The genetic etiology of hearing loss in Japan revealed by the social health insurance-based genetic testing of 10K patients

Abstract

Etiological studies have shown genetic disorders to be a major cause of sensorineural hearing loss, but there are a limited number of comprehensive etiological reports based on genetic analysis. In the present study, the same platform using a diagnostic DNA panel carrying 63 deafness genes and the same filtering algorithm were applied to 10,047 samples obtained from social health insurance-based genetic testing of hearing loss. The most remarkable result obtained in this comprehensive study was that the data first clarified the genetic epidemiology from congenital/early-onset deafness to late-onset hearing loss. The overall diagnostic rate was 38.8%, with the rate differing for each age group; 48.6% for the congenital/early-onset group (~5y.o.), 33.5% for the juvenile/young adult-onset group, and 18.0% for the 40+ y.o. group. Interestingly, each group showed a different kind of causative gene. With regard to the mutational spectra, there are certain recurrent variants that may be due to founder effects or hot spots. A series of haplotype studies have shown many recurrent variants are due to founder effects, which is compatible with human migration. It should be noted that, regardless of differences in the mutational spectrum, the clinical characteristics caused by particular genes can be considered universal. This comprehensive review clarified the detailed clinical characteristics (onset age, severity, progressiveness, etc.) of hearing loss caused by each gene, and will provide useful information for future clinical application, including genetic counseling and selection of appropriate interventions.

Fig. 1

A Responsible genes found in 10,047 hearing loss patients. B The number and types of variants in each gene

Fig. 2

A Responsible genes in each age group (congenital/6–39 y.o./over 40 y.o.). B Responsible genes found in autosomal dominant (AD) and autosomal recessive (AR) patients. Among 89 GJB2-associated hearing loss cases identified from autosomal dominant families, 23 carried autosomal dominant inheritance variants and 66 carried biallelic autosomal recessive variants (pseudo-dominant cases). Similarly, among 75 MYO7A-associated hearing loss cases identified from autosomal dominant families, 71 carried autosomal dominant inheritance variants and only 4 carried biallelic autosomal recessive variants (pseudo-dominant cases). C Responsible genes found in groups classified by severity of HL. It was revealed that the types of genes differed according to severity

Fig. 3

The number and types of variants in each gene identified in each age group (congenital/6–39 y.o./over 40 y.o.) and in autosomal recessive (AR) and autosomal dominant (AD) patients

Fig. 4

A The spectrum of GJB2 mutations. A larger circle indicates a larger number of mutated alleles (from Tsukada et al. 2015b). B Suspected origin of the GJB2 variants (modified from Tsukada et al. 2015b). Suspected origin of GJB2 variants are marked on the human Y-chromosomal haplogroup tree (Karafet et al. 2008), which is applicable to the investigation of human migration. Lineages associated with haplogroup IJ in the Y-haplotype tree based on Karafet et al. (2008). From geographical distribution and haplotype analysis, it is speculated that p. Arg143Trp may have occurred in the Y-chromosomal haplogroup B, p.Val37Ile in D and E, and c.235delC, p.[G45E; Y136X], and c.176_191del, c.299_300delAT in N and O, respectively. C GJB2 founder variants from a human migration perspective based on Y chromosome haplotypes: c.235 del C is considered to have occurred in haplotype N/O from the viewpoint of its geographic distribution. On the other hand, p.Val37Ile is consistent with the area where the haplotype C/D/E was found, so it is probable that it occurred within this haplotype

Fig. 5

Age at onset (awareness) of each gene. Hearing loss related to GJB2, CDH23, SLC26A4, STRC, TECTA, MYO15A, OTOF, USH2A, and LOXHD1 is shown to be congenital/early-onset. In contrast, a significant portion of cases with mutations in KCNQ4, mitochondrial m.3243A > G, MYO6, POU4F3, ACTG1, EYA4, and COCH showed adult-onset hearing loss

Fig. 6

The average audiogram configuration and progressiveness. Hearing in each age group was plotted on the audiogram for each gene. In the case of the GJB2 and STRC genes, hearing is rather stable. On the other hand, hearing loss due to SLC26A4, CDH23, TMPRSS3, LOXHD1, KCNQ4, ACTG1, POU4F3, EYA4, MYO6, and mitochondrial m.1555A > G showed progression with age