Enhancing Genetic Medicine: Rapid and Cost-Effective Molecular Diagnosis for a GJB2 Founder Mutation for Hearing Impairment in Ghana.

Samuel M Adadey,Gordon A Awandare,Adwoa Asante-Poku,Darius Quansah,Elvis Twumasi Aboagye,Edmond Tingang Wonkam,Ambroise Wonkam,Geoffrey K Amedofu,Osbourne Quaye

doi:10.3390/genes11020132

Abstract

In Ghana, gap-junction protein β 2 (GJB2) variants account for about 25.9% of familial hearing impairment (HI) cases. The GJB2-p.Arg143Trp (NM_004004.6:c.427C>T/OMIM: 121011.0009/rs80338948) variant remains the most frequent variant associated with congenital HI in Ghana, but has not yet been investigated in clinical practice. We therefore sought to design a rapid and cost-effective test to detect this variant. We sampled 20 hearing-impaired and 10 normal hearing family members from 8 families segregating autosomal recessive non syndromic HI. In addition, a total of 111 unrelated isolated individuals with HI were selected, as well as 50 normal hearing control participants. A restriction fragment length polymorphism (RFLP) test was designed, using the restriction enzyme NciI optimized and validated with Sanger sequencing, for rapid genotyping of the common GJB2-p.Arg143Trp variant. All hearing-impaired participants from 7/8 families were homozygous positive for the GJB2-p.Arg143Trp mutation using the NciI-RFLP test, which was confirmed with Sanger sequencing. The investigation of 111 individuals with isolated non-syndromic HI that were previously Sanger sequenced found that the sensitivity of the GJB2-p.Arg143Trp NciI-RFLP testing was 100%. All the 50 control subjects with normal hearing were found to be negative for the variant. Although the test is extremely valuable, it is not 100% specific because it cannot differentiate between other mutations at the recognition site of the restriction enzyme. The GJB2-p.Arg143Trp NciI-RFLP-based diagnostic test had a high sensitivity for genotyping the most common GJB2 pathogenic and founder variant (p.Arg143Trp) within the Ghanaian populations. We recommend the adoption and implementation of this test for hearing impairment genetic clinical investigations to complement the newborn hearing screening program in Ghana. The present study is a practical case scenario of enhancing genetic medicine in Africa.

Highlights

The most prevailing sensorineural disorder is hearing impairment (HI) [1], which accounts for about 466 million people worldwide [2]
In most African populations, GJB2 and GJB6 variants are rarely implicated in hearing impairment [7,8] with some GJB2 cases found in Morocco [9,10], Sudan, and Kenya [11], yet an exceptionally high prevalence is found in Ghana [12,13,14]
8 families from Adamorobe were found to have 2 or more family members living with hearing impairment (Figure 2), from which 20 congenital deaf and 10 normal hearing family with hearing impairment (Figure 2), from which 20 congenital deaf and 10 normal hearing family members were identified

Summary

Introduction

The most prevailing sensorineural disorder is hearing impairment (HI) [1], which accounts for about 466 million people worldwide [2]. Gap-junction protein β 2 (GJB2) and gap-junction protein β 6 (GJB6) are the most common genes associated with the condition globally, with high prevalence reported in the European and Asian populations. In Ghana, GJB2 mutation (p.Arg143Trp) in the homozygous state accounts for 25.9% of cases in families segregating non-syndromic HI, as well as 7.9% of non-familial non-syndromic congenital HI cases (Adadey et al, 2019). This Ghanaian exception, in the African context, is predominantly due to a GJB2 founder mutation (p.Arg143Trp), which was first reported in a village known as “the deaf village”, Adamorobe [13].

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Conclusion