Jan 2026· Journal of Neural Transplantation and Plasticity· Vol 2026· 0 citations· 30 references
Medicine
TL;DR
A novel pathogenic variant in the ACTG1 gene responsible for NSHL is identified, which expands the mutational spectrum of ACTG1‐related hearing loss and provides intervention targets for gene therapy of HHL.
Abstract
Background Hearing loss is the most common sensory nervous system defect in humans. Approximately half of hearing loss cases have a genetic etiology. At present, more than 300 genes and 1000 mutations have been identified that cause hereditary hearing loss (HHL). However, there are still a large number of unknown genes related to hearing loss. Objective The purpose of this study was to analyze the clinical audiological characteristics of a family with hereditary nonsyndromic hearing loss (NSHL) and identify the mutation of deafness‐related genes. Material and Methods A Chinese Han–dominant deafness family including six members was enrolled in our study. In addition to collecting detailed clinical data on the audiology of this family, we employed whole‐exome sequencing (WES) and Sanger sequencing to identify the key gene causing deafness. Results The pedigree chart of the HHL family suggested that the disease might be a dominant genetic disease. The WES and Sanger sequencing indicated that a novel mutation (c.842C > G) occurred in the ACTG1 gene on the fifth exon, which caused the change of the coding protein (p.S281C). This variant cosegregated perfectly with the hearing loss phenotype: All affected members carried the heterozygous c.842C > G mutation, whereas the only unaffected family member showed wild‐type ACTG1. Multiple sequence alignment revealed that the p.Ser281 residue was highly conserved across vertebrate species. Bioinformatic analyses showed high conservation of p.Ser281 across species and predicted damaging effects on protein structure and function. Conclusions and Significance On the basis of our research, we identified a novel pathogenic variant in the ACTG1 gene responsible for NSHL, which expands the mutational spectrum of ACTG1‐related hearing loss. Further in vitro and in vivo studies may be performed to elucidate the underlying mechanism by which ACTG1 contributes to hearing function, potentially providing intervention targets for gene therapy of HHL.
A novel likely pathogenic variant in the LOXHD1 gene, c.3713dupA (p.Asp1238Glufs*10), was identified and enhances the comprehension of the genetic underpinnings of hearing loss and may aid in molecular diagnostics and genetic counseling for impacted families.
Solmaz Hassani Fard Katiraei, Milad Gholami, Mohsen Soosanabadi et al.· Journal of clinical laborato...· 0 citations
Purpose Hereditary hearing loss is a genetically heterogeneous disorder, with more than 120 genes implicated in the non-syndromic forms. The genetic cause of non-syndromic hearing loss (NSHL) in a Chinese Han family was investigated, and the function of the identified mutation was characterized. Methods The family members were clinically evaluated. Targeted next-generation sequencing of 414 deafness-related genes was performed on the proband. The identified variants were validated in the family members of the proband using Sanger sequencing and PCR. The functional impacts of the variants on splicing were predicted using SpliceAI and MaxEntScan. Results Two compound heterozygous CDH23 mutations (c.7054+1G>A and c.4209+794_4825 del) were identified in a thirteen-month-old girl with NSHL. Sanger sequencing confirmed recessive inheritance, with each unaffected parent carrying a single heterozygous variant. The c.7054+1G>A variant is a canonical splice donor variant predicted to severely disrupt splicing (SpliceAI donor loss score: 0.99; MaxEntScan score reduced from 10.28 in the wild-type to 2.10 in the mutant, a 79.57% reduction). The c.4209+794_4825 del is a 6.45 kb heterozygous deletion encompassing exons 35–38, predicted to resulted in the in-frame skipping of exons 35–38. AlphaFold-based structural modeling revealed marked conformational changes in the mutant extracellular domain, supporting the hypothesis that these variants compromised CDH23-mediated tip-link formation and mechanotransduction. Conclusion We identified two novel compound heterozygous CDH23 mutations (c.7054+1G>A and c.4209+794_4825 del) in a Chinese Han family, expanding the known spectrum of CDH23 mutation and adding to the understanding of the genotype–phenotype correlations in NSHL.
