Diagnostic outcomes of exome sequencing in patients with syndromic or non-syndromic hearing loss

Abstract

Hereditary hearing loss (HL) is a common sensory disorder, with an incidence of 1–2 per 1000 newborns, and has a genetic etiology in over 50% of cases. It occurs either as part of a syndrome or in isolation and is genetically very heterogeneous which poses a challenge for clinical and molecular diagnosis. We used exome sequencing to seek a genetic cause in a group of 56 subjects (49 probands) with HL: 32 with non-syndromic non-GJB2 HL and 17 with syndromic HL. Following clinical examination and clinical exome sequencing, an etiological diagnosis was established in 15 probands (15/49; 30%); eight (8/17;47%) from the syndromic group and seven (7/32; 21%) from the non-syndromic non-GJB2 subgroup. Fourteen different (half of them novel) non-GJB2 variants causing HL were found in 10 genes (CHD7, HDAC8, MITF, NEFL, OTOF, SF3B4, SLC26A4, TECTA, TMPRSS3, USH2A) among 13 probands, confirming the genetic heterogeneity of hereditary HL. Different genetic causes for HL were found in a single family while three probands with apparent syndromic HL were found to have HL as a separate clinical feature, distinct from the complex phenotype. Clinical exome sequencing proved to be an effective tool used to comprehensively address the genetic heterogeneity of HL, to detect clinically unrecognized HL syndromes, and to decipher complex phenotypes in which HL is a separate feature and not part of a syndrome.

A novel pathogenic variant of NEFL responsible for deafness associated with peripheral neuropathy discovered through next‐generation sequencing and review of the literature

“…Patients carrying the p.(Asn98Ser), motor and sensory neuropathy. 10 The reported audiological curves correspond to ours and could therefore be considered to be a phenotype-genotype correlation (Figure 1). We suggest that a complete audiometry test should be performed in patients who present CMT associated with these variants, as deafness may be underestimated.…”

“…Deafness has been reported in 64% of patients who presented with the p.(Glu90Lys) or p.(Asn98Ser) variants . Likar et al reported a female patient with the p.(Asn98Ser) variant who showed mild sensorineural hearing loss between 0.125 and 4 KHz, moderate hearing loss between 4 and 8 KHz, delayed motoric milestones, difficulty walking, progressive distal weakness of the lower and upper limbs, cerebellar dysfunction, and peripheral motor and sensory neuropathy . The reported audiological curves correspond to ours and could therefore be considered to be a phenotype‐genotype correlation (Figure ).…”

Hearing loss in inherited peripheral neuropathies: Molecular diagnosis by NGS in a French series

“…Pathogenic variants in NEFL responsible for CMT are rare and associated to various phenotypes. However, hearing loss is often linked to neuropathy, up to 64% of cases, especially with the pathogenic variants p.(Glu90Lys) and p.(Asn98Ser) (Likar et al, ), as it was the case in our p.(Glu90Gly) pathogenic variant. All these pathogenic variants are located in the head domain or in the two ends of the rod domain.…”

“…The seven heterozygous variants, including ours, are located on « hot spots» of the protein and seem directly linked to the hearing loss observed in the patients. A tonal audiogram with a moderate slope on the high frequencies is characteristic of variants p.(Asn98Ser) and p.(Glu90Gly) (Likar et al, ). The same audiogram was also observed in patient XIX.…”

Post-lingual non-syndromic hearing loss phenotype: a novel homozygous missense mutation in MITF

“…Up to date, over 115 genes have been linked to non-syndromic HL with GJB2, SLC26A4, MYO15A, OTOF, and CDH23 being considered as the most commonly identified genes. Some of these genes were shown to be associated with both recessive and dominant form of the disease [5] [6].…”