Omics-based approaches for the identification of novel inherited non-syndromic sensorineural hearing loss-related genes

Nonsyndromic Sensorineural hearing loss (NSHL) is the most common sensory disorder in humans, affecting about 278 million people worldwide, with severe consequences on public health. More than 50 genes have been associated with NSHL but many others are still to be discovered. This project aims at identifying new genetic defects underlying NSHL by 2 parallel approaches, both based on the tremendous power of next-generation sequencing (NGS) technologies, which allow the simultaneous analysis of a large fraction of the genome. The first is to explore the pathogenic role of mutations in a particular class of genetic elements called microRNAs (miRNAs). A recent study identified 2 mutations within a specific miRNA (miR-96), as the cause of NSHL. We searched for mutations in this gene in a large number of Italian deaf patients and normal-hearing controls, identifying at least one novel causative mutation in the MIR96 gene. Understanding how perturbation of miR-96 function lead to hearing impairment, in particular identifying the genes dysregulated by mutations in MIR96, through the use of NGS, may lead to the identification of novel disease-causing genes. The second strategy will use NGS to sequence the entire coding portion of the genome in selected families showing a clear autosomal recessive transmission. These families are particularly useful because affected members are expected to have a mutation in the 2 copies (alleles) of one same gene, facilitating the discovery of true pathogenic mutations. Genes and mutations identified by both strategies will be validated by functional studies in human cell lines, in zebrafish (a tropical fish, which is an important model organism in scientific research) and in mouse. Hopefully, this project will allow the further elucidation of the genetic defects and molecular mechanisms underlying the pathogenesis of hereditary NSHL, as well as lead to the identification of new therapeutic targets for treating inherited deafness.