Although LOXHD1 mutations have been increasingly implicated in late-onset hereditary hearing loss, the genetic spectrum and underlying molecular mechanisms in the Chinese population remain inadequately characterized. This study aims to delineate the genetic landscape of LOXHD1 in Chinese families with non-syndromic hearing loss and to determine the pathogenic significance of the identified variants.

In this study, we conducted targeted whole-exome sequencing along with Sanger sequencing on 157 probands with non-syndromic hearing loss, as well as their family members. We identified novel variants in the LOXHD1 gene. Additionally, we employed bioinformatic analyses to investigate the potential molecular functions of these variants.

In this study, potential causal variants were identified in 95 (60.51%) affected individuals and variants in SLC26A4 and GJB2 were most frequent in this cohort. we identified ten different variants in the LOXHD1 gene from five patients in their families. Among them, five novel LOXHD1 gene variants linked to hearing loss were recognized: c.3734G>A, c.4952T>A, c.4486C>T, c.6375G>C, and c.5002del. The pathogenicity of these variants was evaluated through multiple bioinformatics analyses. Notably, two patients with severe bilateral sensorineural hearing loss associated with LOXHD1 mutations showed significant improvement after cochlear implantation, attaining receptive and expressive language skills appropriate for their chronological age.

We have identified five novel variants of the LOXHD1 gene in Chinese family affected by nonsyndromic hearing loss. These findings enrich the current understanding of LOXHD1-related pathogenic variants and offer important implications for molecular diagnosis, genetic counseling, and prenatal screening in hereditary hearing loss.

The PTPRQ gene is essential for preserving the structure and function of stereocilia in inner ear. However, research on splicing mutations within this gene is limited. This study aims to investigate novel splicing mutations in PTPRQ, clarify their molecular mechanisms, and provide new insights into the genetic factors associated with hearing loss, ultimately enhancing diagnostic accuracy.

Clinical data and peripheral blood samples were obtained from members of a family with congenital hearing loss. Variants were identified through high-throughput sequencing and confirmed by Sanger sequencing to ensure genealogical co-segregation. The splicing effects of PTPRQ variants were evaluated using bioinformatics tools and minigene assays.

We used whole exome sequencing to identify novel double compound heterozygous splice-altering variants (c.5426+1 G>A and c.6603-3 T>G) in the PTPRQ gene with DFNB84A. We molecularly characterized these variants, and they were found to co-segregate with the disease within the family. Minigene assays and Sanger sequencing confirmed that the c.6603-3 T > G variant caused exon 43 skipping, resulting in a frameshift mutation (p.Ser2201ArgfsTer112). Further bioinformatic analysis supported these findings.

This study identifies a novel compound heterozygous splicing variant in the PTPRQ gene in a Chinese family with DFNB84A, expanding the known spectrum of PTPRQ mutations. These findings enhance the understanding of PTPRQ-related hearing loss and may aid in early diagnosis, prevention, and therapeutic strategies.