Genetic screening of a Chinese cohort of children with hearing loss using a next-generation sequencing panel

Abstract

Background At present, the hereditary hearing loss homepage, (https://hereditaryhearingloss.org/), includes 258 deafness genes and more than 500 genes that have been reported to cause deafness. With few exceptions, the region-specific distributions are unclear for many of the identified variants and genes. Methods Here, we used a custom capture panel to perform targeted sequencing of 518 genes in a cohort of 879 deaf Chinese probands who lived in Yunnan. Mutation sites of the parents were performed by high-throughput sequencing and validated by Sanger sequencing. Results The ratio of male to female patients was close to 1:1 (441:438) and the age of onset was mainly under six. Most patients (93.5%) were diagnosed with moderate to severe deafness. Four hundred and twenty-eight patients had variants in a deafness gene, with a detection rate of 48.7%. Pathogenic variants were detected in 98 genes and a number of these were recurrent within the cohort. However, many of the variants were rarely observed in the cohort. In accordance with the American College of Medical Genetics and Genomics, pathogenic, likely pathogenic and variants of uncertain significance accounted for 34.3%, 19.3% and 46.4% of all detected variants, respectively. The most common genes included GJB2, SLC26A4, MYO15A, MYO7A, TMC1, CDH23, USH2A and WFS1, which contained variants in more than ten cases. The two genes with the highest mutation frequency were GJB2 and SLC26A4, which accounted for 28.5% (122/428) of positive patients. We showed that more than 60.3% of coding variants were rare and novel. Of the variants that we detected, 80.0% were in coding regions, 17.9% were in introns and 2.1% were copy number variants. Conclusion The common mutation genes and loci detected in this study were different from those detected in other regions or ethnic groups, which suggested that genetic screening or testing programs for deafness should be formulated in accordance with the genetic characteristics of the region.

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

“…Further, the variant is classified as pathogenic in reference databases for variant interpretation such as the HGMD [11] and the Deafness Variation Database [12], which report possibly disease-causing variants identified in patients affected by different conditions. Finally, the variant has already been identified in compound heterozygosis with other variants in two additional USH patients [18,19].…”

The prevalence and clinical features of MYO7A-related hearing loss including DFNA11, DFNB2 and USH1B

“…Among the 20 cases, one case was DFNA11 (0.7%, 1/141 autosomal dominant HL cases), three cases were DFNB2 (0.36%, 3/830 autosomal recessive HL or sporadic cases), and 16 cases were USH1B (1.68%, 14/830 autosomal recessive HL or sporadic cases, one case identified as AD, and one case identified with an unknown family history). Ma et al 13 , reported the NGS analysis results for 879 Chinese HL patients, with the prevalence of MYO7A -associated HL being 2.39% (21/879 cases). Eleven cases were DFNA11 (6.88%, 11/160 autosomal dominant HL cases) and 10 cases were DFNB11 or USH1B (1.70%, 10/589 autosomal recessive HL or sporadic cases).…”

Structure, function and drug discovery of GPCR signaling

“…Additionally, associations have been drawn between ADGRF1 (GPR110) and breast cancer progression [ 62 ], as well as ADGRL3 and attention-deficit/hyperactivity disorder [ 63 , 64 ]. Mutations in ADGRV1 have been implicated in Usher syndrome type 2C, leading to deafness and blindness [ 65 ]. Thus, understanding the structural characteristics and operational modes of aGPCRs holds promise for revealing the molecular basis of biological processes, disease mechanisms, and the development of novel therapeutic strategies.…”