DYM – Smith-McCort Dysplasia

Smith-McCort dysplasia (SMC) is an autosomal recessive spondyloepimetaphyseal dysplasia characterized by short trunk stature and lacy iliac crests but normal cognitive development. SMC is allelic to Dyggve-Melchior-Clausen syndrome (DMC) and is caused by bi-allelic non-synonymous variants in DYM that permit residual dymeclin function. Two unrelated consanguineous families with SMC1 have been reported, each segregating homozygous DYM missense variants and showing complete co-segregation in affected members ([PMID:16470731]).

Functional studies of DYM-deficient chondrocytes and fibroblasts demonstrate enlarged endoplasmic reticulum networks and intracytoplasmic vesicle accumulation, supporting a loss-of-function mechanism in Golgi trafficking ([PMID:15464420]). The variant spectrum in DYM includes missense changes as well as frameshift and splice variants; one recurrent DMC-associated allele, c.719C>A (p.Ser240Ter), was observed in multiple probands ([PMID:35477554]). No conflicting reports dispute the association of DYM with SMC. Taken together, bi-allelic DYM variants consistently yield a Mendelian recessive skeletal dysplasia without intellectual disability, underpinning diagnostic molecular testing and carrier screening.

Key Take-home: DYM loss-of-function variants cause Smith-McCort dysplasia via autosomal recessive inheritance, with clear genotype–phenotype correlation and supportive cellular pathology.

References

• Molecular genetics and metabolism • 2004 • Recent advances in Dyggve-Melchior-Clausen syndrome PMID:15464420
• American journal of medical genetics. Part A • 2006 • Dyggve-Melchior-Clausen syndrome and Smith-McCort dysplasia: clinical and molecular findings in three families supporting genetic heterogeneity in Smith-McCort dysplasia PMID:16470731

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