Identification of Coding Variants in 10q22.1 Associated with Vitiligo in the Chinese Han Population.

Objective: This study aims to identify causal variants associated with vitiligo in an expanded region of 10q22.1. Materials and Methods: We conducted a fine-scale deep analysis of the expanded 10q22.1 region using in a large genome-wide association studies dataset consisting of 1117 cases and 1701 controls through imputation. We selected five nominal coding single nucleotide polymorphisms (SNPs) located in SLC29A3 and CDH23 and genotyped them in an independent cohort of 2479 cases and 2451 controls in a Chinese Han population cohort using the Sequenom MassArray iPLEX1 system. Results: A missense SNP in SLC29A3, rs2252996, showed strong evidence of association with vitiligo (p = 1.34 × 10-8, odds ratio [OR] = 0.82). Three synonymous SNPs (rs1084004 in SLC29A3; rs12218559 and rs10999978 in CDH23) provided suggestive evidence of association for vitiligo (p = 1.69 × 10-6, OR = 0.84; p = 9.47 × 10-5, OR = 1.18; p = 6.90 × 10-4, OR = 1.16, respectively). Stepwise conditional analyses identified two significant independent disease-associated signals from the four SNPs (both p < 0.05; both D' = 0.03; and r2 = 0.00). Conclusion: The study identifies four genetic coding variants in SLC29A3 and CDH23 on 10q22.1 that may contribute to vitiligo susceptibility with one missense variant affecting disease subphenotypes. The presence of multiple genetic variants underscores their significant role in the genetic pathogenesis of the disease.

Disruption of Cdh23 exon 68 splicing leads to progressive hearing loss in mice by affecting tip-link stability.

Inner ear hair cells are characterized by the F-actin-based stereocilia that are arranged into a staircase-like pattern on the apical surface of each hair cell. The tips of shorter-row stereocilia are connected with the shafts of their neighboring taller-row stereocilia through extracellular links named tip links, which gate mechano-electrical transduction (MET) channels in hair cells. Cadherin 23 (CDH23) forms the upper part of tip links, and its cytoplasmic tail is inserted into the so-called upper tip-link density (UTLD) that contains other proteins such as harmonin. The Cdh23 gene is composed of 69 exons, and we show here that exon 68 is subjected to hair cell-specific alternative splicing. Tip-link formation is not affected in genetically modified mutant mice lacking Cdh23 exon 68. Instead, the stability of tip links is compromised in the mutants, which also suffer from progressive and noise-induced hearing loss. Moreover, we show that the cytoplasmic tail of CDH23(+68) but not CDH23(-68) cooperates with harmonin in phase separation-mediated condensate formation. In conclusion, our work provides evidence that inclusion of Cdh23 exon 68 is critical for the stability of tip links through regulating condensate formation of UTLD components.

Spectrum of genetic variants in bilateral sensorineural hearing loss.

Background: Hearing loss (HL) is an impairment of auditory function with identified genetic forms that can be syndromic (30%) or non-syndromic (70%). HL is genetically heterogeneous, with more than 1,000 variants across 150 causative genes identified to date. The genetic diagnostic rate varies significantly depending on the population being tested. Countries with a considerably high rate of consanguinity provide a unique resource for studying rare forms of recessive HL. In this study, we identified genetic variants associated with bilateral sensorineural HL (SNHL) using whole-exome sequencing (WES) in 11 families residing in the United Arab Emirates (UAE). Results: We established the molecular diagnosis in six probands, with six different pathogenic or likely pathogenic variants in the genes MYO15A, SLC26A4, and GJB2. One novel nonsense variant, MYO15A:p.Tyr1962Ter*, was identified in a homozygous state in one family, which has not been reported in any public database. SLC26A4 and GJB2 were found to be the most frequently associated genes in this study. In addition, six variants of uncertain significance (VUS) were detected in five probands in the genes CDH23, COL11A1, ADGRV1, NLRP3, and GDF6. In total, 12 variants were observed in eight genes. Among these variants, eight missense variants (66.7%), three nonsense variants (25.0%), and one frameshift (8.3%) were identified. The overall diagnostic rate of this study was 54.5%. Approximately 45.5% of the patients in this study came from consanguineous families. Conclusion: Understanding the genetic basis of HL provides insight for the clinical diagnosis of hearing impairment cases through the utilization of next-generation sequencing (NGS). Our findings contribute to the knowledge of the heterogeneous genetic profile of HL, especially in a population with a high rate of consanguineous marriage in the Arab population.

Which Came First? When Usher Syndrome Type 1 Couples with Neuropsychiatric Disorders.

Usher syndrome (USH) is an autosomal recessive disorder characterized by sensorineural hearing loss (HL), retinopathy, and vestibular areflexia, with variable severity. Although a high prevalence of behavioural and mental disorders in USH patients has been reported, few studies on these psychiatric and psychological issues have been conducted. This work describes the case of a 16-year-old boy affected by congenital bilateral sensorineural HL, presenting a suddenly altered behaviour concomitant with a decrease in visual acuity. To establish a molecular diagnosis, Whole-Exome Sequencing analysis was performed, detecting a pathogenetic homozygous variant (c. 5985C>A, p.(Tyr1995*)) within the CDH23 gene. CDH23 is a known USH type 1 causative gene, recently associated with schizophrenia-like symptoms and bipolar disorders. To date, no studies have provided evidence of a direct genotype-phenotype correlation between USH patients carrying CDH23 variants and mental/behavioural issues; however, considering the multiple biological functions of CDH23, it can be hypothesised that it could have a pleiotropic effect. Overall, this study highlights the relevance of a continuous clinical evaluation of USH patients, to monitor not only the disease progression, but to early detect any psychological or behavioural alterations, thus allowing a rapid implementation of therapeutic strategies aimed at improving their quality of life and well-being.