Exome sequencing reveals novel variants and unique allelic spectrum for hearing impairment in Filipino cochlear implantees

Abstract

To the Editor: Genetic hearing impairment is mostly non-syndromic (80%), and >6000 causal variants in >100 genes have been identified. Generally, in hearing-impaired patients of Asian descent, GJB2 variants are most common (36%), followed by variants in SLC26A4 (MIM 605646), MYO15A (MIM 602666) and CDH23 (MIM 605516). Here, we report seven novel variants in Filipino cochlear implantees, suggesting that the allelic spectrum for non-/syndromic hearing impairment in Filipinos is unique. The UP Manila Research Ethics Board approved the study. Adult subjects and parents of pediatric patients provided informed consent. DNA samples and clinical data were obtained from 30 cochlear implantees with bilateral, severe-to-profound, congenital, non-progressive hearing loss as previously described. After excluding one patient with GJB2 c.[35delG];[235delC], 29 DNA samples were submitted for exome sequencing, of which four are homozygous for SLC26A4 c.706C>G (p.(Leu236Val)). For the 25 GJB2-/SLC26A4negative patients, homozygous/heterozygous coding variants within 132 non-/syndromic hearing impairment genes were selected if with minor allele frequency (MAF) < 0.005 in any gnomAD population. Rare variants were selected further if considered damaging by MutationTaster (www.mutationtaster.org) and/or ≥2 dbNSFP (sites.google. com/site/jpopgen/dbNSFP) tools. Eleven Filipino-descent US families with no history of hearing impairment were ascertained for MAF estimation for speech delay (SDFIL) and were Sanger-sequenced for selected exome variants. Variants with zero MAF in the SDFIL cohort were then screened using samples from ≥88 unrelated Filipinos from the Cebu Longitudinal Health and Nutrition Survey, a cohort examined for various health outcomes. Screened exome variants were excluded due to increased MAF, lack of a second rare variant in an autosomal recessive gene and/or poor clinical correlation. Of 30 Filipino cochlear implantees, we identified a genetic cause in half. Seven novel hearing loss variants were discovered (Table 1): CHD7 (MIM 608892) c.7312C>G (p.(Gln2438Glu)); COL4A3 (MIM 120070) c.764C>T (p.(Thr255Met)); DFNA5 (MIM 600994) c.1277_1279delATG (p.(Asp426del)); EYA4 (MIM 603550) c.1109G>A (p.(Arg370His)); MYH14 (MIM 608568) c.2971G>A (p.(Glu991Lys)); MYO15A c.263C>T (p.(Thr88Met)); and OTOA (MIM 607038) c.2301 +1G>T. Patient #28 with the CHD7 variant has microcephaly and seizures, both known features of CHARGE syndrome (MIM 214800). Additionally, he has left superior semicircular canal dehiscence (SSCD) but no vertigo or dizziness. Both DFNA5 c.1277_1279delATG and EYA4 c.1109G>A were previously identified through systematic clinical genetic screening and are annotated in ClinVar (www.ncbi.nlm.nih. gov/clinvar/) as variants of unknown significance. Patient #4 with the EYA4 variant complains of dizziness and balance problems; temporal bone findings include right enlarged vestibular aqueduct and a left jugular bulb diverticulum that impinges onto the ipsilateral vestibular aqueduct. COL4A3 c.764C>T was previously reported for familial kidney disease but not hearing impairment. MYH14 c.2971G>A is cited in the Leiden Open Variation Database (www.lovd.nl/3.0/) as likely benign but was not clarified for non-syndromic DFNA4A (MIM 600652) or peripheral neuropathy, myopathy, hoarseness and hearing loss (PNMHH; MIM 614369). ThisMYH14 variant is the only rare, damaging variant identified in patient #26, who has developmental delay and left foot inversion. Variants CDH23 c.68-3C>T and c.4762C>T (p.(Arg1588Trp)), KCNQ4 (MIM 603537) c.546C>G (p.(Phe182Leu)), and WFS1 (MIM 606201) c.708C>G (p.(Ser236Arg)) have been previously reported for hearing impairment. Patient #10 with the KCNQ4 variant has SSCD on the left but no vestibular symptoms. WFS1 c.708C>G was reported in a patient with compound heterozygous WFS1 variants and autosomal recessive Wolfram syndrome (MIM 222300). Patient #16 has no second WFS1 coding variant but has birth history of cord coil, white matter disease and mild motor delay. Clinical data helped identify the correct gene when multiple potentially causal variants were present. Patients with pathogenic variants had higher pre-surgical audiometric thresholds at ≥1 kHz (Wilcoxon P < 0.05). However, there was no significant difference in post-surgical thresholds, suggesting that carriage of the genetic variants reported here does not determine the outcome of cochlear implantation, with average implant-aided hearing at 38 dB across frequencies. Therefore for carriers of these variants, cochlear implantation remains an excellent option for rehabilitation. Received: 11 December 2018 Revised: 18 January 2019 Accepted: 23 January 2019 DOI: 10.1111/cge.13515