Highlighting the different facets of SMC1A truncating variants: Two patients with novel SMC1A pathogenic variants

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SMC1A pathogenic variants were initially reported in Cornelia de Lange syndrome type 2.1, 2 In 2016, Jansen et al.3 described a phenotypic entity under the name “Intellectual disability and therapy resistant epilepsy” (ID-TRE) caused by truncating SMC1A pathogenic variants. ID-TRE overlaps with CDL but presents a more severe clinical spectrum.3 Furthermore, SMC1A pathogenic variants have also been implicated in Rett-like phenotypes.2, 4, 5 Here, we report two novel SMC1A truncating variants in two female patients, and we compare molecular and clinical data of these cases with 28 others to help develop possible genotype–phenotype correlations. The first patient is an 8-year-old girl who was referred to our genetic consultation for congenital hypotonia, developmental delay, and therapy-resistant epilepsy. She is the second child of a non-consanguineous marriage. Born at term, she exhibited psychomotor delay and intellectual disability from an early age. Her epilepsy, characterized by generalized tonic seizures, began at 18 months and has been resistant to antiepileptic drugs. Notably, she has an absence of speech, gait abnormalities, and stereotypic hand movements since the age of 6 months. An EEG revealed multifocal abnormalities, although her brain MRI was normal. At clinical examination, she exhibited short stature (25th percentile) but no facial dysmorphia. The second patient is a 7-year-old girl referred for psychomotor delay, epilepsy, and facial dysmorphia. She is the firstborn of a non-consanguineous family. She has a history of congenital hypotonia and has been treated for generalized epilepsy since the age of 3 years, though the seizures have been resistant to therapy. Like the first patient, she has an absence of speech, gait abnormalities, and a history of repeating only a few words consistently. She has unilateral myopia and has aggressive, antisocial behavior. Her facial dysmorphia includes characteristic features of CDL, such as synophrys, thick eyebrows, a short nose with an upturned nasal tip, a long and small philtrum, a thin upper lip vermillion, downturned corners of the mouth, and hand oligodactyly. We obtained informed consent from the parents of both patients to perform Clinical Exome Sequencing. The detected variants were confirmed using conventional Sanger sequencing. Patient 1 harbors the novel heterozygous truncating variant NM_006306(SMC1A):c.3186del(p.Lys1063Argfs*149), while Patient 2 harbors another novel heterozygous truncating variant NM_006306(SMC1A): c.664C > T(p.Gln222*). Both variants are classified as likely pathogenic according to the American College of Medical Genetics (ACMG) guidelines. p.Gln222* was confirmed as de novo and is therefore pathogenic by the ACMG. Parents of Patient 1 were unavailable for testing. The SMC1A gene (located at Xp11.22) belongs to the Structural Maintenance of Chromosomes family that plays vital roles in DNA transactions.6 To the best of our knowledge, 30 cases involving SMC1A truncating variants have been reported, including our own (See Table S1). All reported cases are females. Reported males with non-missense variants typically present with in-frame deletions.4, 7 Analysis of clinical data from all 30 cases reveals consistent findings. Developmental delay is observed in all cases (100%), with 73% (22) exhibiting an absence of speech and intellectual disability. Microcephaly is present in 87% (26) of the cases, while 60% (18) show prenatal growth retardation. Abnormal muscle tone is present in 70% (21) of the cases. Epilepsy is a common finding, present in 97% (29) of the cases, with 79% (23) experiencing therapy-resistant epilepsy and 60% (18) having seizures in clusters (Figure 1A). The analysis further indicates that the reported variants are distributed across the protein without a specific hotspot (Figure 1B). Notably, p.Arg975* has been reported three times, twice in association with ID-TRE and once with atypical CDL. p.Asn788Lysfs*10 and p.Leu808Argfs*6 are associated with both ID-TRE and Rett-like phenotypes. Additionally, p.Asn826Thrfs*3 has been identified twice in ID-TRE. The variants identified in our patients are localized in Coiled-Coil regions CC2 and CC1, respectively. These regions are thought to be involved in protein–protein interactions.8 There seems to be no clear correlation between the affected protein domain and the resulting phenotype. Given these findings, it is evident that truncating SMC1A variants consistently leads to a range of clinical features, including developmental delay, speech absence, intellectual disability, microcephaly, abnormal muscle tone, and therapy-resistant epilepsy with a rate of over 80%. This underscores the importance of comprehensive analysis of the entire SMC1A gene in diagnosing patients presenting these characteristics. NA collected the genetic data and literature search, analyzed, interpreted, the data, and wrote the original draft. JL performed NGS data analysis and reviewed the manuscript. YK and LA participated in data collection. AS supervised the study. SCE participated in clinical data analysis and draft writing. All authors read and approved the final manuscript. The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. The authors have no relevant financial or non-financial interests to disclose. Informed consent was obtained from the parents of our two patients to publish this work. However, we did not obtain their consent to include the patients’ photographs in this article. Table S1: Table S1: Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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