Carrier frequency of the GJB2 mutations that cause hereditary hearing loss in the Japanese population

Abstract

Hearing impairment is one of the most common sensory disorders that affect ~1 in 1000 children, and half of them are considered to be hereditary. Information about the carrier frequencies of mutations that underlie autosomal recessive disorders is indispensable for accurate genetic counseling to predict the probability of patients' children's disease. However, there have been few reports specific to the Japanese population. GJB2 mutations are reported to be the most frequent cause of hereditary hearing loss, and the mutation spectrum and frequency of GJB2 mutations were reported to vary among different ethnic groups. In this study, we investigated the carrier frequency of GJB2 mutations and the mutation spectrum in 509 individuals randomly selected from the general Japanese population. We show that the carrier frequencies of the two most common pathogenic mutations are 1.57% (8/509) for c.235delC and 1.77% (9/509) for p.Val37Ile. In addition to these mutations, we found two pathogenic variants (p.[Gly45Glu;Tyr136*] and p.Arg143Trp), and the total carrier frequency was estimated to be around 3.73% (19/509). We also detected six unclassified variants, including two novel variants (p.Cys60Tyr and p.Phe106Leu), with the former predicted to be pathogenic. These findings will provide indispensable information for genetic counseling in the Japanese population.

Figure 1

Alignment of amino-acid sequences of human and other species' connexin26 (Cx26) showing the mutation sites of two novel variants, p.Cys60Tyr and p.Phe106Leu, and functional prediction of p.Cys60Tyr and p.Phe106Leu. We found two novel variants p.Cys60Tyr and p.Phe106Leu. To predict their pathogenesis, we compared amino-acid sequences of human and other species' Cx26. As Cys60 is evolutionarily conserved, p.Cys60Tyr could be pathogenic; p.Phe106Leu is probably a non-pathogenic polymorphism because Xenopus has a leucine at this position. The functional prediction of p.Cys60Tyr was Damaging (1.0) by SIFT, and Damaging (1.0) by PolyPhen2. That of p.Phe106Leu was Tolerated (0.23) by SIFT and Benign (0) by PolyPhen2. Prediction by SIFT and PolyPhen2 also showed that p.Cys60Tyr would be pathogenic and p.Phe106Leu would be a non-pathogenic polymorphism.