ClinGen Dosage Sensitivity Curation Page

SMC1A

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
24896178 Gilissen et al. 2014. In an effort to find molecular causes of extensive genetic heterogeneity of ID, author did WGS on 50 patients with severe ID and their unaffected parents. All patients included had not received a molecular diagnosis after extensive genetic prescreening, including microarray-based CNV studies and exome sequencing. As a result, a total of 84 coding de novo mutation were identified and confirmed by Sanger, including a fs variant (c.2364delC aka p.Asn788Lysfs*fs10) and a 2.1 kb deletion involving exon 16 [resulting in p.(Leu808Argfs*6)] in the female Probands from trio 13 and trio 48 respectively. Both de novo changes are considered the molecular diagnosis for the patients ( Note: the patient with de novo fs variant also had 3 other de novo missense variants in 3 other genes of unknown function). Jansen S et. al. 2016 further presented the detailed phenotype of these two females. And by combining these 2 patients with the other recently reported females carrying SMC1A LoF mutations, the author ascertained a phenotypic spectrum of (severe) ID, therapy-resistant epilepsy, absence/delay of speech, hypotonia and small hands and feet, considered a novel phenotypic entity - distinct from CdLS - and caused by de novo SMC1A LoF mutations.
26386245 Goldstein et al. 2015. Reported two unrelated girls who had developmental delay and medically refractory seizures, with either mild or absent classic CdLS facial features and unrevealing initial laboratory, imaging and genetic evaluations. WES identified two novel de novo heterozygous frameshift mutations in the SMC1A gene [c.2853_2856delTCAG (p.Ser951Argfs*12) and c.3549_3552dupGGCC (p.Ile1185Glyfs*23)]. Author also observed marked skewing of X-inactivation in one patient. The individual with the p.Ser951Argfs*12 mutation represents an extreme on the CdLS phenotypic spectrum, with prominent neurological involvement of severe developmental delay and refractory epilepsy, with mild craniofacial features. Both individuals eventually had incomplete clinical responses to therapy with valproic acid. (Note: each patient also has 2 other variants in other genes, however they are either heterozygous for an recessive condition or homozygous for a variant of unknown clinical significant for an recessive condition. And parental testing were not performed for these variants)
28166369 Ten female cases with de novo truncation mutations in SMC1A were identified from the Deciphering Developmental Disorders (DDD) study (n = 8), from postmortem testing of an affected twin (n = 1), and from clinical testing with an epilepsy gene panel (n = 1). All 10 mutations identified are predicted to result in premature truncation of the SMC1A protein. All cases are female, and none had a clinical diagnosis of CdLS. All 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. These mutations are likely to be nonviable in males.

Haploinsufficiency phenotype comments:

Other publications that reported de novo truncating variants: (not limited to the following) PMID:27171548 Sajan et al. 2017 carried out a combination of exome sequencing and high density single nucleotide polymorphism (SNP) array-based copy number variant (CNV) analyses on a total of 22 Rett syndrome cases (both typical and atypical) lacking mutations in MECP2, CDKL5, and FOXG1 genes, and identified a de novo nonsense variant (c.C2161T aka p.Q721X) identified in a patient ( patient 100976-t). PMID: 27334371 Halvardson et al. 2016 Did WES on 39 trios where Proband has epilepsy and ID. Identified a de novo nonsense variant (p.Q871*) in a female Proband. This individual also had 2 other de novo variants in KIAA1244 (no OMIM disease association) and TBC1D4 genes (OMIM susceptibility gene) PMID:27848944 Reported a de novo nonsense variant (c.2897C>G aka p.(S966*) in a 14 yro female patient (00080991) with self-mutilation, delayed speech and language development, intellectual disability, motor delay and generalized seizures ( Suppl. Table S3.) PMID: 26795593 Helbig et al. 2016 WES of an unselected sample of 1131 patients with or without epilepsy. Identified a de novo fs variant (c.3549_3552dupGGCC aka p.I1185Gfs*23) in a patient with Cornelia de Lange syndrome 2 with infantile onset Epileptic Encephalopathy. Affected males and females carrying pathogenic SMC1A variants account for about 5% of CdLS, and typically resulting in a milder phenotype without major structural anomalies. Please refer to GeneReviews for more information about Cornelia de Lange syndrome 2 (https://www.ncbi.nlm.nih.gov/books/NBK1104/)

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

So far, no focal duplication reported in the literature.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.