Phenotypes and Genotypes in Patients with SMC1A-Related Developmental and Epileptic Encephalopathy

Abstract

The X-linked SMC1A gene encodes a core subunit of the cohesin complex that plays a pivotal role in genome organization and gene regulation. Pathogenic variants in SMC1A are often dominant-negative and cause Cornelia de Lange syndrome (CdLS) with growth retardation and typical facial features; however, rare SMC1A 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 SMC1A variants, SMC1A-DEE loss-of-function (LOF) variants are found exclusively in females due to presumed lethality in males. It is unclear how different SMC1A variants cause CdLS or DEE. Here, we report on phenotypes and genotypes of three females with DEE and de novo SMC1A variants, including a novel splice-site variant. We also summarize 41 known SMC1A-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 SMC1A transcription, these variants strongly suggest that a differential SMC1A dosage effect of SMC1A-DEE variants is closely associated with the manifestation of DEE phenotypes.

Heterozygous loss-of-function SMC3 variants are associated with variable growth and developmental features

“…The SMC1A LoF phenotype, SMC1A-related developmental and epileptic encephalopathy, results in early-onset intractable epilepsy and severe intellectual disability in females and is presumed to be developmentally lethal in most males. 76 This contrasts with the overall milder SMC3 pLoF phenotype described above. This difference could be due to moonlighting functions of SMC1A, or perhaps more obviously because of SMC1A being X-linked and subject to incomplete X-inactivation (reviewed in references 77 , 78 , 79 ).…”

Video-electroencephalographic findings and clinical characteristics of bathing seizures in children

“…The SMC1A gene mutation was first described in a patient with rare Cornelia de Lange syndrome (CdLS), characterized by growth retardation and typical facial deformities ( 21 ). There have also been recent reports of phenotypes such as seizures, developmental epileptic encephalopathy, or Rett syndrome ( 22 , 23 ). The phenotypic characteristics of the patient in this particular case were developmental delay, finger deformity, a slow EEG background, multifocal interictal discharges, and uncontrollable focal seizures—all of which were consistent with developmental epileptic encephalopathy.…”

Early onset developmental and epileptic encephalopathy and Rett-like phenotype in a 15-year-old girl affected by Cornelia de Lange syndrome type 2 due to a SMC1A gene mutation

“…SMC1A protein is one of the components of the ring-shaped cohesion complex, which functions by forming heterodimers with RAD21 and SMC3. This core subunit orchestrates long-range DNA interactions to mediate sister chromatid cohesion during the cell cycle, which is essential for accurate chromosome segregation, DNA repair, and regulation of chromosomal architecture [6] , [7] . Heterozygous de novo SMC1A loss-of-function mutations have recently been described in a limited number of affected females with a more severe DEE clinical phenotype.…”

“…Interestingly, SMC1A -DEE and PCDH19 -related epilepsy share some epileptic features, e.g. drug resistance and seizure clustering [7] .…”

“…It is involved in chromosome segregation, DNA repair, and regulation of chromosomal architecture. Heterozygous de novo SMC1A loss-of-function mutations have been recently described in females with a more severe DEE clinical phenotype [6] , [7] .…”