Further Characterization of SMC1A Loss of Function Epilepsy Distinct From Cornelia de Lange Syndrome

Abstract

Cornelia de Lange syndrome is a rare developmental malformation syndrome characterized by small stature, limb anomalies, distinctive facial features, developmental delays, and behavioral issues. The diagnosis of Cornelia de Lange syndrome is made clinically or on the basis of an identified variant in one of the genes associated with Cornelia de Lange syndrome. SMC1A variants are the cause of 5% of the cases of Cornelia de Lange syndrome. SMC1A is located on the X-chromosome and is thought to escape X-inactivation in some females. Patients with SMC1A variants are being increasingly identified through panel testing or exome sequencing without prior clinical suspicion of Cornelia de Lange syndrome. In general, intractable epilepsy is not considered a prominent feature of Cornelia de Lange syndrome, yet this is found in these patients with SMC1A variants. Here we report on a series of patients with SMC1A variants and intractable epilepsy. In contrast to patients with typical SMC1A-associated Cornelia de Lange syndrome, all of the identified patients were female, and when available, X-inactivation studies were highly skewed with truncating variants. We describe the medical involvement and physical appearance of the participants, compared to the diagnostic criteria used for classical Cornelia de Lange syndrome. We also report on the clinical characteristics of the epilepsy, including age of onset, types of seizures, electroencephalographic (EEG) findings, and response to various antiepileptic medications. These findings allow us to draw conclusions about how this population of patients with SMC1A variants fit into the spectrum of Cornelia de Lange syndrome and the broader spectrum of cohesinopathies and allow generalizations that may impact clinical care and, in particular, epilepsy management.

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

“…Thus, it corresponds to c.615G>A in NM_006306. This variant has also been reported in a new patient (case 12) [ 19 ]. In addition, two other variants (c.616-2A>G, VCV000159962.5; c.615+2T>C, VCV000804008.1) out of a total of seven pathogenic splicing variants deposited in ClinVar also affect this splice-site but has not been reported in any literature, strongly indicating a pathogenic splicing hotspot.…”

“…Characterization and comparison of de novo SMC1A-DEE variants in our study and literature: Sanger sequencing for PCR products flanking the variant confirmed that P1 carries an unreported de novo heterozygous splice-site mutation (c.615+5G>A) in intron 4 of SMC1A ( Figure S1 ). Interestingly, two variants (c.615G>A and c.615+1G>C) were recently reported to affect the same splice site ( Table 3 ) [ 15 , 19 ]. Note that in the report by Symonds et al [ 15 ], case 3 is identified as a splice-site variant at c.549G>A, which is at the exon junction of the SMC1A transcript NM:001281463 but not NM_006306.…”

“…Our characterization of these three heterozygous SMC1A -DEE variants and their XCI patterns suggests a possible link between SMC1A dosage reduction to the severity of phenotype ( Figure 3 ). To further test this, we surveyed 41 known SMC1A -DEE variants, including ours and one unreported, and characterized common and patient-specific features ( Table 3 ) [ 9 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ]. Clearly, SMC1A -DEE variants are mostly LOF caused by nonsense, frameshift, or splice-site interference ( Figure 2 ).…”

“…Intriguingly, cases have been increasingly reported of females with heterozygous de novo SMC1A pathogenic variants, mostly loss-of-function mutations (LOFs). These variants are associated with a more severe clinical phenotype of developmental and epileptic encephalopathy (DEE), a devastating form of early onset intractable epilepsy beginning in infancy and associated with global developmental delay, cognitive dysfunction, and ongoing epileptiform activity [ 9 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ]. Most reported cases did not show significant brain MRI abnormalities, but cases with holoprosencephaly have been reported [ 15 , 23 ].…”

Neurobehavioral and developmental profiles: genotype–phenotype correlations in individuals with Cornelia de Lange syndrome

“…A pathogenic variant in NIPBL is responsible for the majority of cases of CdLS, more commonly those with classic syndrome phenotype (~ 60–70%, [ 14 ]). Variants in SMC1A make up about 5% of those with CdLS [ 11 ], largely presenting with the non-classic form, although there is a group of individuals with loss of function variants in SMC1A presenting with a Rett syndrome-like phenotype [ 5 ]. Variants in RAD21, SMC3, BRD4, and ANKRD11 have also been seen among those with atypical CdLS [ 3 , 7 , 9 , 10 , 18 ], while pathogenic HDAC8 variants have been linked to both classic and non-classic forms [ 3 ].…”