ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000009.11) (NC_000009.12)

Haploinsufficiency phenotype comments:

Nicolaides-Baraitser syndrome (NBS) is characterized by sparse hair, distal-limb anomalies, intellectual disability and a distinctive facial morphology. The main differential diagnosis for NBS is Coffin-Siris syndrome. The following two publications describe SMARCA2 mutations in patients with NBS or Coffin-Siris. However, in neither paper is evidence provided for a loss of function effect of the mutation. Van Houdt et al. (2012; PMID:22366787) performed WES on 10 individuals with a clinical diagnosis of Nicolaides-Baraitser syndrome (NBS). Eight of the 10 were found to have previously undescribed missense mutations in SMARCA2. Thirty-four additional patients were analyzed by Sanger sequencing for SMARCA2 mutations. Twenty-seven missense mutations and one +2 splice site mutation were found. Fifteen of the 36 mutations found in this study were determined to be de novo. The +2 splice mutation, categorized here as a loss of function mutation due to the interruption of the consensus splice donor sequence, did not have both parental samples available for study. It was also found in an individual with a "low certainty of NBS diagnosis." These authors also point out that patients with 9p deletions that overlap SMARCA2 do not have NBS and speculate that loss of function is not the mechanism for this condition. See Christ et al (1999, PMID:10521304) for information on 9p-deletion syndrome. Wolff et al. (2012; PMID:22822383 ) identify 32-kb de novo in-frame deletion within SMARCA2 including exons 20 to 26. The phenotype of this patient was consistent with NBS. Sequencing of SMARCA2 in two additional, unrelated patients with similar clinical features revealed de novo heterozygous missense mutations in both individuals. Both mutations and the in-frame deletion affect the C-terminal helicase of the SMARCA2 protein. The authors speculate that the mutations may result in a gain of function effect of the mutant protein. Tsurusaki et al. (2012; PMID:22426308) used a combination of WES and Sanger sequencing of 15 genes in the SWI/SNF complex in 28 individuals with Coffin-Siris syndrome. Twenty-two out of 28 (79%) individuals were positive for a mutation in one of these genes, one had a de novo in-frame deletion in SMARCA2. The deletion encompasses exons 20 to 27, which includes the helicase domain of SMARCA2, as well as part of the SNF2 domain, another DNA-dependent ATPase domain. The phenotype of this individual overlaps, but is not entirely consistent with NBS. Note that SMARCA2 (also called SNF2alpha or Brm) knockout mice are viable and fertile (PMID: 11163203), suggesting that the mutational effect in NBS is different from simple inactivation.

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