Exome sequencing: Defining hereditary deafness

Precise diagnosis of disease and developmental syndromes often depends on understanding the genetics underlying them. Most cases of early onset hearing loss are genetic in origin but there are many different forms. Heretofore, it has been difficult to identify the gene responsible for the hearing loss of each affected child, because the critical mutations differ among countries and populations. New research published in BioMed Central's open access journal Genome Biology has identified six critical mutations in Israeli Jewish and Palestinian Arab families. Mutations in one gene, TMC1, was found in 38% of children with genetic hearing loss in the Moroccan Jewish population.

Using targeted DNA capture and massively parallel sequencing (MPS), researchers screened 246 deafness-related genes in 11 unrelated individuals, all of whom were diagnosed with deafness that ran in their families. Once a mutation was found, the mutation was then tested in an extended series of families with hearing loss, and DNA sequences compared to those of people with normal hearing. Mutations were found in five genes -- CDH23, MYO15A, TECTA, TMC1, and WFS1. A mutation not previously observed in any family, TMC1 p.S647P, was found in 34% of people with hearing loss who are of Moroccan Jewish ancestry. This mutation was not found in deaf individuals of other ancestries. Each new mutation was specific to families of one ancestry, indeed most were private, in only to one family.

Prof Karen Avraham from Tel Aviv University explained, "Our two-tier approach allowed us to scan exons of genes, thought to be involved in hereditary deafness, and their flanking sequences. This meant that we were able to quickly target specific genes and find multiple mutations responsible for hearing loss." Prof Moein Kanaan of Bethlehem University added, "Use of genomic analysis in early clinical diagnosis of hearing loss will enable us to predict how each child's hearing loss will progress. It will also show us where to look for the biological mechanisms involved in hearing loss."

This article is part of a special Genome Biology issue focusing on exome sequencing. Sequencing is still expensive and time consuming. However exome sequencing, where only the exons of a subject are sequenced, by first capturing the DNA with relevant probes, significantly reduces the costs compared to whole genome sequencing. It allows researchers to zone in on specific sites, reducing the amount of code they need to cover, to find causative mutations.

Source : BioMed Central