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.

Molecular diagnosis of non-syndromic hearing loss patients using a stepwise approach

“…The most common mutations in many populations are in the GJB2 gene, which encodes the connexin 26 protein, and cause severe-to-profound autosomal recessive NSHL 1 , 5 . Sanger sequencing of GJB2 was therefore performed in previous studies 6 , 7 . In the Saudi population, the OTOF gene, rather than GJB2 , was revealed to be a major and potential contributor to hearing loss 7 .…”

Auditory Neuropathy Spectrum Disorder due to Two Novel Compound Heterozygous OTOF Mutations in Two Chinese Families

“…As the mutation spectrum of the OTOF gene shows great discrepancies between different countries and ethnic populations, including high frequencies of the mutation p.E1700Q in Chinese from Taiwan [5], p.R1939Q in Japanese [6, 17], p.Val1778Phe in Ashkenazi Jewish [18], Q829X in Spanish [19], c.2905-2923delinsCTCCGAG-CGCA in Argentinean [9], and p.R1792H in Saudi Arabian [20], understanding of the molecular mechanism of ANSD needs to be improved. Here, we report two novel compound heterozygous OTOF mutations in different Chinese families, which provide more information about the etiology of ANSD at the molecular level.…”

A splice-site variant (c.3289-1G>T) in OTOF underlies profound hearing loss in a Pakistani kindred

“…Previous studies have also shown that OTOF mutation causes profound hearing loss. In a recent cohort study, OTOF was found to contribute most to AR hearing loss in the Saudi Arabian population, responsible for 21.1% (7/11) of cases in the study population [4]. Wang et al also reported that OTOF mutations cause mild, moderate, or profound hearing loss [2].…”

“…Hearing loss is characterized by any degree (mild, moderate, severe, or profound) of loss of the ability to hear that can occur at any stage of life [1,2]. Congenital hearing loss is the fourth highest cause of disability globally with a prevalence ranging from 0.2 to 1% among newborns worldwide [3,4]; currently, there are approximately 466 million people with hearing loss [5]. In Pakistan, hereditary deafness covers 70% of cases, and autosomal recessive hearing impairment accounts most due to the high rate of consanguineous marriages [6].…”