Phenotypes and genotypes in individuals with SMC1A variants

SMC1Aencodes one of the proteins of the cohesincomplex. SMC1Avariants are known to cause a phenotyperesembling Cornelia de Lange syndrome(CdLS). Exome sequencinghas allowed recognizing SMC1Avariants in individuals with encephalopathy with epilepsy who do not resemble CdLS. We performed an international, interdisciplinary study on 51 individuals with SMC1Avariants for physical and behavioral characteristics, and compare results to those in 67 individuals with NIPBLvariants. For the Netherlands all known individuals with SMC1Avariants were studied, both with and without CdLS phenotype. Individuals with SMC1Avariants can resemble CdLS, but manifestations are less marked compared to individuals with NIPBLvariants: growth is less disturbed, facial signs are less marked (except for periocular signs and thin upper vermillion), there are no major limb anomalies, and they have a higher level of cognitive and adaptive functioning. Self-injurious behavior is more frequent and more severe in the NIPBLgroup. In the Dutch group 5 of 13 individuals (all females) had a phenotypethat shows a remarkable resemblance to Rett syndrome: epileptic encephalopathy, severe or profound intellectual disability, stereotypic movements, and (in some) regression. Their missense, nonsense, and frameshift mutationsare evenly spread over the gene. We conclude that SMC1Avariants can result in a phenotyperesembling CdLS and a phenotyperesembling Rett syndrome. Resemblances between the SMC1Agroup and the NIPBLgroup suggest that a disturbed cohesinfunction contributes to the phenotype, but differences between these groups may also be explained by other underlying mechanisms such as moonlightingof the cohesingenes.