Nonsyndromic genetic deafness is a genetically heterogeneous condition with over 100 genes that have been identified involved in its development[6]. In most cases, NSHL is the result of monogenic mutations. However, digenic mutations have also been reported recently[7–12]. In our cases, the compound heterozygous for GJB2 variants (p.V37I ) and MYO7A (p.L347I) variant were found in the proband using whole-exome sequencing. GJB2 gene accounts for about 50% of nonsyndromic autosomal recessive hearing loss in different populations[13–14]. GJB2 encodes the gap junction subunit protein connexin 26 (Cx26), a proteitn which plays a crucial role in intercellular communication by forming the cochlear gap junction. In the inner ear, GJB2 plays a vital role in many auditory processes including potassium recycling, energy supply, and maintenance of the endolymphatic homeostasis[15–16].To date, more than 300 variants within GJB2 are associated with hearing loss ( HGMD, http://www.hgmd.cf.ac.uk/ac/). The p.V37I variant of GJB2 has a high allele frequency (up to 10%) in East Asians[13, 17–18]. However, the pathogenicity of the p.V37I has yet to be elucidated. early studies regarded the p.V37I as a benign polymorphism, as it was observed in unaffected heterozygous controls. However, research findings increasingly indicated that both homozygotes and compound heterozygous p.V37I variants were associated with mild to moderate hearing impairment [19–20].
MYO7A gene encodes the actin-based motor protein myosin-VIIa, which is especially crucial for the function of cochlear hair cells and eye development [21]. The myosin VIIa protein contains a conserved N-terminal actin-binding and ATPase domain (motor domain), a neck region containing five isoleucine-glutamine (IQ) motifs, and a short predicted coiled-coil domain, followed closely by two myosin tail homology 4 (MyTH4) domains, two-band 4.1-ezrin radixin-moesin (FERM) domains and an SH3 domain [21]. MYO7A gene has long been associated with Usher Syndrome type 1B (USH1B), which is characterized by sensorineural hearing loss, retinitis pigmentosa, and vestibular dysfunction[21–22]. In 1997, Weil and Liu[23–24] identified that MYO7A gene mutations are associated with non-syndromic autosomal recessive hearing loss (DFNB2). So far, majority of the mutations identified in MYO7A are associated with USH1B, whereas only about 17 MYO7A mutations have bee found to be responsible for DFNB2 [25–26]. The novel MYO7A missense p.l347I variant identified in our study located in the motor domain and was predicted to be damaging by in silico analysis. The absence of vestibular and retinal defects in the affected patients suggests that this family have isolated non-syndromic hearing loss presentation, instead of USH1B.
It is estimated that 6–20% of GJB2 mutations in hearing loss subjects were monoallelic mutations[27]. Some researchers hypothesize that a single heterozygous GJB2 mutant allele is possibly contributing to deafness via digenic inheritance. In 2009, Liu et al. [8] identified heterozygous GJB2 and GJB3 mutations in NHSL patients. Since then, many other digenic inheritance has been reported[7–12], such as GJB2/GJB3, GJB2/MITF, and GJB2/ TMPRSS3 (Table 1). Although the digenic inheritance has been increasingly described in NSHL, the prevalence is unknown. Chen et al. [7] assess the contributions of variants in GJB3 or GJB6 in a cohort of 100 NSHL patients with likely pathogenic heterozygous GJB2 mutations. Putatively causative GJB3 variant were 1% (1/100) and no GJB6 mutation was found in this cohort. Monika Ołdak et al. [28] also screened the GJB2 variants in 42 hearing loss patients with at least one TMPRSS3 pathogenic variants and identified four individuals who were double heterozygous for pathogenic GJB2 and TMPRSS3 variants. They proposed that the contributions of GJB2 digenic inheritance may not be predominant. In our case, we found the proband, his father and uncle; all were digenic compound heterozygote for the variant in MYO7A p.L347I and GJB2 p.V37I variant. Base on the co-segregated analysis, we implied a possible GJB2 /MYO7A digenic inheritance of NSHL in this family. To the best of our knowledge, it is a novel GJB2 /MYO7A digenic combination involved in hearing loss development. However, our study has some weaknesses. First, it relies exclusively on data from only one family. Second, there is an absence of in vitro data that demonstrate a functional link between these two genes.Third, a dominant character of the identified GJB2 p.V37I variant with a possible incomplete penetrance in the family can not be excluded. Further animal models or cell biology experiments and studies with a large sample size are still needed to clarify the role of digenic mutations involved.
In the present study, the proband was also diagnosed with 48, XXYY syndrome. 48, XXYY syndrome is a rare sex chromosome abnormality. Although the proband had some physical features similar to 47, XXY Klinefelter syndrome (tall stature, hypogonadism, and infertility), he had delayed speaking, learning difficulty and challenging IQ, which was consistent with previous studies that mental retardation is observed in 26% of the subjects with 48, XXYY syndrome and almost all have learning difficulty[2]. To the best of our knowledge, it is also the first case being reported in the literature with concomitant NSHL and 48, XXYY syndrome.