Ghosh M, Vijaya R, Kabra M
Genetics Unit, Department of Pediatrics, All India, Institute of Medical Sciences, New Delhi
Genetics Unit, Department of Pediatrics, All India, Institute of Medical Sciences, New Delhi
Linkage analysis in families with hereditary hearing loss have revealed a plethora of chromosomal locations linked to deafness reflecting the extreme heterogeneity of the disorder. 40 of the genes contained within these loci have been mapped lending an insight into the diverse molecules operating in the inner ear and the remarkable complexity of the cellular and molecular processes involved in the transucdation of sound in the auditory system. Among this diversity, Connexin 26 has been found to be the most common cause of deafness the world around. The authors review here the prevalence of this gene in the Indian population as found in their study, together with other deafness genes segregating non-syndromic deafness, accounting for approximately 40% of all cases. This indicates there are several more to be identified yet. Knowledge of the genetic cause of deafness in our families is important for accurate genetic counseling and early diagnosis for timely intervention and treatment options.
Indian J Pediatr 2004;71:531-533.
It has long been known that ‘deafness’- the most common and perhaps one of the most distressing disorders affecting humanity, is due to environmental and genetic causes. With recognition and containment of the environmental causes (intra-uterine viral infections, drugs, trauma and noise) the genetic factors remain to be contended. For many years, genetic analysis of deafness eluded researchers and medical geneticists on account of assortative matings and extreme genetic heterogeneity. However, in the recent past, with better understanding and strategy of linkage studies, there has been an explosion of reports on numerous chromosomal locations and genes linked to deafness. The GJB2 gene has emerged as the predominant cause of deafness world wide. Identification of mutation in families together with study of the functional role of the genes have contributed significantly to the understanding of the cellular and molecular mechanisms underlying deafness. The authors review here the prevalence of GJB2 gene mutations and other deafness genes segregating nonsyndromic deafness in India as found in the study. This study was undertaken as an Indo-US collaborative study between AIIMS, New Delhi and NIDCD, NIH, Maryland, USA.
The world-wide incidence of profound hearing loss is estimated to be approximately 1 in 1000 live births, of which half is attributed to genetic origin, that segregate as monogenic traits., Although there has been a significant advance in the knowledge of the molecular basis of hereditary deafness in recent years, the magnitude of the problem in India remains largely undefined. However, extrapolating the world wide incidence to our 1 billion population, compounded by the large prevalence of consanguineous marriages, prevalence of deafness in our country is likely to be of significant public health concern.
Genetics of deafness
About 50% of hearing loss may be genetic or hereditary, that may segregate as syndromic , i.e., associated with defects in other organ systems , or more often non-syndromic, when it presents as an isolated problem. Syndromic hearing loss, contributing to 30% of all genetic causes, can often be identified by the non-random association with defects in other organ systems. There are greater than 500 syndromes associated with deafness. Conversely, non-syndromic deafness is an enigma, that can be resolved only through genetic tests. 70-80% of non-syndromic hearing loss segregates autosomal recesive inheritance and only 20-22% manifests dominant forms, with X-linked and mitochondrial inheritance observed in only 2% cases. The dominantly inherited deafness loci are conventionally designated with a suffix ‘A’, ie, DFNA, the recessive with suffix ‘B’, ie, DFNB, to a number, indicating the order of their discovery and DFN for X-linked inheritance.
As the genes involved in deafness, are being discovered and their gene product studied, it is becoming increasingly clear that numerous genes are involved in orchestrating the complex process of sound transduction in the auditory system. Already around 80 chromosomal locations harbouring genes involved in non-syndromic hearing loss have been reported, (Hereditary hearing loss Homepage) with mapping of approximately half the genes in these loci. The protein products of these genes range from transriptional factors (POU3F4, EYA4, TFCP2L3), motor molecules (myosin 2,6,7 and 15), ion channel, transporter (pendrin, KCNQ4), integral membrane protein (TMC1, TMIE), adhesion molecules (cadherin and protocadherin), gap junction proteins (connexins 26, 30, 31 and 43), extracellular protein and many other novel molecules. Knowledge of the function of these molecules has provided insight into the complex mechanics of sound transduction in the inner ear.
