ClinGen Dosage Sensitivity Curation Page

BRWD3

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
17668385 Field et al. (2007): 2 reportedly unrelated families are described with truncating muations. The first family included a nephew and an uncle with mild-to-moderate mental retardation and an aunt with mild cognitive difficulties during early childhood. The affected males were also noted to have macrocephaly and prominent ears. A mutation of the highly conserved +1 position of the 5? donor splice site of intron 29 of the BRWD3 gene, c.3325+1G?T was identified; this mutation leads to complete skipping of exon 29 and the introduction of a premature stop codon, p.W1089CfsX4 . The second family includes two maternal half-brothers with mild-moderate intellectual disability, macrocephaly, and cupped helices. A BRWD3 frameshift mutation, c.946-947insA, which leads to a predicted truncated protein p.R316KfsX21, was identified in both affected males from this family. A third family was reported in this paper, though this family was found to have a missense BRWD3 variant, c.4786A?G (p.K1596E). The affected males in this family were said to have a milder intellectual phenotype compared to the others (borderline-mild intellectual disability), and did not have macrocephaly. The truncating mutations from this paper were also summarized in Tarpey et al. (2009), PMID:19377476

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.

Evidence for Triplosenstive Phenotype

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.

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.