Prevalence and clinical features of hearing loss caused by EYA4 variants

Abstract

13 , takashi ishino 14 , natsumi Uehara 15 & Shin-ichi Usami 1,2* Variants in the EYA4 gene are known to lead to autosomal dominant non-syndromic hereditary hearing loss, DFNA10. To date, 30 variants have been shown to be responsible for hearing loss in a diverse set of nationalities. To better understand the clinical characteristics and prevalence of DFNA10, we performed genetic screening for EYA4 mutations in a large cohort of Japanese hearing loss patients. We selected 1,336 autosomal dominant hearing loss patients among 7,408 unrelated Japanese hearing loss probands and performed targeted genome enrichment and massively parallel sequencing of 68 target genes for all patients. Clinical information of cases with mutations in EYA4 was gathered and analyzed from medical charts. Eleven novel EYA4 variants (three frameshift variants, three missense variants, two nonsense variants, one splicing variant, and two single-copy number losses) and two previously reported variants were found in 12 probands (0.90%) among the 1,336 autosomal dominant hearing loss families. The audiometric configuration of truncating variants tends to deteriorate for all frequencies, whereas that of non-truncating variants tends to show high-frequency hearing loss, suggesting a new correlation between genotype and phenotype in DFNA10. The rate of hearing loss progression caused by EYA4 variants was considered to be 0.63 dB/year, as found in this study and previous reports. Hearing loss is the most common sensory disorder and more than 50% of cases of congenital or early onset hearing loss are caused by genetic factors 1. Regarding hereditary hearing loss, over 100 genes are known to be causative based on genetic analysis [Hereditary Hearing Loss Homepage: https://hereditaryhearingloss.org/ accessed

Genetic background in late-onset sensorineural hearing loss patients

“…The EYA4 gene is known as a genetic cause of ADNSHL (DFNA10). The audiometric configuration for EYA4 -associated HL was gradual high-frequency HL or flat-type HL [ 23 , 24 ]. In this study, we identified two patients with different frame-shift variants.…”

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

“…Etiological studies have shown that genetic causes are the most common etiology of deafness, and approximately two-thirds of congenital/early-onset sensorineural hearing loss in developed countries is estimated to be due to genetic causes (Morton and Nance 2006). Recent studies have indicated that a significant portion of late-onset hearing loss is also due to genetic causes (Kitano et al 2017;Kobayashi et al 2018;Shinagawa et al 2020a;Yasukawa et al 2019;Oka et al 2020;Miyajima et al 2020). A series of etiological studies has demonstrated genetic disorders to be a common cause of all types of sensorineural hearing loss, but there has been no detailed genetic epidemiological data covering a wide range of ages.…”

“…With regard to progression, in the case of the GJB2 and STRC , hearing is rather stable and progression of hearing loss is rarely observed (Tsukada et al 2010;Yokota et al 2019). On the other hand, hearing loss due to SLC26A4 (Suzuki et al 2007;Miyagawa et al 2014), CDH23 (Miyagawa et al 2012, TMPRSS3 (Miyagawa et al 2015c), LOXHD1 (Maekawa et al 2019), KCNQ4 (Naito et al 2013), ACTG1 (Miyajima et al 2020), POU4F3 (Kitano et al 2017), EYA4 (Shinagawa et al 2020a), MYO6 (Oka et al 2020), and mitochondrial m.1555A > G (Usami et al 1997) requires a good deal of attention as it is progressive. Figure 6 demonstrates the progressive or non-progressive nature of each gene, and supports our previous data regarding progressiveness.…”

Prevalence and Clinical Characteristics of Hearing Loss Caused by MYH14 Variants

“…Various genes have been reported to be causative in ADNSHL families [6,8]; however, at present, there is no particular major responsible deafness gene for ADNSHL. Our screening using the same cohort clarified the frequencies for the other causative genes in ADNSHL patients; KCNQ4: 6.6% [37], POU4F3: 4% [38], TECTA: 2.9% [39], WFS1: 2.5% [40], MYO6: 2.4% [41], ACTG1: 1.1% [42], and EYA4: 0.9% [43]. Although MYH14-associated HL is rare, the present results indicated that this gene should be included in HL screening, especially that for ADNSHL.…”