Early onset or syndromic epilepsy

Gene: SMC1A

Green List (high evidence)

Sufficient evidence provided by PMID: 28166369. This group identified ten heterozygous de novo, predicted LOF, variants in the SMC1A gene. All cases were female, and none had a clinical diagnosis of CdLS. They presented with onset of epileptic seizures between <4 weeks and 28 months of age. In the majority of cases, a marked preponderance for seizures to occur in clusters was noted. Seizure clusters were associated with developmental regression. Moderate or severe developmental impairment was apparent in all cases.

Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.

Panel Version: 1.188

Mode of inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)

Phenotypes
Cornelia de Lange syndrome 2, 300590

Publications

• 28166369

I don't know

Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: Alison Callaway and John Taylor. Suggested gene rating: Green.

Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.

Panel Version: 1.189

Comment on mode of inheritance: Set MOI to X-linked dominant to match Gene2Phenotype and the MOI for SMC1A on the Intellectual disability panel. So far, mostly females have gross gene alterations of SMC1A, which are likely not tolerated in males (PMID:19842212).

Created: 2 Jul 2019, 3:11 p.m. | Last Modified: 2 Jul 2019, 3:11 p.m.

Panel Version: 1.108

Comment on list classification: Updated rating from Amber to Green based on external review by Deb Pal, and a literature review. Plenty of recent papers reporting SMC1A variants causing epilepsy in female patients (e.g. PMIDs:31098032, 28677859, 28166369, 26752331,26386245,26358754). SMC1A variants can cause Cornelia de Lange syndrome (CdLS) but can also cause ID and epilepsy in the absence of CdLS features (PMID:31185419). Plus 'confirmed' rating in Gene2Phenotype for EPILEPTIC ENCEPHALOPATHY.

Created: 2 Jul 2019, 3:08 p.m. | Last Modified: 2 Jul 2019, 3:08 p.m.

Panel Version: 1.107

PMID:31185419: Oguni et al 2019 report a missense variant (c.2683C>G:pArg895Gly) of SMC1A affecting a daughter (proband) and her mother. The daughter began having epileptic seizures age 2 years 1 month, progressing into cluster seizures. The mother began to have cluster seizures age 12 and had moderate ID. Neither individual had typical CdLS morphological features. Sequencing confirmed the variant was present in daughter and mother, but not other maternal family members. Blood samples from the paternal side were unavailable.

Created: 2 Jul 2019, 2:59 p.m. | Last Modified: 2 Jul 2019, 3 p.m.

Panel Version: 1.101

Green List (high evidence)

Amplexa CHE-114 epilepsy panel

Created: 21 Feb 2019, 3:52 p.m.

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
Rett-like phenotype

Publications

• 28677859
• 28548707
• 28166369
• 26752331
• 26386245
• 26358754

Variants in this GENE are reported as part of current diagnostic practice

Comment when marking as ready: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least four variants reported four unrelated cases in which seizures are a phenotypic feature.

Created: 11 Dec 2018, 2:12 p.m.

I don't know

XLD. Seizures reported in some patients with this syndromic disorder.

Created: 21 Aug 2018, 11:25 a.m.

Mode of inheritance
Other

Phenotypes
Cornelia de Lange syndrome 2, MIM#300590

Variants in this GENE are reported as part of current diagnostic practice