In this study, we identified several variants in genes reported to cause hearing loss that co-segregated in the pedigree. For HL1 pedigree, the variant in GIPC3 gene may cause the disorder. GIPC3 encodes a 312-residue protein that contains three predicted low complexity regions and a central conserved PDZ domain . The PDZ domain of GIPC3 is required for the survival of spiral ganglion and hair cells in the mouse ears. This gene was reported to cause autosomal recessive deafness 15, non-syndromic genetic deafness and audiogenic seizures. Currently 11 pathogenic variants were reported in this gene from clinvar.
For HL2 pedigree, the variant in LOXHD1 gene was the likely causative one. LOXHD1 encodes a highly conserved stereociliary protein consisting of 15 polycystin-1/lipoxygenase/alpha-toxin (PLAT) domains, which facilitates proteins interacting with the plasma membrane . Loxhd1 in mice plays a crucial role in maintaining normal function of cochlear hair cells . It was reported to cause disorders including autosomal recessive deafness 77. Currently 28 pathogenic variants were reported in this gene from clinvar.
For HL3 pedigree, a homozygous variant in TECTA and two compound heterozygous variants in MYO15A were the likely candidates. TECTA encodes a protein containing 2,155 amino acids that is one of the major non-collagenous glycoproteins of the tectorial membrane, a non-cellular matrix overlying the cochlear neuroepithelium that lies over stereocilia of the hair cells and is critical for the mechanical amplification and transmission of sound [28, 29]. This gene was reported to cause autosomal recessive deafness 21, and 40 pathogenic variants were reported in this gene from clinvar. The protein encoded by MYO15A is a member of the unconventional myosin super-family and plays an indispensable role in the graded elongation of stereocilia and actin organization in hair cells of the inner ear, which are essential for normal hearing function . MYO15A was reported to cause autosomal recessive deafness 3, and 112 pathogenic variants were reported in this gene from clinvar. Considering the transmission of variants in the pedigree (this is a consanguineous pedigree), we thought the homozygous variant in TECTA was more likely to cause the disorder in this pedigree.
For HL4 pedigree, homozygous variants were detected in both DFNB59 and TRIOBP genes. DFNB59 encodes a protein contains 352 amino acids which plays a crucial role in auditory nerve signaling transmission . It was reported to cause autosomal recessive deafness 59, and 9 pathogenic variants were reported in this gene from clinvar. TRIOBP encodes a protein contains 652 amino acids which plays a role in regulation of adherens junctions as well as reorganization of the actin cytoskeleton . Actually, little is known about the exact function of TRIOBP, and multiple roles of this gene raised the issue why pathogenic variants in this gene do not lead to other pathologies than isolated hearing loss. This gene was reported to cause autosomal recessive deafness 28, and 26 pathogenic variants were reported in this gene from clinvar. The variant in TRIOBP was annotated as likely benign in deafness variation database. So, we thought the variant in DFNB59 was more likely to be responsible for the disorder in this pedigree.
For HL5 pedigree, the variant in TMPRSS3 may cause the disorder. The protein encoded by this gene contains a serine protease domain, a transmembrane domain, an LDL receptor-like domain, and a scavenger receptor cysteine-rich domain. It plays an important role in activating the ENaC sodium channel, which is regulated by serine protease activity , and maintains a low Na+ concentration in the endolymph of the inner ear . TMPRSS3 was reported to cause autosomal recessive deafness 8, and 23 pathogenic variants were reported in this gene from clinvar.
We calculated the density of reported pathogenic variants in these genes and they were 11.7/kb, 4.2/kb, 6.2/kb, 10.6/kb, 8.5/kb, 3.7/kb and 16.8/kb for GIPC3, LOXHD1, TECTA, MYO15A, DFNB59, TRIOBP and TMPRSS3, respectively. The density may indicate the degree of understanding or focusing for different genes. And the genes with low density such as LOXHD1 and TRIOBP may have potential research value.
The majority of causing genes we identified for these pedigrees were not common hearing loss genes. If we applied common hearing loss gene panel to screen these patients, we would obtain negative results and the causing gene/variant for the patients would be missed. So, WES may be better strategy than panel sequencing for hearing loss screening even in clinical detection.