Mutations in GJB2, GJB6, and mitochondrial DNA are rare in African American and Caribbean Hispanic individuals with hearing impairment

Abstract

Autosomal recessive nonsyndromic sensorineural hearing impairment (ARNSHI) comprises 80% of familial hearing loss cases. Approximately half result from mutations in the connexin 26 (Cx26) gene, GJB2, in Caucasian populations. Heterozygous mutations in GJB2 occasionally co-occur with a deletion of part of GJB6 (connexin 30; Cx30). It is estimated that approximately 1% of deafness is maternally inherited, due to mutations in mitochondrial DNA (mtDNA). Few studies have focused on the frequency of mutations in connexins or mtDNA in African American (AA) and Caribbean Hispanic (CH) admixture populations. In this study, we performed bidirectional sequencing of the GJB2 gene and polymerase chain reaction (PCR) screening for the common GJB6 deletion, as well as PCR/RFLP analysis for three mutations in mtDNA (A1555G, A3243G, A7445G), in 109 predominantly simplex AA and CH individuals. Variations found were a 101T > C (M34T; 1/101 cases), 109G > A (V37I; 1/101), 35delG (mutation; 4/101, (3/4) of non-AA/CH ethnicity), 167delT (mutation; 1/101), 139G > T (mutation; E47X; 1/101 homozygote, consanguineous), -15C > T (1/101), 79G > A (V27I; 9/101), 380G > A (R127H; 4/101; Guyana, India, Pakistan ethnicity), 670A > C (Indeterminate; K224Q; 1/101), 503A > G (novel; K168R; 3/101) and 684C > A (novel; 1/101). All but one of the AA and CH patients had monoallelic variations. There were no hemizygous GJB6 deletions in those with monoallelic GJB2 variations. We also did not identify any patients with the three mutations in mtDNA. Bidirectional sequencing of the GJB2 gene was performed in 187 AA and Hispanic healthy individuals. Our results reveal that GJB2 mutations, GJB6 deletions, and mtDNA mutations may not be significant in these minority admixture populations.

No evidence for clinical utility in investigating the connexin genes GJB2, GJB6 and GJA1 in non-syndromic hearing loss in black Africans

“…As in previous studies in Africans, [17] African Americans and Caribbean Hispanics with GJB6 mutations, [19] we did not find either the GJB6-D13S1830 deletion or coding region changes. Similarly, no pathogenic variants were detected in GJA1, suggesting their nonimplication in hearing loss among the Cameroonians and black South Africans studied, [15] as has been reported in African Americans.…”

“…[24] Funding. 19 and ** Pandya et al 20 indicate that the mutation was found neither in patients nor in controls.…”

“…[15] Few mutations in GJB2, GJB6 or GJA1 genes among other populations of African ancestry Our report and review of the literature confirmed that GJB2 gene is of little significance in non-syndromic hearing loss in populations of African descent (Table 1). [10,14,[16][17][18][19][20] In addition, by combining data from previously unstudied deaf Xhosa patients in SA, Cameroonian patients, previous studies in Africans and the 1000 Genomes Project, …”

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

“…Similar to Africans, Caribbean Hispanics, probably due to their African ancestry, do not show a large contribution to deafness from GJB2 variations (Samanich et al, 2007).…”

Evidence for Central Asian Origin of the p.Val27Ile Variant in the GJB2 Gene

“…The p.Val27Ile polymorphism seems to be rare or absent in European and African populations [26,32]. The second most frequent polymorphism of GJB2 is p.Glu114Gly; it occurs almost exclusively in the Asian continent (in the same regions as p.Val27Ile) and its highest AFs are found in East Asia: Koreans and Chinese 17% [13,14,18] and Japanese 13% [12] followed by Mongolians and Altaian ethnic group 11% in Central Asia [15,16].…”