Balkan medical journal · 2026
A Novel Pathogenic Haplotype in CDH23 Causing DFNB12: The Combined Effect of Two Individually Benign Variants.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Tian Zi-Xin, Zhang Jun, Wang Zi-Xuan, Song Xi, Zhou Yi-Tao, Hu Ying-Yi
Аннотация
BACKGROUND: Aberrations in cadherin-related 23 (CDH23) account for a significant proportion of familial autosomal recessive non-syndromic hearing loss (DFNB12), a common subtype of hereditary hearing loss worldwide.
AIMS: To elucidate the molecular basis and pathogenic mechanism of DFNB12 in an affected girl from a nine-member pedigree.
STUDY DESIGN: Family-based genetic study with pedigree analysis.
METHODS: Clinical whole-exome sequencing combined with pedigree analysis was used to identify disease-causing mutations. The potential functional consequences of these mutations were investigated using structural bioinformatic approaches, including homology modeling, molecular dynamics simulations, and other relevant tools.
RESULTS: The proband carried compound heterozygous variants: a known pathogenic maternal variant (c.6049G > A) and a paternal haplotype comprising two linked variants (c.3262G > A and c.6911G > A), each individually classified as benign. Pedigree segregation analysis demonstrated that the paternal haplotype acts as a single pathogenic allele.
CONCLUSION: Two individually benign variants can combine to form a novel pathogenic haplotype (c.3262A–c.6911A). This mechanism may be under-recognized in routine variant interpretation pipelines. Our findings underscore the importance of evaluating the combined effects of linked benign variants to ensure accurate genetic counseling.
AIMS: To elucidate the molecular basis and pathogenic mechanism of DFNB12 in an affected girl from a nine-member pedigree.
STUDY DESIGN: Family-based genetic study with pedigree analysis.
METHODS: Clinical whole-exome sequencing combined with pedigree analysis was used to identify disease-causing mutations. The potential functional consequences of these mutations were investigated using structural bioinformatic approaches, including homology modeling, molecular dynamics simulations, and other relevant tools.
RESULTS: The proband carried compound heterozygous variants: a known pathogenic maternal variant (c.6049G > A) and a paternal haplotype comprising two linked variants (c.3262G > A and c.6911G > A), each individually classified as benign. Pedigree segregation analysis demonstrated that the paternal haplotype acts as a single pathogenic allele.
CONCLUSION: Two individually benign variants can combine to form a novel pathogenic haplotype (c.3262A–c.6911A). This mechanism may be under-recognized in routine variant interpretation pipelines. Our findings underscore the importance of evaluating the combined effects of linked benign variants to ensure accurate genetic counseling.