Usher syndrome type III (USH3) is a genetic disorder characterized by progressive, post-lingual hearing loss, variable vestibular dysfunction, and onset of retinitis pigmentosa. USH3 is caused by mutations in CLRN1, which encodes clarin-1, a tetraspanin-like protein. Mutations in CLRN2, which encodes the related protein clarin-2, are also implicated in progressive, non-syndromic hearing loss in both humans and mice. USH3 patients show considerable phenotypic variability, even among individuals with the same mutation. This variability may result from environmental factors or interactions with other inner ear genes, such as CLRN2. To investigate the functional interplay of these genes, we generated Clrn1- /-Clrn2-/- double knockout mice. RNA-sequencing and functional/physiological analyses revealed that clarin-1 and clarin-2 jointly regulate mechanoelectrical transduction, ionic homeostasis, and synaptic organization. Their combined loss leads to more severe hearing phenotype compared to Clrn1-/- and Clrn2-/- mice, which reveals a functional compensation between them. CLRN2 variants may exacerbate hearing loss in USH3 patients, supporting inclusion of CLRN2 in genetic screening. By revealing a functional, compensatory interplay between clarin-1 and clarin-2, this study reframes CLRN1-associated deafness as a network-dependent disorder and provides a mechanistic basis for genetic stratification and therapeutic directions in USH3 and related sensorineural hearing loss.

Non-syndromic sensorineural hearing loss (NSHL) significantly affects quality of life and is often associated with the MT-RNR1 A1555G variant. This meta-analysis investigated the global prevalence of the A1555G variant, considering factors such as age of onset and aminoglycoside exposure. A systematic review of 97 studies published between 2000 and the present included 31,013 participants. The overall prevalence of the A1555G variant was 3.37 %, with higher rates in East Asia. Subgroup analysis revealed variant frequencies of 7.24 % in postlingual deafness cases and 1.45 % in prelingual cases. Familial cases and those with aminoglycoside exposure showed significantly higher prevalence rates (9.2 % vs. 1.9 %). These findings underscore the variant's critical role in NSHL etiology and the necessity of incorporating genetic screening into clinical practices, especially for patients with aminoglycoside exposure.

Hearing loss (HL) is the most prevalent sensorineural disorders, affecting about one in 1000 newborns. Over half of the cases are attributed to genetic factors; however, due to the extensive clinical and genetic heterogeneity, many cases remain without a conclusive genetic diagnosis. The advent of next-generation sequencing methodologies in recent years has greatly helped unravel the genetic etiology of HL by identifying numerous genes and causative variants. Despite this, much remains to be uncovered about the genetic basis of sensorineural hearing loss (SNHL). Here, we report an Iranian consanguineous family with postlingual, moderate-to-severe autosomal recessive SNHL. After first excluding plausible variants in known deafness-causing genes using whole exome sequencing, we reanalyzed the data, using a gene/variant prioritization pipeline established for novel gene discovery for HL. This approach identified a novel homozygous frameshift variant c.1934_1937del; (p.Thr645Lysfs*52) in ANKRD24, which segregated with the HL phenotype in the family. Recently, ANKRD24 has been shown to be a pivotal constituent of the stereocilia rootlet in cochlea hair cells and interacts with TRIOBP, a protein already implicated in human deafness. Our data implicate for the first time, ANKRD24 in human nonsyndromic HL (NSHL) and expands the genetic spectrum of HL.

