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A Novel Missense Pathogenic Variant C.9455T > G (P.L3152r) in Cdh23 Underlies Autosomal Recessive Non-Syndromic Hearing Loss Publisher



L Sadeghian LADAN ; M Hoseinzadeh MARZIYEH ; Mr Pourreza Mohammad REZA ; S Khalili SAEED ; N Fattahi NAJMEH ; Ma Tabatabaiefar Mohammad AMIN
Authors

Source: Egyptian Journal of Medical Human Genetics Published:2025


Abstract

Background: Hearing loss (HL) is the most common sensory-neural defect worldwide and the second most common disability in Iran. This study aimed to identify the genetic cause of autosomal recessive non-syndromic hearing loss (ARNSHL) in a large Iranian family using next-generation sequencing and structural bioinformatics. Methods: After a comprehensive clinical evaluation of a large family with a history of HL the GJB2 gene was sequenced, and 7 loci were screened through genetic linkage analysis. Targeted next-generation sequencing was applied following proper variant filtration, co-segregation analysis, in silico assessment, and protein modeling. The variant was checked in 50 unrelated ethnically matched controls using the HRM technique. Results: The pedigree was a large autosomal recessive non-syndromic hearing loss family negative for GJB2 variants and unlinked to the selected loci. A novel missense variant, c.9455 T > G (p.L3152R), was identified in the CDH23 gene. The prediction software tools regarded it as damaging. The variant co-segregated with the phenotype in the pedigree and was absent in the controls. The variant interpretation was done based on the literatures and the American College of Medical Genetics and Genomics (ACMG) guidelines. Conclusion: The present study extends the genetic variants spectrum of hereditary HL. Our analysis revealed a novel missense variant, c.9455T > G (p.L3152R), in exon 66 of the DFNB12 phenotype. Our data can be helpful for genetic counseling and preventing hereditary HL, especially in families with consanguineous marriage. Based on the ACMG. © 2025 Elsevier B.V., All rights reserved.
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