype in DS. Two segmental mouse models in widely use are Ts65Dn [18] and Ts1Cje [19, 20]. Moreover, the discovery of new editing technology CRISPR/Cas9 DNA repairing processes has facilitated the development of new therapeutic strategies to cure human genetic diseases and associated chromosomal abnormalities [21].

Besides mental retardation, DS individuals are also affected by multiple diseases. Congenital heart defect such as atrioventricular septal defect (AVSD) is prevalent among 40–60% of DS individuals [22]. Further investigation on AVSD revealed that there is an association between CRELD1 gene and AVSD in DS and euploid individuals [23]. A growing body of evidence shows that a major portion of DS population acquires Alzheimer’s Disease, such as neuropathological changes by the age of 55–60 years, and develops dementia [24]. Recent studies [25] revealed that there is a close association between Alzheimer’s disease and Down syndrome, and this may be due to the fact that they also share common genetic risk factors. Two genes, Presenilin-1 (PSEN-1) and Apolipoprotein E (APOE), are found to be associated with early- and late- onset Alzheimer’s disease in Down syndrome. On the other hand, the incidence of acute leukemia (AL) is very high in children with Down syndrome (70–100%) compared with children without this syndrome. Among the children with DS who develop leukemia, 60% is classified as having acute lymphoblastic leukemia (ALL) and 40% with acute myeloblastic leukemia (AML) [26].

Recent studies on the infection with COVID-19 virus show that DS patients are at increased risk for death from infection with the virus since the DS patients are associated with dysfunction of immune system, congenital heart disease, and pulmonary pathology [27].

2. Other chromosome syndromes

Down syndrome is the most frequent autosomal abnormality and shows a strong association with advanced maternal age and reduced recombination. With advancement of our knowledge on diagnostic procedures such as karyotyping, fluorescence in situ hybridization (FISH) and molecular diagnosis involving microsatellite markers result in the recognition of an increasing number of new chromosome abnormalities, which include both numerical and structural chromosomal aberrations. Though on an individual basis these disorders are rare in occurrence, together they account for a loss of very high proportion of human conceptions. To date, well over 100 chromosome syndromes have been reported [5]. Most of these disorders are either autosomal or sex chromosomal in origin, while a small percentage of such patients have a structural chromosome abnormalities such as deletion, duplication, or translocation. Here, we have discussed some common chromosomal syndromes.

Edward’s syndrome or trisomy 18 where there is a nondisjunction of chromosome no. 18. Most trisomic 18 individuals die in embryonic or fetal stage [28], while nondisjunction of chromosome 13 leads to trisomy 13 syndrome or Patau’s syndrome. Cases with trisomy 13 mosaicism most often show a less severe clinical phenotype. Survivors have severe mental retardation and fail to thrive [29]. Patients with trisomy 8 syndrome revealed mild to severe mental deficiency with craniofacial and skeletal abnormalities. Majority of patients are mosaic while full trisomy is lethal in embryonic stage [30]. Besides autosomes, sex chromosomes are also involved in different types of congenital disorders. In 45X (Turner syndrome), nondisjunction of paternal X chromosome is responsible for its origin [31]. Consistent clinical features include female in appearance with short stature, increased carrying angles at the elbows, broad chest with widely spaced nipples, and ovarian dysgenesis. In Klinefelter syndrome, chromosome analysis revealed 47XXY karyotype where patient is characterized by relatively tall stature, hypogonadism with small testes, and inadequate testosterone production. Virilization is partial with gynaecomastia [32]. On the other hand, hermaphroditism is not very frequent in occurrence where an individual has both male and female gonads. External genitalia is also ambiguous in nature. Most patients with true hermaphroditism have a 46XX karyotype with X chromosome, which derived from paternal source carries Y chromosome specific DNA sequences, originated as a result of crossing over. Surgical intervention in early childhood could repair the ambiguous external genitalia and provide either a male or female sex matching the karyotype of the respective individuals.

Deletion 5p syndrome is originated due to partial deletion of the short arm of the chromosome number 5 (5p-). This syndrome is also known as Cri Du Chat syndrome because there is a mewing cry or cat-like cry after birth due to abnormal laryngeal development, and in most cases the deleted chromosome is of paternal origin. There are multiple clinical abnormalities along with severe mental retardation and failure to thrive [33]. In duplication 15q syndrome there is a duplication of distal arm (q) of chromosome 15. Patients are characterized by growth deficiency, craniofacial abnormalities, and congenital heart defects [34].

Progress in the understanding of the etiology and pathogenesis of different congenital disorders and technological advancement in the identification of abnormal fetus before birth have made it possible the prenatal diagnosis of child having congenital abnormalities. There are several methods for prenatal diagnosis such as amniocentesis where chromosome analysis is made using amniotic fluid collected at 11–12 weeks of pregnancy [35]. On the other hand, noninvasive serum screening involves triple markers such as alpha feto protein, human chorionic gonadotropin, and unconjugated estriol [36]. Association of neural tube defect and high levels of alpha fetoprotein (AFP) in serum samples as well as in amniotic fluid are also important markers for prenatal diagnosis of chromosomal disorders [37]. Currently, screening techniques involving sequencing and genotyping of fetal DNA are most promising techniques for rapid prenatal diagnosis of chromosomal abnormalities [38]. The complex nature of Down syndrome and other chromosome abnormalities create the need for collaborative, multidisciplinary research to understand the complex pathophysiology of these syndromes.