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A novel COMP mutation in a Chinese family with multiple epiphyseal dysplasia
Jiashen Shao1,2,3, Sen Zhao1,2, Zihui Yan1,2,3
1Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, No. 1 Shuaifuyuan, Beijing, 100730, China.
Background:
Multiple epiphyseal dysplasia (MED) is a skeletal disorder characterized by delayed and irregular ossification of the epiphyses and early-onset osteoarthritis. At least 66% of the reported autosomal dominant MED (AD-MED) cases are caused by COMP mutations.
Methods:
We recruited a four-generation Chinese family with early-onset hip osteoarthritis, flatfoot, brachydactyly, and mild short stature. An assessment of the family history, detailed physical examinations, and radiographic evaluations were performed on the proband and other family members, followed by the performance of whole-exome sequencing (WES). The pathogenicity of the candidate mutation was also analyzed.
Results:
An AD-MED family with 10 affected members and 17 unaffected members was recruited. The main radiographic findings were symmetrical changes in the dysplastic acetabulum and femoral heads, irregular contours of the epiphyses, a shortened femoral neck, and flatfoot. Lower bone density was also observed in the ankle joints, wrist joints, and knees, as well as irregular vertebral end plates. In the proband, we identified the missense mutation c.1153G > T (p. Asp385Tyr), located in exon 11 of the COMP gene. This mutation was assessed as 'pathogenic' because of its low allele frequency and its high likelihood of co-segregation with disease in the reported family. Sanger sequencing validated the novel heterozygous mutation c.1153G > T (p. Asp385Tyr) in exon 11 of COMP in all affected individuals in the family.
Conclusions:
Our results underlined a key role of the Asp385 amino acid in the protein function of COMP and confirmed the pathogenicity of the COMP (c.1153G > T; p. Asp385Tyr) mutation in AD-MED disease. We have therefore expanded the known mutational spectrum of COMP and revealed new phenotypic information for AD-MED.
Insights
A novel COMP gene mutation, c.1153G>T (p.Asp385Tyr), causes autosomal dominant Multiple Epiphyseal Dysplasia (AD-MED). This finding expands the known COMP mutations and provides new insights into AD-MED phenotypes.
Area of Science:
- Genetics
- Skeletal Dysplasias
- Molecular Biology
Background:
- Multiple Epiphyseal Dysplasia (MED) is a skeletal disorder affecting ossification and leading to early osteoarthritis.
- Autosomal dominant MED (AD-MED) is frequently linked to mutations in the COMP gene, accounting for at least 66% of cases.
Purpose of the Study:
- To investigate the genetic basis of early-onset osteoarthritis and skeletal abnormalities in a Chinese family.
- To identify the specific mutation responsible for AD-MED in the studied family and analyze its pathogenicity.
Main Methods:
- Recruitment of a four-generation Chinese family with affected and unaffected members.
- Comprehensive clinical assessments including family history, physical examinations, and radiographic evaluations.
- Whole-exome sequencing (WES) to identify genetic variants, followed by Sanger sequencing for validation.
Main Results:
- Radiographic findings included dysplastic acetabulum, irregular epiphyses, shortened femoral neck, flatfoot, and reduced bone density.
- A novel heterozygous missense mutation, c.1153G>T (p.Asp385Tyr) in exon 11 of the COMP gene, was identified in all affected individuals.
- The mutation co-segregated with the disease phenotype within the family and was classified as pathogenic due to its low allele frequency.
Conclusions:
- The identified COMP mutation (c.1153G>T; p.Asp385Tyr) is pathogenic and causes AD-MED.
- The Asp385 amino acid residue plays a crucial role in COMP protein function.
- This study expands the mutational spectrum of COMP and provides new phenotypic information for AD-MED.
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