GJB2 and GJB6 Mutations in Non-Syndromic Childhood Hearing Impairment in Ghana

Abstract

Our study aimed to investigate GJB2 (connexin 26) and GJB6 (connexin 30) mutations associated with non-syndromic childhood hearing impairment (HI) as well as the environmental causes of HI in Ghana. Medical reports of 1,104 students attending schools for the deaf were analyzed. Families segregating HI, as well as isolated cases of HI of putative genetic origin were recruited. DNA was extracted from peripheral blood followed by Sanger sequencing of the entire coding region of GJB2. Multiplex PCR and Sanger sequencing were used to analyze the prevalence of GJB6-D3S1830 deletion. Ninetyseven families segregating HI were identified, with 235 affected individuals; and a total of 166 isolated cases of putative genetic causes, were sampled from 11 schools for the deaf in Ghana. The environmental factors, particularly meningitis, remain a major cause of HI impairment in Ghana. The male/female ratio was 1.49. Only 59.6% of the patients had their first comprehensive HI test between 6 to 11 years of age. Nearly all the participants had sensorineural HI (99.5%; n = 639). The majority had pre-lingual HI (68.3%, n = 754), of which 92.8% were congenital. Pedigree analysis suggested autosomal recessive inheritance in 96.9% of the familial cases. GJB2-R143W mutation, previously reported as founder a mutation in Ghana accounted for 25.9% (21/81) in the homozygous state in familial cases, and in 7.9% (11/140) of non-familial non-syndromic congenital HI cases, of putative genetic origin. In a control population without HI, we found a prevalent of GJB2-R143W carriers of 1.4% (2/145), in the heterozygous state. No GJB6-D3S1830 deletion was identified in any of the HI patients. GJB2-R143W mutation accounted for over a quarter of familial non-syndromic HI in Ghana and should be investigated in clinical practice. The large connexin 30 gene deletion (GJB6-D3S1830 deletion) does not account for of congenital non-syndromic HI in Ghana. There is a need to employ next generation sequencing approaches and functional genomics studies to identify the other genes involved in most families and isolated cases of HI in Ghana.

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

“…The GJB2-p.Arg143Trp variant results from a pathogenic point mutation (c.427C > T) in the exon 2 of the connexin 26 gene on chromosome 13 [13,14]. The drive for an efficient and cost-effective test was from the fact that the founder mutation, GJB2-p.Arg143Trp, is the most common variant associated with hearing impairment in Ghana [12][13][14].…”

“…Congenital hearing-impaired patients were recruited from schools for the deaf and from the Adamorobe community following procedures reported previously [12]. Briefly, all participants' details, as well as their personal and family histories, were obtained; medical records were reviewed by a medical geneticist and an ear, nose, and throat (ENT) specialist when possible; and relevant data were extracted, including three-generation pedigrees and perinatal histories, using a structured questionnaire to query possible environmental causes of hearing impairment.…”

“…A total of 111 individuals with non-familial isolated non-syndromic HI, whose samples were previously Sanger sequenced for GJB2 variants [12], were analyzed using the developed GJB2-p.Arg143Trp NciI-RFLP test. Table 1 illustrates that the GJB2-p.Arg143Trp NciI-RFLP test was found to have 100% sensitivity compared to Sanger sequencing as the gold standard.…”

“…Thus, the GJB6 gene itself plays no role in the development of hearing impairment but the surrounding sequences consisting of the cis-acting elements are responsible for the development of hearing impairment [5,6]. Nevertheless, 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]. Indeed, 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).…”

“…Nevertheless, 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]. Indeed, 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].…”