Global Distribution of Founder Variants Associated with Non-Syndromic Hearing Impairment
Date
2023
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
MDPI
Abstract
The genetic etiology of non-syndromic hearing impairment (NSHI) is highly heterogeneous
with over 124 distinct genes identified. The wide spectrum of implicated genes has challenged
the implementation of molecular diagnosis with equal clinical validity in all settings. Differential
frequencies of allelic variants in the most common NSHI causal gene, gap junction beta 2 (GJB2), has
been described as stemming from the segregation of a founder variant and/or spontaneous germline
variant hot spots. We aimed to systematically review the global distribution and provenance of
founder variants associated with NSHI. The study protocol was registered on PROSPERO, the International
Prospective Register of Systematic Reviews, with the registration number “CRD42020198573”.
Data from 52 reports, involving 27,959 study participants from 24 countries, reporting 56 founder
pathogenic or likely pathogenic (P/LP) variants in 14 genes (GJB2, GJB6, GSDME, TMC1, TMIE,
TMPRSS3, KCNQ4, PJVK, OTOF, EYA4, MYO15A, PDZD7, CLDN14, and CDH23), were reviewed.
Varied number short tandem repeats (STRs) and single nucleotide polymorphisms (SNPs) were used
for haplotype analysis to identify the shared ancestral informative markers in a linkage disequilibrium
and variants’ origins, age estimates, and common ancestry computations in the reviewed
reports. Asia recorded the highest number of NSHI founder variants (85.7%; 48/56), with variants
in all 14 genes, followed by Europe (16.1%; 9/56). GJB2 had the highest number of ethnic-specific
P/LP founder variants. This review reports on the global distribution of NSHI founder variants
and relates their evolution to population migration history, bottleneck events, and demographic
changes in populations linked with the early evolution of deleterious founder alleles. International
migration and regional and cultural intermarriage, coupled to rapid population growth, may have
contributed to re-shaping the genetic architecture and structural dynamics of populations segregating
these pathogenic founder variants. We have highlighted and showed the paucity of data on hearing
impairment (HI) variants in Africa, establishing unexplored opportunities in genetic traits.
Description
Research Article
Keywords
hearing impairment, non-syndromic, gab junction beta 2 (GJB2)
Citation
Aboagye, E.T.; Adadey, S.M.;Wonkam-Tingang, E.; Amenga-Etego, L.; Awandare, G.A.; Wonkam, A. Global Distribution of Founder Variants Associated with Non-Syndromic Hearing Impairment. Genes 2023, 14, 399. https://doi.org/ 10.3390/genes14020399