Phenotypes and Genotypes in Patients with -Related Developmental and Epileptic Encephalopathy.

The X-linked gene encodes a core subunit of the cohesin complex that plays a pivotal role in genome organization and gene regulation. Pathogenic variants in are often dominant-negative and cause Cornelia de Lange syndrome (CdLS) with growth retardation and typical facial features; however, rare variants cause a developmental and epileptic encephalopathy (DEE) with intractable early-onset epilepsy that is absent in CdLS. Unlike the male-to-female ratio of 1:2 in those with CdLS associated with dominant-negative variants, -DEE loss-of-function (LOF) variants are found exclusively in females due to presumed lethality in males. It is unclear how different variants cause CdLS or DEE. Here, we report on phenotypes and genotypes of three females with DEE and de novo variants, including a novel splice-site variant. We also summarize 41 known -DEE variants to characterize common and patient-specific features. Interestingly, compared to 33 LOFs detected throughout the gene, 7/8 non-LOFs are specifically located in the N/C-terminal ATPase head or the central hinge domain, both of which are predicted to affect cohesin assembly, thus mimicking LOFs. Along with the characterization of X-chromosome inactivation (XCI) and transcription, these variants strongly suggest that a differential SMC1A dosage effect of -DEE variants is closely associated with the manifestation of DEE phenotypes.