Abstract
Mutations in connexins are the most common causes of hearing impairment (HI) in many populations. Our aim was to review the global burden of pathogenic and likely pathogenic (PLP) variants in connexin genes associated with HI. We conducted a systematic review of the literature based on targeted inclusion/exclusion criteria of publications from 1997 to 2020. The databases used were PubMed, Scopus, Africa-Wide Information, and Web of Science. The protocol was registered on PROSPERO, the International Prospective Register of Systematic Reviews, with the registration number “CRD42020169697”. The data extracted were analyzed using Microsoft Excel and SPSS version 25 (IBM, Armonk, New York, United States). A total of 571 independent studies were retrieved and considered for data extraction with the majority of studies (47.8% (n = 289)) done in Asia. Targeted sequencing was found to be the most common technique used in investigating connexin gene mutations. We identified seven connexin genes that were associated with HI, and GJB2 (520/571 publications) was the most studied among the seven. Excluding PLP in GJB2, GJB6, and GJA1 the other connexin gene variants (thus GJB3, GJB4, GJC3, and GJC1 variants) had conflicting association with HI. Biallelic GJB2 PLP variants were the most common and widespread variants associated with non-syndromic hearing impairment (NSHI) in different global populations but absent in most African populations. The most common GJB2 alleles found to be predominant in specific populations include; p.Gly12ValfsTer2 in Europeans, North Africans, Brazilians, and Americans; p.V37I and p.L79Cfs in Asians; p.W24X in Indians; p.L56Rfs in Americans; and the founder mutation p.R143W in Africans from Ghana, or with putative Ghanaian ancestry. The present review suggests that only GJB2 and GJB3 are recognized and validated HI genes. The findings call for an extensive investigation of the other connexin genes in many populations to elucidate their contributions to HI, in order to improve gene-disease pair curations, globally.
Highlights
Hearing impairment (HI) is the most common sensorineural disability worldwide, with a global prevalence of 1.3 per 1000 population [1,2]
Using a systematic review approach, we provided summary data on connexin gene variants associated with HI, and the global contribution of connexin genes to non-syndromic HI (NSHI)
We identified a cocktail of methods used by the researchers to investigate connexin gene variants in hearing-impaired patient samples
Summary
Hearing impairment (HI) is the most common sensorineural disability worldwide, with a global prevalence of 1.3 per 1000 population [1,2]. It occurs in about 1 per 1000 live births in high-income countries, with a much higher incidence of up to 6 per 1000 in the lower-income countries [3]. If there are no other distinguishing clinical findings, HI is classified as non-syndromic [6]. About 80% of non-syndromic HI (NSHI) cases are inherited in an autosomal recessive mode, while an autosomal dominant pattern of inheritance is observed in 18% of cases [7]. In the remaining 2% of cases, the mode of inheritance is either X-linked or mitochondrial [7]
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