Hearing loss exhibits significant clinical and genetic heterogeneity. More than 50% of Hearing loss cases have a genetic etiology. In terms of genetics,, hearing loss can be classified as either syndromic or non-syndromic. It has been demonstrated that over 100 genes and 1,000 associated mutations are involved in hearing loss that can be inherited through autosomal recessive, autosomal dominant, X-linked, or mitochondrial mechanisms This vast genetic heterogeneity has posed a significant challenge for genetic researchers in identifying the specific mutated gene in affected individuals from diverse ethnic backgrounds. However, recent advancements in next-generation sequencing technologies, particularly whole-exome sequencing (WES), have facilitated the identification of mutated genes in individuals with deafness. The primary objective of this study was to employ whole-exome sequencing (WES) to ascertain the genetic underpinnings of non-syndromic hearing loss in a Kurdish consanguineous family and to examine the associated clinical manifestations of the identified genetic mutation. A cohort of fifteen affected (fourteen with prelingual and one with postlingual hearing loss) and fifteen unaffected individuals from a Kurdish family was enrolled in this study. A comprehensive evaluation was conducted, encompassing meticulous physical examinations and audiometric assessments, to ascertain the presence of hearing impairment among the affected participants. Genomic DNA was extracted from blood samples and subjected to whole-exome sequencing. Subsequent variant identification and annotation were conducted to identify potential pathogenic mutations. To corroborate the finding of whole-exome sequencing (WES), a polymerase chain reaction (PCR) was performed on the flanking region encompassing the identified variant. Subsequent Sanger sequencing of the PCR product verified the presence of the WES-derived variant. The variant was than investigated in additional affected families through Sanger sequencing and restriction fragment length polymorphism (RFLP)-PCR analysis. A thorough analysis of whole-exome sequencing data led to the identification of a pathogenic c.1180 C > T variant (NM_198159.3) in the MITF gene, which is likely to be a causative factor for non-syndromic hearing loss in this family. This particular nucleotide substitution leads to the formation of a premature stop codon at amino acid position 394 (p. Arg394Ter, NP_937802.1) of the MITF protein. It is predicted that this will result in a truncated and potentially non-functional protein product. The identified pathogenic variant was detected in a heterozygous state in 13 of the affected individuals, which is consistent with an autosomal dominant inheritance pattern. However, the pathogenic variant was also detected in a homozygous state in 2 individuals. Also, in examining the clinical manifestations of this mutation, no notable differences were observed between homozygous and heterozygous individuals. The c.1180C>T variant in MITF (NM_198159.3), previously reported in ClinVar (Variation ID: 995923) as pathogenic for Waardenburg syndrome type 2A, was identified. Unlike prior reports associating this variant with a broad spectrum of symptoms, including pigmentation abnormalities, our study found it to be linked solely to hearing loss in this population. Notably, no differences in clinical manifestations were observed between homozygous and heterozygous individuals, suggesting population-specific factors may influence the phenotypic expression of this variant.

Classically, Usher syndrome is characterized by the association of sensorineural hearing loss (SNHL), retinitis pigmentosa (RP) and possible vestibular dysfunction. Pathogenic bi-allelic variants in CEP250 cause atypical autosomal recessive Usher syndrome, which is associated with SNHL and photoreceptors dysfunction without vestibular signs. To date, only 19 scattered descriptions have been reported. In this study, we present detailed clinical and genetic description of 7 unrelated individuals with CEP250 related disease, along with a literature review to provide new insight on the severity and course of the disease. We retrospectively recruited 7 unrelated individuals who underwent genetic testing (targeted gene panel or whole genome sequencing) and were found to carry CEP250 pathogenic variants. Most patients (5/7) exhibit both retinal dystrophy and SNHL. Two patients appear to present either isolated hearing loss or visual impairment, but further investigations are needed to confirm a possible non-syndromic presentation. All patients harbored isolated truncating variants. CEP250 pathogenic variants are associated with post-lingual SNHL, and most often progressive photoreceptor dysfunction. The disease may begin with ocular features or hearing loss. We strongly recommend genetic analysis of classical and atypical Usher related-genes, in patients with isolated retinal dystrophy or SNHL. We also recommend ophthalmological evaluation and follow-up in patients with isolated SNHL, and conversely. The coexistence of loss- and gain-of-function effects may exist, complicating the development of gene therapy.