Global Distribution of Founder Variants Associated with Non-Syndromic Hearing Impairment

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.

Keywords: founder variant; gab junction beta 2 (GJB2); genetics; global populations; hearing impairment; non-syndromic.

Figure 1

Standard information retrieval chart. The schematic flow illustrates extracted article screening and selection for data extraction, synthesis, and analysis.

Figure 2

Distribution profile of NSHI-associated genes with founder variants; (A) A bar chart showing the distribution of publications retrieved per year range reporting NSHI-associated P/LP founder variants between 1998 and 2022. (B) A network of reported genes with the mutations plotted against continents from which the mutations were reported. The continents denote the nodes on the left and nodes on the right represent the individual genes harboring the PLP reported founder mutations. The thick blue line depicts GJB2 as the gene with most reported mutations across the continents. The network was constructed using the Gephi software. (C) Genotyping methods were used to investigate founder mutations for common ancestor or haplotype sharing in individuals segregating the ethnic- and population-specific PLP NSHI founder mutations. At least one of the methods listed was used for the genotype analysis in each of the studies reviewed: Sanger Seq = Sanger sequencing, SSCP = Single-strand conformational polymorphism analysis, Array = Affymetrix GeneChip Array, Otoscope = OtoSCOPE platform, AS-PCR = Allele-specific polymerase chain reaction, PCR-RFLP = Polymerase chain reaction-restriction fragment length polymorphisms, ARMS-PCR = Amplification-refractory mutation system, WES = Whole exome sequencing, PCR-DHPLC = Polymerase chain rection Denaturing High Performance Liquid Chromatography, and Duplex, and PCR = Duplex polymerase chain reaction. (D) A bar chart of the distribution of reviewed articles by continents.

Figure 3

A global map showing countries that reported at least one gene with P/LP founder variant in NSHI. Ethnic- and country-specific reported NSHI founder mutations are depicted with blue dots, with the reported genes and mutations listed in specific countries, respectively. The map was created using Tableau Software [73]. * = number of times variant has been reported as founder.

Figure 4

Reported variant classification. (A) ClinVar classification of the reported founder variants. (B) American College of Medical Genetics and Genomics (ACMG) and Association of Medical Pathology (AMP) guideline classification of reported founder variants. (C) A pie chart showing the different genes and proportions reported for NSHI founder mutations. (D) The number, proportions, and types of variants reported. (E) ClinVar and ACMG/AMP proportions compared. P = Pathogenic; LP = Likely pathogenic; B = Benign; LB = Likely benign; US = Uncertain significance; and NR = Not reported. Note: (A) and (B) were normalized by adding “+1” to all values obtained for each category to obtained consistent color coding of sections.