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Review
. 2025 Jan;13(1):e70058.
doi: 10.1002/mgg3.70058.

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

Ying Yang  1 , Liqing Chen  2 , Zhenzhen Wang  3 , Yaling Ding  4 , Yan Liu  2
Affiliations
Review

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

Ying Yang et al. Mol Genet Genomic Med. 2025 Jan.

Abstract

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.

Keywords: SMC1A; Cornelia de Lange syndrome; double outlet right ventricle; epilepsy; non‐classic.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Characteristic facial features (a) and small hands (b) of the proband.
FIGURE 2
FIGURE 2
Video‐EEG of the proband.
FIGURE 3
FIGURE 3
(a) gliosis in the left occipital lobe (red arrow), atrophy of the left hippocampus(yellow arrow). (b) cerebromalacia in right cerebellum (red arrow).
FIGURE 4
FIGURE 4
A de novo heterozygous frameshift variant in SMC1A was detected in the proband, and this variant was not identified in her parents.
See this image and copyright information in PMC

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References

    1. Barañano, K. W. , Kimball A., Fong S. L., Egense A. S., Hudon C., and Kline A. D.. 2022. “Further Characterization of SMC1A Loss of Function Epilepsy Distinct From Cornelia de Lange Syndrome.” Journal of Child Neurology 37, no. 5: 390–396. 10.1177/08830738221081244. - DOI - PubMed
    1. Borck, G. , Zarhrate M., Bonnefont J. P., Munnich A., Cormier‐Daire V., and Colleaux L.. 2007. “Incidence and Clinical Features of X‐Linked Cornelia de Lange Syndrome due to SMC1L1 Mutations.” Human Mutation 28, no. 2: 205–206. 10.1002/humu.9478. - DOI - PubMed
    1. Bozarth, X. L. , Lopez J., Fang H., Lee‐Eng J., Duan Z., and Deng X.. 2023. “Phenotypes and Genotypes in Patients With SMC1A‐Related Developmental and Epileptic Encephalopathy.” Genes 14, no. 4: 852. 10.3390/genes14040852. - DOI - PMC - PubMed
    1. Chatfield, K. C. , Schrier S. A., Li J., et al. 2012. “Congenital Heart Disease in Cornelia de Lange Syndrome: Phenotype and Genotype Analysis.” American Journal of Medical Genetics. Part A 158A, no. 10: 2499–2505. 10.1002/ajmg.a.35582. - DOI - PMC - PubMed
    1. Deardorff, M. A. , Kaur M., Yaeger D., et al. 2007. “Mutations in Cohesin Complex Members SMC3 and SMC1A Cause a Mild Variant of Cornelia de Lange Syndrome With Predominant Mental Retardation.” American Journal of Human Genetics 80, no. 3: 485–494. 10.1086/511888. - DOI - PMC - PubMed

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