Recurrent variants in OTOF are significant contributors to prelingual nonsydromic hearing loss in Saudi patients

Abstract

PurposeHearing loss is more prevalent in the Saudi Arabian population than in other populations; however, the full range of genetic etiologies in this population is unknown. We report the genetic findings from 33 Saudi hearing-loss probands of tribal ancestry, with predominantly prelingual severe to profound hearing loss.MethodsTesting was performed over the course of 2012-2016, and involved initial GJB2 sequence and GJB6-D13S1830 deletion screening, with negative cases being reflexed to a next-generation sequencing panel with 70, 71, or 87 hearing-loss genes.ResultsA "positive" result was reached in 63% of probands, with two recurrent OTOF variants (p.Glu57* and p.Arg1792His) accountable for a third of all "positive" cases. The next most common cause was pathogenic variants in MYO7A and SLC26A4, each responsible for three "positive" cases. Interestingly, only one "positive" diagnosis had a DFNB1-related cause, due to a homozygous GJB6-D13S1830 deletion, and no sequence variants in GJB2 were detected.ConclusionOur findings implicate OTOF as a potential major contributor to hearing loss in the Saudi population, while highlighting the low contribution of GJB2, thus offering important considerations for clinical testing strategies for Saudi patients. Further screening of Saudi patients is needed to characterize the genetic spectrum in this population.

Figure 1

Schematic diagram of the genetic testing strategy used to identify causal variants in Saudi patients with prelingual sensorineural hearing loss (SNHL). CNVs, copy-number variants; ddPCR, droplet digital PCR; indels, insertions and/deletions; NGS, next-generation sequencing.

Figure 2

Regional distribution of the Saudi families with a “positive” genetic testing result in our cohort. For families with a nonrecurring variant, family IDs are shown in red near the province (in white) of their current place of residence. The family IDs of the recurrent p.Glu57* and p.Arg1792His variants are shown in dark blue and yellow, respectively.

Figure 3

Diagnostic rate and distribution of variants across genes in 33 Saudi sensorineural hearing loss probands. (a) Counts of total variants across hearing loss genes by classification. (b) Diagnostic rate of DFNB1 screening/OtoGenome NGS panel testing for this cohort (c). Gene contribution of causative variants in “positive” probands. LP/P: likely pathogenic/pathogenic variant; VUS, variant of uncertain significance.

Figure 4

Pedigrees for Saudi families with clinically significant variants or suspect VUS variants (F-14). The OtoGenome panel version used for proband testing is shown below the pedigree. For Family F-30, a causative variant (GJB6-D13S1830) was identified on the initial DFNB1 assay. Please note that the parents in in families F-8, F-9, F-21, F-25, F-26, F-27, F-30, F-31, F-33 were not tested and represent obligate carriers (see Supplementary Table 1 for a list of all family members who were screened for familial variants). Het, heterozygous; Hom, homozygous.