Background/Objectives: Multiple epiphyseal dysplasia (MED) is a clinically and genetically heterogeneous group of disorders characterized by a waddling gait, joint pain, and early-onset osteoarthritis. The aim of this study was to compare the genetic characteristics and long-term clinical follow-up findings of 22 patients with MED from 17 unrelated families. Methods: Molecular diagnosis was performed using clinical exome analysis and exome sequencing. Seventeen children were followed for a median of 5.5 years. Results: Eighteen disease-related variants were identified: 47% in COMP, 11.8% each in COL9A2 and COL9A3 in a monoallelic state, 17.6% in SLC26A2, and 11.8% each in MATN3 and CANT1 in a biallelic state. Some COMP mutations previously identified in pseudoachondroplasia, an allelic disorder of MED1, were shown in our study to exhibit a typical MED1 or intermediate phenotype. In contrast, it was confirmed that certain mutations in SLC26A2 lead to MED4 phenotype. Furthermore, it has been observed that biallelic variants in MATN3 may be associated with the MED5 phenotype. In patients with MED2 and MED3, the knee joint is affected, while in other types, the hip joint is predominantly affected. In 15 children followed until ages 11-18, height decreased slightly as they grew older but remained normal or at the lower limit, and slow progression was observed in the waddling gait and joint pain, except in the intermediate form. Conclusions: This study reveals the frequency of disease-related variants, including seven novel ones, in genes leading to MED1-5 and 7 phenotypes, and expands the spectrum of genetic and clinical phenotypes.
Keywords: CANT1; COL9A2; COL9A3; COMP; MATN3; SLC26A2; multiple epiphyseal dysplasia; phenotype variability.