Exome Sequencing Identifies a Novel Splicing Variant in COL9A3 Resulting in Multiple Epiphyseal Dysplasia: A Case Report

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BACKGROUND: Multiple epiphyseal dysplasia (MED, OMIM #600969) is sometimes a mild skeletal dysplasia with diverse clinical findings, including early-onset osteoarthritis and short stature. Radiographic surveys can identify delayed epiphyseal ossification and cartilaginous changes. Due to genetic heterogeneity in MED, with dominant or recessive inheritance, molecular testing is essential for its diagnosis. METHODS: The clinical manifestations, the results of laboratory examinations, and genetic analysis of a 14-year-old Pakistani male with MED are reported. CASE PRESENTATION: Here we present a male patient with type-1 diabetes and hypothyroidism with bilateral knee effusions, right knee flexion contracture, and chronic arthralgias in his elbows and wrists. Given his symptomatology, a diagnosis of juvenile idiopathic arthritis (JIA) was initially suspected. Radiographs revealed sclerotic changes and fragments in the femoral and tibial epiphyses, suggesting destructive arthropathy. Genetic testing identified a COL9A3 variant (c.148-1G>C), as well as CTLA4 deficiency. The COL9A3 gene produces type IX collagen, and mutations in this gene can disrupt collagen folding or its interaction with other cartilage components. Complications include joint damage and early osteoarthritis, possibly requiring surgery. DISCUSSION: To date, only three COL9A3 splice-site mutations have been linked to MED. Our patient's splicing variant (c.148-1G>C) is novel and is likely causative, based on similar pathogenic mutations. Our patient presented with symptoms suggestive of JIA, but radiographic findings were inconsistent with this diagnosis. Genetic testing revealed a new pathogenic splicing variant in the COL9A3 gene, confirming MED. CONCLUSION: This case highlights the importance of early molecular testing if radiographic sclerotic changes are seen in the epiphyses due to the clinical and genetic heterogeneity of MED.