ARNSHL gene identification: past, present and future

• Published in: Molecular genetics and genomics : MGG 2022-09, Vol.297 (5), p.1185-1193
• Main Author: Imtiaz, Ayesha
• Format: Article
• Language: English
• Subjects: Animal Genetics and Genomics; Biochemistry; Biomedical and Life Sciences; Cochlea; Deafness; Etiology; Gene loci; Gene mapping; Genetic analysis; Genetic screening; Genotyping; Hearing loss; Human Genetics; Life Sciences; Localization; Microbial Genetics and Genomics; Mutation; Plant Genetics and Genomics; Review; Single-nucleotide polymorphism
• ISSN: 1617-4615; 1617-4623
• DOI: 10.1007/s00438-022-01926-x

Autosomal recessive non-syndromic hearing loss (ARNSHL) is the most common hereditary deafness. It is genetically highly heterogeneous and about 89 gene loci and 76 gene’s mutations have been implicated in the etiology of ARNSHL. Molecular basis of ARNSHL remains unresolved in 60% of cases and gene mutations are unknown for 23 of 89 reported loci. Techniques used to identify reported ARNSHL gene mutations can be divided into position-dependent and position-independent approaches. The localization of the loci has been facilitated by homozygosity mapping or linkage studies using STR or SNP genotyping in large consanguineous families. First few genes identified for hearing loss exhibited such wide diversity of function and expression patterns that candidate gene approach was not a viable option. The mapping of the disorder to a chromosomal location has been followed by Sanger sequencing of all genes in the target region or confining of the massively parallel sequencing data analyses to the linkage region. Sometimes genes located in the linkage interval were prioritized because there was a reported orthologs with mutations causing hearing loss in mouse or when mutations in the gene caused a related disorder. Position-independent approaches involving use of mouse subtractive cochlear libraries, forward genetic screening, and position-independent analyses of massively parallel sequencing data have helped identify 17 of 68 reported ARNSHL gene mutations. A thorough study of the strategies used in the identification of reported ARNSHL genes and of their relative success can help increase the success rate of future studies.