Diversity of the causal genes in hearing impaired Algerian individuals identified by whole exome sequencing

Abstract

The genetic heterogeneity of congenital hearing disorders makes molecular diagnosis expensive and time-consuming using conventional techniques such as Sanger sequencing of DNA. In order to design an appropriate strategy of molecular diagnosis in the Algerian population, we explored the diversity of the involved mutations by studying 65 families affected by autosomal recessive forms of nonsyndromic hearing impairment (DFNB forms), which are the most prevalent early onset forms. We first carried out a systematic screening for mutations in GJB2 and the recurrent p.(Arg34*) mutation in TMC1, which were found in 31 (47.7%) families and 1 (1.5%) family, respectively. We then performed whole exome sequencing in nine of the remaining families, and identified the causative mutations in all the patients analyzed, either in the homozygous state (eight families) or in the compound heterozygous state (one family): (c.709C>T: p.(Arg237*)) and (c.2122C>T: p.(Arg708*)) in OTOF, (c.1334T>G: p.(Leu445Trp)) in SLC26A4, (c.764T>A: p.(Met255Lys)) in GIPC3, (c.518T>A: p.(Cys173Ser)) in LHFPL5, (c.5336T>C: p.(Leu1779Pro)) in MYO15A, (c.1807G>T: p.(Val603Phe)) in OTOA, (c.6080dup: p.(Asn2027Lys*9)) in PTPRQ, and (c.6017del: p.(Gly2006Alafs*13); c.7188_7189ins14: p.(Val2397Leufs*2)) in GPR98. Notably, 7 of these 10 mutations affecting 8 different genes had not been reported previously. These results highlight for the first time the genetic heterogeneity of the early onset forms of nonsyndromic deafness in Algerian families.

A novel biallelic splice site mutation of TECTA causes moderate to severe hearing impairment in an Algerian family

“…we selected a family based on the auditory phenotype of the three affected siblings (IV.1, IV.2, and IV.3), who were affected by prelingual, symmetric, moderate to severe hearing impairment, with audiograms showing down-sloping curves ( Figure 1C). We did not detect mutations in LRTOMT, OTOF, and TMC1, three DFNB genes previously shown to be involved in Maghrebian populations (11)(12)(13)(14), by Sanger sequencing of the coding exons in patient IV.1. We therefore carried out whole-exome sequencing on pooled genomic DNA from two affected siblings, as previously described (7).…”

Mutational Spectrum ofMYO15Aand the Molecular Mechanisms of DFNB3 Human Deafness

“…[Ammar‐Khodja et al., ], [Atik et al., ], [Bademci et al., ],[Bashir et al., ], [Belguith et al., ], [Brownstein et al., ], [Brownstein et al., ], [Cengiz et al., ], [Chang et al., ], [Chen et al., ], [Diaz‐Horta et al., ], [Duman et al., ], [Fattahi et al., ], [Gao et al., ], [Gu et al., ], [Imtiaz et al., ], [Kalay et al., ], [Lezirovitz et al., ], [Li et al., ], [Liburd et al., ], [Miyagawa et al., ; Miyagawa et al., ], [Miyagawa et al., ], [Moteki et al., ], [Nal et al., ], [Neveling et al., ], [Park et al., ], [Rehman et al., ], [Riahi et al., ], [Schrauwen et al., ], [Shafique et al., ], [Shahin et al., ], [Shearer et al., ], [Sloan‐Heggen et al., ], [Sloan‐Heggen et al., ], [Vona et al., ], [Vozzi et al., ], [Wang et al., ], [Woo et al., ], [Xia et al., ], [Yano et al., ], [Yang et al., ]…”

Genetic causes of moderate to severe hearing loss point to modifiers

“…It has been stated that PTPRQ mutations show weak evidence for association to deafness . However, different studies and the frameshift variant identified in three affected cousins in a participating family in our research (Table ) together establish PTPRQ as a bona fide deafness gene.…”