Rare Genetic Mechanisms in Dyggve-Melchior-Clausen Disease

Abstract Dyggve-Melchior-Clausen disease (DMC) is a rare skeletal dysplasia caused by biallelic variants in DYM. We investigated four affected individuals from three families with classical DMC features and non-diagnostic whole-exome sequencing. Reanalysis identified a homozygous deep intronic variant, DYM: c.193+132G>T, in Family 1 and a homozygous 331-bp AluYb8 insertion in exon 12 in Family 2. CRISPR prime editing and transcript analysis demonstrated that c.193+132G>T activates cryptic splice sites, resulting in 13-bp and 67-bp pseudoexon inclusion predicted to disrupt the reading frame. A missense variant of uncertain significance was identified in Family 3. These findings expand the mutational spectrum of DYM and highlight the value of investigating non-coding and structural variants in patients with a strong DMC phenotype.