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.
Abstract
SLITRK6 is essential for inner-ear neuronal survival and retinal development, and pathogenic variants in this gene cause syndromic sensorineural hearing loss (HL) with high myopia. This study aimed to identify the genetic basis of HL and myopia in a consanguineous Iranian family with two affected children and to characterize the molecular consequences of the detected variant. One sibling with bilateral congenital HL and myopia was evaluated using whole-exome sequencing (WES). Common variants (MAF >1%) were excluded, and rare exonic changes were prioritized. Variant pathogenicity was assessed according to ACMG guidelines, and segregation was confirmed by Sanger sequencing in two affected children and their parents. ProtParam was used to compare physicochemical properties of wild-type and truncated proteins, and STRING was applied to assess predicted protein-protein interactions. WES identified a novel homozygous nonsense variant in SLITRK6, NM_032229.3:c.1795C>T (p.Arg599Ter), located in exon 2. The parents were heterozygous carriers, and the variant was ultra-rare in public databases. In silico analyses predicted that the premature termination codon produces a truncated protein with loss-of-function effects. These findings are consistent with previously described SLITRK6-associated HL with myopia. We report a novel likely pathogenic SLITRK6 variant associated with congenital HL and myopia in an Iranian family. The predicted loss-of-function supports an important role for SLITRK6 in auditory and visual system development. Further studies are needed to elucidate the molecular mechanisms underlying SLITRK6-related disorders.
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
ABSTRACT Background Hearing loss is one of the most common sensory disorders caused by genetic and environmental factors. Autosomal recessive non‐syndromic hearing loss (ARNSHL) is extremely heterogeneous, with over 100 genes known to be involved. Hearing loss can result from mutations in the LOXHD1 gene, which codes a highly conserved protein known as lipoxygenase and is located at 18q21.1. Despite the association between LOXHD1 mutations and ARNSHL, there are still few documented cases. Methods We examined a case of non‐syndromic hearing loss in an Iranian family with a history of consanguinity and several affected siblings. Next‐generation sequencing (NGS) was conducted on the proband to discover causal genetic alterations. Sanger sequencing was employed to confirm the identified variation. Results A novel likely pathogenic variant in the LOXHD1 gene, c.3713dupA (p.Asp1238Glufs*10), was identified. Sanger sequencing was used to confirm that the affected family members had this frameshift mutation. Conclusion Our findings broaden the mutational range of LOXHD1 linked to ARNSHL. This unique variant 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
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.
Ya-Jing Zhu, Tianyu Wang, Xiang-Lan Sun et al.· Journal of Neural Transplant...· 0 citations
Background Primary ciliary dyskinesia (PCD) is a rare autosomal recessive disorder characterized by defective motile cilia function, affecting approximately one in 7,500 to one in 10,000 live births. Pathogenic variants in radial spoke head genes, including RSPH4A, cause PCD with distinctive central-microtubular-pair defects. However, the functional consequences of novel RSPH4A variants remain poorly characterized, limiting genetic counseling and prenatal diagnostic capabilities. This study aims to reveal the genetic etiology of PCD in an affected family and the clinical significance of the two novel RSPH4A variants identified in this PCD-affected pedigree. Methods We recruited a five-member Chinese family including an 11-year-old female PCD proband presenting with chronic bronchiectasis and recurrent respiratory infections. Comprehensive clinical evaluations, whole exome sequencing (WES), and Sanger sequencing were performed to identify genetic variants. Bioinformatics analyses including protein sequence alignment and structural modeling were conducted. Experimental validation employed site-directed mutagenesis, quantitative real-time PCR, and Western blotting in HEK293T cells to characterize variant effects on mRNA stability and protein expression. Results WES identified compound heterozygous RSPH4A variants in the proband: RSPH4A (NM_001010892.3): c.2T>C (p.Met1Thr) inherited from the mother and RSPH4A (NM_001010892.3): c.854delA (p.Lys286Serfs*22) inherited from the father, showing strict co-segregation with the disease phenotype. The c.2T>C variant disrupted the translation initiation codon, while c.854delA introduced a premature termination codon within the radial spoke head domain. Cross-species analysis demonstrated high conservation of the affected region across 15 vertebrate species. Structural modeling predicted complete loss of the radial spoke head domain in the truncated protein. Functional studies revealed that c.2T>C severely impaired protein translation despite intact mRNA levels, whereas c.854delA triggered nonsense-mediated mRNA decay and produced unstable truncated protein. Both variants resulted in substantial reduction in functional RSPH4A protein expression. Conclusion This study identifies novel loss-of-function RSPH4A variants causing PCD through distinct molecular mechanisms, expanding the mutational spectrum of radial spoke head protein-related ciliopathies. These findings offer compelling proof in favor of a molecular diagnosis of PCD in this family and enable carrier screening for at-risk relatives. The experimental validation strategy establishes a framework for interpreting variants of uncertain significance in PCD genes, facilitating accurate prenatal diagnosis and preimplantation genetic testing to reduce the recurrence risk and birth defect incidence in PCD. Furthermore, understanding the precise functional consequences of RSPH4A variants informs genotype-phenotype correlations and may guide future development of targeted therapeutic interventions for this debilitating respiratory disorder.
Yuting Lu, Hui-Yan Tang, Kai Chen et al.· Frontiers in Genetics· 0 citations
The findings suggest that PPP1R12A-related disorders may exhibit a broader phenotypic variability than previously recognized and it is proposed that HL and inner ear malformations may represent novel features associated with this clinical spectrum.
G. Pianigiani, Lara Emily Rosso, Anna Morgan et al.· Genes· 0 citations
Objective: To study the Progressive myoclonic epilepsies (PME) that is genetic disorders resulting from mutations in different genes, all characterized by the early onset of myoclonic seizures, and cognitive decline. The Potassium Channel Tetramerization Domain Containing seven (KCTD7) gene encodes for the BRC (broad complex), ttk (tramtrack), and bab/pox virus, and zinc finger domain, containing KCTD7 protein.
Methodology: The study was done in the Center of Excellence in Genomic Medicine and Research (CEGMR). The affected patient, a three-year-old Saudi female born to consanguineous parents, she underwent laboratory tests, EEG assessments, and Whole-Exome Sequencing (WES).
Results: Our results showed a novel five base pair deletion that was detected in homozygous state in the KCTD7 gene. Both the unaffected parents showed heterozygous mutation of the KCTD7 gene. Segregation analysis via Sanger sequencing supported the existence of the homozygous splice donor variant in NM_153033.4:c.493+2_493+6delTGA of KCTD7 gene in the patient.
Conclusion: The mutation is not reported in the literature yet; the particular phenotype that was observed in our 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. This finding will further increase our insight of the genetic basis of PMEs and role of KCTD7 gene mutations in Saudi population.
S. Alharazy, Peter Natesan Pushparaj, Rose Jelani et al.· Pakistan Journal of Medical...· 0 citations