ClinGen Dosage Sensitivity Curation Page

BRWD3

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency 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

Haploinsufficiency phenotype comments:

Mild-moderate intellectual disability; macrocephaly; prominent ears; Associated with X-linked ID 93 Of note - PMID:17666407: de Smith et al (2007): In this study of structural variation amongst 50 reportedly normal Caucasian males from Northern France, a single, 380 kb deletion encompassing part of BRWD3 was noted. No information was provided regarding the method of ascertainment for these individuals, or the specific phenotype of the individual with the deletion involving BRWD3.

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:

No evidence supporting or refuting triplosensitivity for this gene found.

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.