Submission Details

SMARCA2 was first reported in relation to autosomal dominant intellectual disability-sparse hair-brachydactyly syndrome (also known as Nicolaides-Baraitser syndrome) in 2012 (Van Houdt et al., PMID: 22366787). Numerous missense variants, all of which occur in highly conserved ATPase motifs, have been reported in humans. Evidence supporting the relationship between SMARCA2 and intellectual disability-sparse hair-brachydactyly syndrome includes case-level, and experimental data. Summary of case-level data: 11.5 points. De novo missense variants in SMARCA2 with proposed dominant negative mechanism (PMIDs: 8871545, 22366787) have been reported in at least 17 probands in 5 publications (PMIDs: 22366787, 25249037, 23906836, 25724810, 22822383). Of note: a handful of loss-of-function variants in SMARCA2 have been identified in large neurodevelopmental disorder cohorts (example PMID 31112269), however the clinical features were not described in depth. Since it’s unclear if loss-of-function variants cause the full clinical spectrum, they were not included in this curation. Summary of experimental data: 1.5 pts. This gene-disease association is supported by in vitro functional assays and cell culture models. In summary, SMARCA2 is definitively associated with autosomal dominant intellectual disability-sparse hair-brachydactyly syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Working Group on 8/18/2020 (SOP Version 7).

Lumping and splitting considerations:

SMARCA2 is associated with: Orphanet: Intellectual disability-sparse hair-brachydactyly syndrome OMIM: Nicolaides-Baraitser syndrome

Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability (which can include intellectual disability, sparse hair, prominent interphalangeal joints, coarse facies, microcephaly, and seizures). Therefore, all of the disease entities have been lumped into one disease entity, intellectual disability-sparse hair-brachydactyly syndrome.

SMARCA2 was first reported in relation to autosomal dominant intellectual disability-sparse hair-brachydactyly syndrome, also known as Nicolaides-Baraitser syndrome, in 2012 (Van Houdt et al., PMID: 22366787). Numerous missense variants, all of which occur in highly conserved ATPase motifs, have been reported. Sixteen de novo missense variants that have been reported in 17 probands in 5 publications (PMIDs: 22366787, 22822383, 23906836, 25249037, 25724810) are included in this curation. The mechanism of pathogenicity is suggested to be dominant negative (PMIDs: 8871545, 22366787). Note that a few loss-of-function variants in SMARCA2 have been identified in large neurodevelopmental disorder cohorts (e.g., PMID: 31112269), but the clinical features were not described in depth. Since it is unclear if loss-of-function variants cause the full clinical spectrum, they were not included in this curation. This gene-disease relationship is also supported by in vitro functional assays and cell culture models.

In summary, there is definitive evidence supporting the relationship between SMARCA2 and autosomal dominant intellectual disability-sparse hair-brachydactyly syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on August 18, 2020 (SOP Version 7).