A De Novo Frameshift Variant in SMC1A Causes Non-Classic Cornelia de Lange Syndrome With Epilepsy: A Case Report and Literature Review.

Background: Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder. Although individuals with variants in the SMC1A gene are less commonly seen in CdLS, they exhibit a high incidence of epilepsy and atypical phenotypic variability.

Methods: The clinical data of a patient with non-classic CdLS and epilepsy caused by an SMC1A variant were summarized. A literature review was conducted to analyze the genotype-phenotype correlations and epilepsy characteristics in related cases.

Results: A 5-year-6-month-old female patient presented with facial features, double outlet right ventricle (DORV), and recurrent epilepsy. Whole exome sequencing (WES) identified a de novo heterozygous frameshift mutation, c.2890_2893del (p.Ser964Valfs*26), in the SMC1A gene. A review of the literature identified several characteristics of non-classic CdLS with epilepsy caused by SMC1A variants: the majority of cases were non-classic (81.5%), predominantly female (68.2%), with a median onset age of 11.5 months. Common features included severe/profound developmental delay (52.6%), hypotonia (18.2%), cardiovascular anomalies (36.4%), and intrauterine growth retardation (IUGR) (22.7%). Among the non-classic cases, seizure clusters occurred in 22.7%, status epilepticus in 18.2%, and drug-resistant epilepsy in 33.3%. Genotypes in non-classic cases included missense mutations (40.9%), frameshift mutations (31.8%), splice site variants (9.1%), nonsense mutations (9.1%), deletions (4.5%), and truncations (4.5%).

Conclusion: Our study expanded the phenotypic data and mutational spectrum of non-classic CdLS with epilepsy caused by SMC1A variants. Compared to individuals with the classic form of CdLS, the non-classic cases appeared more frequently in females and were associated with a higher prevalence of severe/profound developmental delay and cardiovascular anomalies. In contrast, IUGR was significantly less common in non-classic individuals. Regarding epilepsy characteristics, some individuals including seizure clusters, status epilepticus, drug resistance, and hypotonia, no significant differences were observed between classic and non-classic cases. The predominant genotypes in non-classic cases were missense and frameshift mutations.