DYM – Dyggve-Melchior-Clausen Syndrome

Dyggve-Melchior-Clausen syndrome (DMC) is a rare autosomal recessive spondyloepimetaphyseal dysplasia characterized by progressive skeletal abnormalities, disproportionate short stature, and intellectual disability. Positional cloning mapped the DMC locus to chromosome 18q21.1, and deleterious DYM mutations were identified in 10 unrelated families ([PMID:12554689]).

Biallelic loss-of-function variants—nonsense (e.g., c.1205T>A (p.Leu402Ter)), frameshift, and splice-site changes—have been reported in over 50 probands. Founder mutations include c.2043del (p.Lys681fs) in Moroccan patients ([PMID:22090722]) and multiple truncating alleles in Egyptian cohorts ([PMID:19816730]).

Inheritance is autosomal recessive; segregation studies confirm homozygous or compound heterozygous DYM variants in affected individuals, with parental carriers often asymptomatic. Additional affected relatives within pedigrees have been reported primarily among siblings in consanguineous families.

Functional assays of patient fibroblasts and chondrocytes demonstrate dilated rough endoplasmic reticulum, enlarged vesicles, and impaired intracellular trafficking. Splice-site mutations such as IVS15+3G>T disrupt normal transcripts ([PMID:20865280]), consistent with a loss-of-function mechanism.

No conflicting evidence has emerged; the concordance of genetic, segregation, and cellular findings establishes a definitive gene–disease relationship.

Key Take-home: Biallelic DYM loss-of-function variants are a definitive cause of DMC; genetic testing of DYM is critical for accurate diagnosis, carrier screening, and management.

References

• Human molecular genetics • 2003 • Mutations in a novel gene Dymeclin (FLJ20071) are responsible for Dyggve-Melchior-Clausen syndrome. PMID:12554689
• Journal of children’s orthopaedics • 2009 • Dyggve-Melchior-Clausen syndrome: clinical, genetic, and radiological study of 15 Egyptian patients from nine unrelated families. PMID:19816730
• American journal of medical genetics. Part A • 2024 • Further defining the molecular spectrum and long-term follow-up of 17 patients with Dyggve-Melchior-Clausen and Smith-McCort dysplasia type 2. PMID:38860472
• Indian journal of human genetics • 2011 • A recurrent mutation in Moroccan patients with Dyggve-Melchior-Clausen syndrome: Report of a new case and review. PMID:22090722
• European journal of pediatrics • 2011 • Dyggve-Melchior-Clausen syndrome: novel splice mutation with atlanto-axial subluxation. PMID:20865280

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