EPS8L2 is a new causal gene for childhood onset autosomal recessive progressive hearing loss

Abstract

BackgroundMore than 70 % of the cases of congenital deafness are of genetic origin, of which approximately 80 % are non-syndromic and show autosomal recessive transmission (DFNB forms). To date, 60 DFNB genes have been identified, most of which cause congenital, severe to profound deafness, whereas a few cause delayed progressive deafness in childhood. We report the study of two Algerian siblings born to consanguineous parents, and affected by progressive hearing loss.MethodAfter exclusion of GJB2 (the gene most frequently involved in non-syndromic deafness in Mediterranean countries), we performed whole-exome sequencing in one sibling.ResultsA frame-shift variant (c.1014delC; p.Ser339Alafs*15) was identified in EPS8L2, encoding Epidermal growth factor receptor Pathway Substrate 8 L2, a protein of hair cells’ stereocilia previously implicated in progressive deafness in the mouse. This variant predicts a truncated, inactive protein, or no protein at all owing to nonsense-mediated mRNA decay. It was detected at the homozygous state in the two clinically affected siblings, and at the heterozygous state in the unaffected parents and one unaffected sibling, whereas it was never found in a control population of 150 Algerians with normal hearing or in the Exome Variant Server database.ConclusionWhole-exome sequencing allowed us to identify a new gene responsible for childhood progressive hearing loss transmitted on the autosomal recessive mode.

Navigating genetic diagnostics in patients with hearing loss

“…Each year, more genes are implicated in hearing loss, most of which are identified using WES (Reviewed through 2014 in[49], [4–17,18*]). These discoveries mean that a targeted panel must be regularly updated to be comprehensive.…”

“…In 2015 and the first half of 2016, for instance, 14 additional genes were identified as causing NSHL in humans [4–17,18*], increasing the number of NSHL genes to nearly 100 (http://www.hereditaryhearingloss.org). Prior to TGE+MPS, the best genetic diagnosis for NSHL required serial gene-by-gene Sanger sequencing, a constraint that made comprehensive diagnostic testing prohibitively slow and expensive.…”

Molecular Analysis of Twelve Pakistani Families with Nonsyndromic or Syndromic Hearing Loss

“…Because the frameshift mutations in MYO7A (c. 4184dupA [p. Gln1395Thrfs*9]) and EPS8 L2 (c.737delC [p. Ala246Alafs* 6]) produce stop codons in the middle of the two genes, they may activate NMD pathways and could conceivably underlie the pathogenesis of hearing loss through a loss-of-function mechanism (Dahmani et al, 2015). With respect to the nonsense mutations in ESPN (c. 2519G > A [p. Trp840*]) and PCDH15 (c. 4726 C > T [p. Gln1576*]) that are located in the last exons of both genes, these mutant mRNAs might escape degradation by the NMD pathway and are predicted to result in truncation of the encoded proteins.…”

Growth factor and receptor malfunctions associated with human genetic deafness

“…60 The epidermal growth factor receptor pathway substrate 8 (EPS8) and epidermal growth factor receptor pathway substrate 8-like protein 2 (EPS8L2) are also required for hearing. 61,62 EPS8 is part of N-methyl-d-aspartate (NMDA) receptor complex, 63 which controls transduction of signals from RAS to RAC. EPS8L2 acts by stimulating RAC (GTPase)-guanine nucleotide exchange factor activity of SOS1.…”

“…In the inner ear, EGFR signaling is important for proliferation of supporting cells . The epidermal growth factor receptor pathway substrate 8 (EPS8) and epidermal growth factor receptor pathway substrate 8‐like protein 2 (EPS8L2) are also required for hearing . EPS8 is part of N‐methyl‐d‐aspartate (NMDA) receptor complex, which controls transduction of signals from RAS to RAC.…”