Molecular genetics & genomic medicine · 2025
Genetic Analysis of Familial Developmental Dysplasia of the Hip Associated With a Heterozygous Variant in the COMP Gene: A Case Report.
СтатьяКлинический случайНазвание и аннотация: Перевод в очереди
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Miao Yan, Li Jiashan, Liang Siying, Li Shuo
Аннотация
BACKGROUND: Developmental dysplasia of the hip (DDH) is a prevalent congenital musculoskeletal disorder characterized by structural abnormalities of the hip joint. While its etiology involves genetic and environmental factors, specific genetic mechanisms remain poorly understood. Mutations in the COMP gene (COMP; OMIM: 600310), classically associated with skeletal dysplasias such as pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED), are rarely linked to isolated DDH.
METHODS: A 29-year-old male proband with familial DDH underwent clinical evaluation and radiographic imaging. Whole-exome sequencing (WES) was performed on the proband and his parents, followed by Sanger sequencing to validate variants in affected family members. Pathogenicity was assessed using ACMG guidelines, incorporating population frequency, conservation scores (e.g., REVEL), and clinical correlation.
RESULTS: WES identified a heterozygous missense variant (COMP c.1133A>C, p.D378A) in exon 10, co-segregating with the DDH phenotype across three generations. Radiographic and clinical findings excluded PSACH and MED. Functional predictions (REVEL score: 0.84) and absence in population databases supported its classification as "likely pathogenic." Additional susceptibility genes (e.g., GDF5, OMIM: 601146; TBX4, OMIM: 601719) were detected but did not explain the familial pattern.
CONCLUSIONS: The heterozygous COMP c.1133A>C variant may be a highly penetrant pathogenic contributor to familial DDH in this pedigree, suggesting autosomal dominant inheritance. This finding suggests that COMP mutations might extend beyond classical skeletal dysplasias to significantly increase DDH risk, likely interacting with other genetic or environmental factors in line with the multifactorial etiology of DDH.
METHODS: A 29-year-old male proband with familial DDH underwent clinical evaluation and radiographic imaging. Whole-exome sequencing (WES) was performed on the proband and his parents, followed by Sanger sequencing to validate variants in affected family members. Pathogenicity was assessed using ACMG guidelines, incorporating population frequency, conservation scores (e.g., REVEL), and clinical correlation.
RESULTS: WES identified a heterozygous missense variant (COMP c.1133A>C, p.D378A) in exon 10, co-segregating with the DDH phenotype across three generations. Radiographic and clinical findings excluded PSACH and MED. Functional predictions (REVEL score: 0.84) and absence in population databases supported its classification as "likely pathogenic." Additional susceptibility genes (e.g., GDF5, OMIM: 601146; TBX4, OMIM: 601719) were detected but did not explain the familial pattern.
CONCLUSIONS: The heterozygous COMP c.1133A>C variant may be a highly penetrant pathogenic contributor to familial DDH in this pedigree, suggesting autosomal dominant inheritance. This finding suggests that COMP mutations might extend beyond classical skeletal dysplasias to significantly increase DDH risk, likely interacting with other genetic or environmental factors in line with the multifactorial etiology of DDH.