Pengcheng Xu, Qi Liao, Yun Lin et al.· International Journal of Gen...· 0 citations
The predicted loss-of-function of SLITRK6 supports an important role for SLITRK6 in auditory and visual system development and is consistent with previously described SLITRK6-associated HL with myopia.
Deafness is a common multifactorial sensory disorder with numerous underlying causes (genetic, environmental) and a broad range of impact on humans. To date, 156 non-syndromic hearing loss-associated genes have been identified (DFN) and 75%-80% follow a recessive inheritance pattern (DFNB). OTOG (MIM: 604487, chr11:17,547,259-17,646044, GrCh38) encodes otogelin, a non-collagenous protein specific to the inner ear tectorial membrane. Biallelic pathogenic variants in OTOG result in mild to moderate autosomal recessive non-syndromic SNHL (DNF18B). To date, only 41 families (63 individuals) have been reported in the literature.We report an additional seven families from the Irish Traveller population (16 individuals), with a recurrent homozygous variant in OTOG (c.3700C>T; p.Arg1234*) causing non-syndromic early-onset SNHL. The median current age is 9.5 years (IQR: 5.75-14.5 years). Two-thirds (n=11) were identified after failing newborn hearing screening, with others referred due to speech delay. All individuals have mild to moderate SNHL, with a characteristic U-shaped or 'cookie bite' audiogram. Similar to previously reported cases of OTOG-associated SNHL, in our cohort, SNHL was non-progressive even in our adult patients. There were no features of vestibular dysfunction or neurodevelopmental impairment.We reviewed all reported cases to date, in addition to our families (n=79). We demonstrate that protein-truncating variants are scattered throughout the length of the OTOG protein. However, pathogenic missense variants occur only in key domains such as vWD and trypsin inhibitor-like cysteine-rich domains.This report highlights a founder variant in OTOG within the Irish Traveller population. Clinicians should ensure that this is requested in all infants who fail newborn screening from this ethnicity.
Aoife Flynn, Rebecca Finnegan, Aisling Stafford et al.· Journal of Medical Genetics· 0 citations
Background: Hearing loss affects over 430 million people globally, with genetic factors accounting for at least 50% of congenital cases. The GJB2 gene mutations are the most common cause of non-syndromic hearing impairment (NSHI) worldwide, but the clinical characteristics of c.109G>A (p.V37I) mutation in the GJB2 gene are still indistinct. Objective: To evaluate the prevalence and clinical impact of the c.109G>A (p.V37I) mutation in the GJB2 gene among neonates through audiological and genetic tests. Methods: A cohort of 848 neonates was enrolled between February 2022 and February 2024. All subjects underwent hearing screening and deafness genetic screening for 7 hotspot variants in the GJB2 gene (c.109G>A, c.35delG, c.176_191del16, c.235delC, c.299_300delAT, c.79G>A, and c.341A>G). The association between c.109G>A genotype and hearing phenotype was assessed. Results: The c.109G>A mutation was identified in 24 individuals (2.83%), including 11 heterozygotes, 12 compound heterozygotes, and one homozygote. Audiological test failure rates were significantly higher in c.109G>A carriers compared to non-carriers (18.2% vs. 0.7%, P < 0.001). The homozygous proband exhibited confirmed bilateral hearing loss, and a significant association was observed between genotype and hearing outcomes overall (P = 0.003). Conclusion: This study assessed the prevalence of GJB2 mutations in a Changzhi neonatal cohort. The results demonstrate a significant association between the c.109G>A variant and an increased risk of hearing loss, particularly in homozygous and compound heterozygous carriers. These findings demonstrate that GJB2 variant p.V37I is significantly associated with neonatal hearing loss, underscoring its importance for inclusion in genetic screening programs to facilitate early intervention.
Rui Feng, E. Mangantig, Wan Shahriman Yushdie Wan Yusoff et al.· Journal of Clinical and Heal...· 0 citations
The particular phenotype that was observed in the patient is comparable to the ones that are described in the KCTD7 related pathologies, combined with segregation analysis indicating both parents carried the variant heterogeneously present is a strong indication that the identified mutation consists of probably pathogenic mutation.
S. Alharazy, Peter Natesan Pushparaj, Rose Jelani et al.· Pakistan Journal of Medical...· 0 citations
