Miao Yan, Li Jiashan, Liang Siying, Li Shuo
Women and Children's Hospital, Qingdao University, Qingdao, Shandong, China.
Mol Genet Genomic Med. 2025 Sep;13(9):e70135. doi: 10.1002/mgg3.70135.
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.
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.
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.
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.
发育性髋关节发育不良（DDH）是一种常见的先天性肌肉骨骼疾病，其特征为髋关节结构异常。虽然其病因涉及遗传和环境因素，但具体的遗传机制仍知之甚少。COMP基因（COMP；OMIM：600310）的突变通常与骨骼发育不良如假性软骨发育不全（PSACH）和多发性骨骺发育不良（MED）相关，很少与孤立性DDH相关联。
一名患有家族性DDH的29岁男性先证者接受了临床评估和影像学检查。对先证者及其父母进行了全外显子组测序（WES），随后进行Sanger测序以验证受影响家庭成员中的变异。使用美国医学遗传学与基因组学学会（ACMG）指南评估致病性，纳入人群频率、保守性评分（如REVEL）和临床相关性。
WES在外显子10中鉴定出一个杂合错义变异（COMP c.1133A>C，p.D378A），该变异在三代人中与DDH表型共分离。影像学和临床检查结果排除了PSACH和MED。功能预测（REVEL评分：0.84）以及在人群数据库中的缺失支持将其分类为“可能致病”。检测到其他易感基因（如GDF5，OMIM：601146；TBX4，OMIM：601719），但无法解释家族模式。
杂合的COMP c.1133A>C变异可能是该家系中家族性DDH的一个高外显率致病因素，提示常染色体显性遗传。这一发现表明COMP突变可能超出经典骨骼发育不良的范畴，显著增加DDH风险，可能与其他遗传或环境因素相互作用，符合DDH的多因素病因。