Identification of genes and mutation analysis in families segregating recessive and dominant inheritance have revealed unique behaviour of several mutant alleles. It has been documentated that a gene expressing recessive inheritance in some families was implicated in other families segregating autosomal dominant inheritance. The gene located in the DFNB7/11 interval on chromosome 9, encoding a transmembrane protein TMC1 is example of one such gene, that was identified in several recessive families from India and Pakistan, as well as in an American large kindred segregating dominant inheritance. Furthermore, other genes identified in several families exhibiting non-syndromic deafness was found to be implicated in syndromic deafness in other families. Several genes underlying Usher Syndrome, an extremely heterogenous disorder, were found to express both as non-syndromic deafness, as well as with progressive loss of vision due to retinitis pigmentosa. This phenomenon where mutations within the same gene found to result in a variety of clinical phenotypes with different modes of inheritance has been postulated to be the result of differential behaviour/effect of the mutant alleles. It has been demonstrated that missence and splice site mutations result in non-syndromic deafness, whereas deletion and nonsense mutations result in more severe phenotypes (syndromic) on account of a dominant negative effect of the mutant allele.
Among this mind boggling heterogeneity of deafness genes, an interesting finding that emerged was the revelation of the GJB2 gene encoding connexin 26, a gap junction protein, on chrosome 13q12, that turned out to be responsible for deafness in upto 50% families in certain population groups.,, Having a small single coding exon, this gene has been widely studied in almost all ethnic populations. In some ethnic groups in the Mediterranean region and Askenazi Jews, it is reported in upto 50-80% of the deaf population in sporadic as well as familial cases., A founder mutation, 35delG in the Caucasian and 187delT in the Ashkenazi Jews was the major mutant allele observed.
Studies in Indian families revealed W24X, a trptophan stop codon, to be the founder mutation.,, We screened 320 consanguineous Indian families, for mutations in the GJB2 gene. Among these 200 were sequenced (coding exon), at the Lab of Molecular Genetics, NIDCD, under the collaborative project, to determine the prevalence and profile of mutations in Indian population. Subsequently, the authors screened all the families by allele specific PCR for the 3 common mutations, namely, W24X, W77X, 124X and also 35delG, as these were the major GJB2 mutations found in the families. Bi-allelic W24X was the major mutation observed in the population, with a small number contributed by W77X , Q124X and M1V mutant alleles. Not surprisingly, 35delG mutation was detected in 5 families, with three compound heterozygotes and 2 homozygotes, probably reflecting the Caucasain incursion in the past.
The overall incidence of GJB2 mutations in the study cohort of 320 Indian families was observed to be 22.5%, with a regional variation from 15.4% in Maharashtra to upto 36% in Kerala. However, this may be biased as the number of families studied in Kerala were only 25. Apparently, North India seemed to have a lower prevalence of biallelic W24X mutations. Also W77X and Q124X appeared to be more common in the North. Again the number of families studied were only 42, hence it may not be a true representative of the population. Conversely, W24X allele was the predominant mutation in the GJB2 gene in the southern states of Tamilnadu, Karnataka, Kerala and Andhra Pradesh.
Other Deafness genes in Indian families
Other deafness genes segregating non-syndromic/syndromic autosomal recessive inheritance, contributed to 15% of genetic cause of deafness in India. In order of precedence, the genes associated with deafness in Indian families that were identified in the study were (1) Myo7A, segregating with Ush1B, in the DFNB2 interval on chromosome 11q13.5, (2) Myo 15 (DFNB3) on chromosome 17p11.2. (3) SLC26A4 (DFNB4) on 7q31, also cause of Pendred syndrome, (4)TMC1 gene (DFNB7/11)on chromosome 9q13,, (5) OTOF located in DFNB9 interval on chromosome 2p22-23, 6) Cadherin 23(DFNB12) on chromosome 10q21-q22 segregating with Ush1D , 7) Harmonin (DFNB18) on 11p14-15.1, also causing Ush1C,, and 8) Protocadherin 15 (DFNB23) underlying Ush1F syndrome.
It may be noted that many genes segregating non-syndromic deafness overlap Usher syndrome, type1, which are of 3 types clinically but very heterogenous at the molecular level. Seven loci for Usher type1 have been identified, but only five causative genes have been mapped. Usher syndrome is the second most common cause of deafness after the GJB2 gene.
The GJB2 gene, along with the other genes identified in Indian families account for approximately 40% of the molecular causes of deafness in India, indicating there are several more genes involved in the causation of deafness that need to be unfolded. There is a need to define the magnitude of the problem in India, in view of our large population and social custom of consanguineous marriages among many communities. There is a need for awareness and accurate genetic counseling to high-risk families, for which it is necessary to establish genetic testing of ‘at risk’ couples for the common deafness mutations prevalent in the ethnic population. Newborn screening has been proposed in some countries with high prevalence of GJB2 gene mutations, as early diagnosis would enable better medical management and therapeutic options. As Retimitis Pigmentosa develops usually in the 2nd decade, families with Usher syndrome are often mistaken for non-syndromic deafness. Hence, a thorough clinical history, ophthalmologic evaluation and follow up is mandatory for those at risk of this disorder.
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