De novo heterozygous mutations in SMC3 cause a range of Cornelia de Lange syndrome-overlapping phenotypes

Area of Science:

• Genetics
• Molecular Biology
• Developmental Biology

Background:

• Cornelia de Lange syndrome (CdLS) is a genetic disorder with characteristic facial dysmorphism, growth failure, intellectual disability, limb malformations, and organ involvement.
• Mutations in cohesin complex genes (SMC1A, SMC3, RAD21) and regulators (NIPBL, HDAC8) explain over 70% of CdLS cases.
• Clinical data for CdLS patients with SMC3 mutations are scarce, with only one case previously published.

Purpose of the Study:

• To present a detailed clinical comparison of 16 patients with CdLS-like features caused by SMC3 mutations.
• To investigate the impact of SMC3 mutations on cohesin complex function and associated phenotypes.
• To delineate the specific clinical spectrum of SMC3-related CdLS.

Main Methods:

• International research and clinical collaboration involving 16 patients with CdLS-like features.
• Clinical data collection and comparative analysis of patient phenotypes.
• Protein structure modeling to understand the effect of mutations on the cohesin complex.

Main Results:

• SMC3 mutations account for approximately 1%-2% of CdLS-like phenotypes.
• SMC3-associated phenotypes include postnatal microcephaly, less distinct craniofacial features, milder prenatal growth retardation, fewer congenital heart defects, and absence of limb deficiencies compared to typical CdLS.
• While most mutations were unique, two unrelated patients shared the same mutation but exhibited different phenotypes, suggesting variable expressivity.

Conclusions:

• De novo SMC3 mutations are a cause of CdLS-like phenotypes with a distinct clinical profile.
• The identified SMC3 mutations likely exert a dominant-negative effect on the cohesin complex.
• Further research is needed to understand the variable expressivity observed in patients with identical SMC3 mutations.