Sequencing of GJB2 in Cameroonians and Black South Africans and comparison to 1000 Genomes Project Data Support Need to Revise Strategy for Discovery of Nonsyndromic Deafness Genes in Africans

Abstract

Mutations in the GJB2 gene, encoding connexin 26, could account for 50% of congenital, nonsyndromic, recessive deafness cases in some Caucasian/Asian populations. There is a scarcity of published data in sub-Saharan Africans. We Sanger sequenced the coding region of the GJB2 gene in 205 Cameroonian and Xhosa South Africans with congenital, nonsyndromic deafness; and performed bioinformatic analysis of variations in the GJB2 gene, incorporating data from the 1000 Genomes Project. Amongst Cameroonian patients, 26.1% were familial. The majority of patients (70%) suffered from sensorineural hearing loss. Ten GJB2 genetic variants were detected by sequencing. A previously reported pathogenic mutation, g.3741_3743delTTC (p.F142del), and a putative pathogenic mutation, g.3816G>A (p.V167M), were identified in single heterozygous samples. Amongst eight the remaining variants, two novel variants, g.3318-41G>A and g.3332G>A, were reported. There were no statistically significant differences in allele frequencies between cases and controls. Principal Components Analyses differentiated between Africans, Asians, and Europeans, but only explained 40% of the variation. The present study is the first to compare African GJB2 sequences with the data from the 1000 Genomes Project and have revealed the low variation between population groups. This finding has emphasized the hypothesis that the prevalence of mutations in GJB2 in nonsyndromic deafness amongst European and Asian populations is due to founder effects arising after these individuals migrated out of Africa, and not to a putative "protective" variant in the genomic structure of GJB2 in Africans. Our results confirm that mutations in GJB2 are not associated with nonsyndromic deafness in Africans.

FIG. 1.

Phylogeny constructed from 1000 Genomes and study control data. The phylogeny tree shows the various populations' clusters of the 1000 Genomes. As expected, the South African and Cameroonian controls grouped with the other African populations. Numbers indicate bootstrap values over 1000 iterations. Population abbreviations are: ASW, Americans of African Ancestry in SW USA; CAM_C, Cameroonian control;CEU, Utah Residents (CEPH); CHB, Han Chinese in Beijing; CHS, Southern Han Chinese; CLM, Colombians from Medellin Colombia; FIN, Finnish in Finland; GBR, British in England and Scotland; IBS, Iberian population in Spain; JPT, Japanese in Tokyo Japan; LWK, Luhya in Webuye Kenya; MXL, Mexican Ancestry from Los Angeles USA; PUR, Puerto Ricans from Puerto Rico; SA_C, South African control; TSI, Toscani in Italia; and YRI, Yoruba in Ibadan Nigeria.

FIG. 2.

Principal component analysis (PCA) study and 1000 Genomes populations with respect to variation in GJB2. The PCA explains 40% of the variation between population groups and different populations are characterised by different SNPs. Population abbreviations are: ASW, Americans of African Ancestry in SW USA; CAM_C, Cameroonian control, CEU, Utah Residents (CEPH); CHB, Han Chinese in Beijing; CHS, Southern Han Chinese; CLM, Colombians from Medellin Colombia; FIN, Finnish in Finland; GBR, British in England and Scotland; IBS, Iberian population in Spain; JPT, Japanese in Tokyo Japan; LWK, Luhya in Webuye Kenya; MXL, Mexican Ancestry from Los Angeles USA; PUR, Puerto Ricans from Puerto Rico; SA_C, South African control; TSI, Toscani in Italia; and YRI, Yoruba in Ibadan Nigeria.