Mutations and variants in the cohesion factor genes NIPBL, SMC1A, and SMC3 in a cohort of 30 unrelated patients with Cornelia de Lange syndrome

Abstract

Cornelia de Lange syndrome (CdLS) manifests facial dysmorphic features, growth and cognitive impairment, and limb malformations. Mutations in three genes (NIPBL, SMC1A, and SMC3) of the cohesin complex and its regulators have been found in affected patients. Here, we present clinical and molecular characterization of 30 unrelated patients with CdLS. Eleven patients had mutations in NIPBL (37%) and three patients had mutations in SMC1A (10%), giving an overall rate of mutations of 47%. Several patients shared the same mutation in NIPBL (p.R827GfsX2) but had variable phenotypes, indicating the influence of modifiers in CdLS. Patients with NIPBL mutations had a more severe phenotype than those with mutations in SMC1A or those without identified mutations. However, a high incidence of palate defects was noted in patients with SMC1A mutations. In addition, we observed a similar phenotype in both male and female patients with SMC1A mutations. Finally, we report the first patient with an SMC1A mutation and the Sandifer complex.

FIG. 1

Phenotypes of patients with CdLS and mutations in NIPBL and SMC1A. Individuals C5, C8, C10, C14, C18, C20, C21, C25, C26, C28 and C29 have mutations in NIPBL. Individuals C13 and C30 have mutations in SMC1A. Phenotype of individual C2 has been published elsewhere [Deardorff et al., 2007]. Patients with NIPBL mutations are surrounded by a solid line and patients with SMC1A mutations are surrounded by a dashed line.