ScholarWorks@성균관대학교

초록

Background and Aims: De novo mutations provide a fundamental source of gene pool changes, driving genomic microevolution. Charcot–Marie–Tooth disease (CMT), which is a group of genetically and clinically heterogeneous peripheral neuropathic disorders, is characterized by progressive muscle weakness, hand and foot deformities, and occasional involvement of other organs. This study conducted the first cohort study of de novo mutations in CMT patients. Methods: De novo mutations were examined in 151 genetically diagnosed father–mother–child trio autosomal dominant CMT families except for CMT1A. Results: We identified 49 de novo point or small indel mutations in 61 patients. The frequency of de novo mutations was 40.4%, with gene-specific rates in their distribution. Haplotype analysis revealed predominant paternal origin, consistent with previous reports for CMT1A. Frequent substitutions at highly methylated CpG sites suggested that CpG methylation strongly contributes to the induction of de novo mutations. In particular, this study observed an anticipation of earlier onset in the affected children compared to their parents (founders) with de novo mutations. Interpretation: This study reports de novo mutations that occur frequently in CMT families. Characterization of de novo pathogenic mutations is expected to provide valuable insights not only into the genetic diagnosis and treatment of rare genetic diseases, but also into the evolutionary genomic study of deleterious alleles.

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