Genomic analysis of inherited hearing loss in the Palestinian population

Abstract

The genetic characterization of a common phenotype for an entire population reveals both the causes of that phenotype for that place and the power of family-based, population-wide genomic analysis for gene and mutation discovery. We characterized the genetics of hearing loss throughout the Palestinian population, enrolling 2,198 participants from 491 families from all parts of the West Bank and Gaza. In Palestinian families with no prior history of hearing loss, we estimate that 56% of hearing loss is genetic and 44% is not genetic. For the great majority (87%) of families with inherited hearing loss, panel-based genomic DNA sequencing, followed by segregation analysis of large kindreds and transcriptional analysis of participant RNA, enabled identification of the causal genes and mutations, including at distant noncoding sites. Genetic heterogeneity of hearing loss was striking with respect to both genes and alleles: The 337 solved families harbored 143 different mutations in 48 different genes. For one in four solved families, a transcription-altering mutation was the responsible allele. Many of these mutations were cryptic, either exonic alterations of splice enhancers or silencers or deeply intronic events. Experimentally calibrated in silico analysis of transcriptional effects yielded inferences of high confidence for effects on splicing even of mutations in genes not expressed in accessible tissue. Most (58%) of all hearing loss in the population was attributable to consanguinity. Given the ongoing decline in consanguineous marriage, inherited hearing loss will likely be much rarer in the next generation.

Variants in CDH23 cause a broad spectrum of hearing loss: from non-syndromic to syndromic hearing loss as well as from congenital to age-related hearing loss

“…To date, more than 190 pathologic variants have been reported for the Usher phenotype and 200 pathologic variants for the non-syndromic hearing loss phenotype (DFNB12) (Stenson et al 2003). CDH23-related hearing loss has been reported in many countries with diverse ethnic backgrounds, including Cuba (Bolz et al 2001), Germany (Bolz et al 2001), Japan (Wagatsuma et al 2007;Miyagawa et al 2012;Mizutari et al 2015), Korea (Kim et al 2015(Kim et al , 2016, China (Lu et al 2014), India (Bork et al 2001;Ganapathy et al 2014;Vanniya et al 2018), Pakistan (Bork et al 2001;Park et al 2020), Saudi Arabia (Ramzan et al 2020), Iran (Zardadi et al 2020), Qatar (Alkowari et al 2017), Turkey (Atik et al 2015), Israel (Ashkenazi, Mizurahi, Sephardi) (Brownstein et al 2011), Palestine (Abu Rayyan et al 2020) and the Netherlands (Seco et al 2017).…”

Identification of the First Single GSDME Exon 8 Structural Variants Associated with Autosomal Dominant Hearing Loss

“…In the context of molecular genetic testing, gene panel sequencing using MPS is a powerful strategy to identify causal variants, including single-nucleotide variants, insertions, deletions or CNVs in patients referred for NSHL [ 20 , 21 , 22 ]. Custom computational tools have been successfully used to detect CNVs in hearing gene panels [ 15 , 21 , 23 ], but detection of true single-exon or partial exon deletions is still challenging.…”

Case Report: Novel Compound Heterozygous Variants in TRIOBP Associated With Congenital Deafness in a Chinese Family

“…TRIOBP various is rare in HL patients. There are 45 disease-related variants have been reported in the TRIOBP at present ( Hashem et al, 2006 ; Saima et al, 2006 ; Maiko et al, 2013 ; Shearer et al, 2014 ; Christina et al, 2016 ; Denise et al, 2016 ; Manou et al, 2016 ; Agnieszka et al, 2017 ; Celia et al, 2017 ; Daniel et al, 2017 ; Haiqiong et al, 2018 ; Elodie et al, 2019 ; Songfeng et al, 2019 ; Yan et al, 2019 ; Amal et al, 2020 ; Birgit et al, 2020 ; Yongyi et al, 2020 ), with HL being the only phenotypic manifestation. As presented in Table 1 , although the variants cover the region from exon 4 to exon 23, most of the previously reported variations in TRIOBP are located in exon 7.…”