Global genetic insight contributed by consanguineous Pakistani families segregating hearing loss

Abstract

Consanguineous Pakistani pedigrees segregating deafness have contributed decisively to the discovery of 31 of the 68 genes associated with nonsyndromic autosomal recessive hearing loss (HL) worldwide. In this study, we utilized genome-wide genotyping, Sanger and exome sequencing to identify 163 DNA variants in 41 previously reported HL genes segregating in 321 Pakistani families. Of these, 71 (43.6%) variants identified in 29 genes are novel. As expected from genetic studies of disorders segregating in consanguineous families, the majority of affected individuals (94.4%) are homozygous for HL-associated variants, with the other variants being compound heterozygotes. The five most common HL genes in the Pakistani population are SLC26A4, MYO7A, GJB2, CIB2 and HGF, respectively. Our study provides a profile of the genetic etiology of HL in Pakistani families, which will allow for the development of more efficient genetic diagnostic tools, aid in accurate genetic counseling and guide application of future gene-based therapies. These findings are also valuable in interpreting pathogenicity of variants that are potentially associated with HL in individuals of all ancestries. The Pakistani population, and its infrastructure for studying human genetics, will continue to be valuable to gene discovery for HL and other inherited disorders.

Delineation of Homozygous Variants Associated with Prelingual Sensorineural Hearing Loss in Pakistani Families

“…Similar to our previous studies [25,26], we also found intrafamilial locus and clinical heterogeneity, as some deaf relatives in other branches of family GCNF21 were not segregating the same hearing loss-causal variant (Figure 1). Furthermore, the two affected individuals (V:6,VI:3) homozygous for the variant identified in KCNE1 also had long QT intervals in addition to hearing loss, while the other two affected individuals (IV:5,VI:5) had epilepsy and deafness.…”

Noncoding microdeletion in mouseHgfdisrupts neural crest migration into the stria vascularis, reduces the endocochlear potential and suggests the neuropathology for human nonsyndromic deafness DFNB39

“…By convention the deletion is annotated as the second copy (http://varnomen.hgvs.org/). The location of the 3bp deletion (TGA, short red underline) is the first unambiguous sequence deleted and is also a recessive variant associated with DFNB39 nonsyndromic deafness segregating in numerous human families (Schultz et al, 2009; Richard et al, 2019). E , Schematic gene structures of mouse Hgf/SF , Hgf/NK1 and Hgf/NK0.5 showing the locations of RT-PCR primers.…”

“…Sensorineural deafness segregating as a recessive trait in several families was genetically mapped to human chromosome 7q11.22-q21.12, and designated the DFNB39 locus (Wajid et al, 2003). Sanger sequencing of all genes in the smallest obligate genetic linkage interval revealed 3 base pair (bp) and 10bp deletions in intron 5 of HGF in numerous families segregating nonsyndromic deafness (Schultz et al, 2009; Richard et al, 2019) (Fig. 1 C,D ).…”

Novel Loss-of-Function Mutations inCOCHCause Autosomal Recessive Nonsyndromic Deafness

“…Probands A-C underwent comprehensive genetic testing to screen all known genes implicated in NSHL, common NSHL mimics, and common syndromic forms of deafness using the OtoSCOPE® panel as described [11][12][13][14] . Similarly, a proband from family PKMR266 underwent genetic testing as described 15,16 .…”

“…Bioinformatic and variant analysis were also completed as described [13][14][15] . In brief, after mapping of raw sequence reads and variant calling, variants were annotated and filtered based on quality (depth >5 and call quality >30), minor allele frequency (MAF) <2% in Genome Aggregation Database (gnomAD) 17 and variant effect (missense, nonsense, indel or splice-site).…”