Phenotypes and genotypes in individuals with SMC1A variants.

Area of Science:

• Genetics and Molecular Biology
• Developmental Biology
• Neurology

Background:

• SMC1A gene encodes a cohesin complex protein.
• SMC1A variants are associated with Cornelia de Lange syndrome (CdLS).
• Recent studies identify SMC1A variants in epilepsy encephalopathy cases without CdLS features.

Purpose of the Study:

• To characterize physical and behavioral phenotypes of individuals with SMC1A variants.
• To compare SMC1A variant phenotypes with those caused by NIPBL variants.
• To investigate SMC1A variant phenotypes in a Dutch cohort, including those with and without CdLS.

Main Methods:

• International, interdisciplinary study involving 51 individuals with SMC1A variants.
• Comparison with 67 individuals carrying NIPBL variants.
• Detailed assessment of physical, behavioral, cognitive, and adaptive functioning.

Main Results:

• SMC1A variants can cause CdLS-like phenotypes, generally less severe than NIPBL variants (e.g., milder growth disturbance, fewer major limb anomalies).
• Individuals with SMC1A variants exhibit distinct facial features (periocular signs, thin upper vermillion) and higher cognitive/adaptive functioning compared to NIPBL group.
• A subset of females with SMC1A variants presented with a Rett syndrome-like phenotype (epileptic encephalopathy, intellectual disability, stereotypic movements).

Conclusions:

• SMC1A variants can lead to phenotypes resembling both CdLS and Rett syndrome.
• Shared features between SMC1A and NIPBL groups suggest cohesin dysfunction's role in pathogenesis.
• Differences may indicate additional mechanisms, potentially involving cohesin gene moonlighting.