• 3
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
BRWD3 (HGNC:17342) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
bromodomain and WD repeat domain containing 3
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
No previous names found
Alias symbols
FLJ38568, MRX93
%HI
28.63(Read more about the DECIPHER Haploinsufficiency Index)
pLI
1(Read more about gnomAD pLI score)
LOEUF
0.08(Read more about gnomAD LOEUF score)
Cytoband
Xq21.1
Genomic Coordinates
GRCh37/hg19: chrX:79925002-80065376 NCBI Ensembl UCSC
GRCh38/hg38: chrX:80669503-80809877 NCBI Ensembl UCSC
MANE Select Transcript
NM_153252.5 ENST00000373275.5 (Read more about MANE Select)
Function
Plays a role in the regulation of cell morphology and cytoskeletal organization. Required in the control of cell shape. {ECO:0000269|PubMed:21834987}. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-16544
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency (3)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Last Evaluated:
08/24/2022

Haploinsufficiency (HI) Score Details

HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
  • X-linked intellectual disability Monarch
HI Evidence:
  • PUBMED: PMID:17668385
    Field et al. (2007) reported two unrelated families with truncating mutations. The first family included a nephew and maternal uncle with mild-to-moderate intellectual disability and a maternal 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 was shown to lead to skipping of exon 29 and the introduction of a premature stop codon, p.W1089Cfs*4 . The second family included 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.R316Kfs*21, 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).
  • PUBMED: 24462886
    Grotto et al. (2014) reported a male with a de novo 74 kb intragenic deletion encompassing exons 11 through 41 of BRWD3 at Xq21.1. Grotto also reported exome sequencing of a family with a maternally inherited BRWD3 nonsense mutation (p.Tyr1131*) in four males. Phenotypes included mild to moderate intellectual disability in all. Other recurrent phenotypes included speech delay (n = 8/8), behavioral disturbances (n = 7/8), macrocephaly (n = 7/9), dysmorphic facial features (n = 9/9) including prominent forehead, pointed chin, deep-set eyes, abnormal ears, and broad hands and feet (n = 6/6), and skeletal symptoms (n = 7/7) like pes planus, scoliosis, kyphosis and cubitus valgus.
  • PUBMED: 28475857
    Tatton-Brown et al. (2017) used exome sequencing to assess a cohort of individuals with intellectual disability (ID) and height and/or head circumference at least two standard deviations above the mean (>=+2 SD, UK90 growth data) at some point in childhood (termed OGID (overgrowth and ID)). Six individuals with truncating sequence variants in BRWD3 were identified [c.568C>T,p,(R190*); c.696T>A,p.(Y232*); c.447_451del,p.(R150Ifs*5); c.2062_2064delinsCCAT,p.(M688Pfs*2); c.2312dup,p.(Y771*); c.3601+1G>A,p.?; c.451C>T,p.(Q151*)]. Three were inherited from unaffected mothers and 3 were of unknown inheritance.
  • PUBMED: 31714006
    Ostrowski et al. (2019) provide clinical details of 17 male patients with BRWD3 variants: 13 truncating sequence variants, two with splice-site variants, and two with intragenic deletions (both deletions were de novo). Of the sequence variants tested (n=12/15), all were maternally inherited. Seven patients were previously described in Tatton-Brown et al (PMID:28475857), one in Field et al (PMID: 17668385), and an additional four were included in the DECIPHER patient database. Five represent new patients. All had mild to moderate intellectual disability (100%), 12/17 (71%) with head circumference >=+2 SD. Other recurrent phenotypes included behavioural issues (ASD, ADHD, aggressive, shy), neonatal hypotonia, GU anomalies (cryptorchidism, hypospadias), and joint hypermobililty. Common facial features were reported to include tall chin with associated horizontal skin crease, prognathism, broad forehead and prominent supraorbital ridge.
  • PUBMED: 30628072
    Tenorio et al. (2019) reported five new patients with novel BRWD3 variants. Patient 1 was a male with maternally inherited nonsense variant [NM_153252.4:c.3976C>T,p.(R1326*)]. Phenotypes included macrocephaly, psychomotor developmental delay, speech delay and partial seizures. Patients 3 and 4 were brothers with maternally inherited splice site variant [NM_153252.4:c.1127+1G>A,p.?]. Shared phenotypes included acrocephaly, mild psychomotor developmental delay, ADHD, ASD-traits, shyness, facial anomalies (large forehead, midface hypoplasia and prominent chin). One brother also had genitourinary anomalies (cryptorchidism and small penis). Patient 5 was a male with nonsense variant [NM_153252.4:c.5080C>T,p.(R1694*)] of unknown inheritance. Phenotypes included macrocephaly, ADHD, facial anomalies (asymmetry, large ear lobe, thick eyebrow, short and wide nose with broad nasal tip, short philtrum and prominent chin) and large hands with broad thumbs.
HI Evidence Comments:
BRWD3 encodes Bromodomain And WD Repeat-Containing Protein 3, which is thought to have a chromatin-modifying function, and may therefore play a role in transcription. The BRWD3 gene is located at Xq21.1 and has been associated with Intellectual developmental disorder, X-linked 93 (OMIM 300659). Truncating (nonsense, frameshift), splicing and intragenic multi-exon deletion variants of BRWD3 have been reported in more than 38 individuals in the medical literature. Most affected individuals are males with maternally inherited variants, but some de novo variants have been described, particularly in the case of intragenic multi-exon deletions (PMID: 31714006; 24462886). Most females are unaffected carriers, although two affected females have been reported, without assessment of X-inactivation patterns (PMID:17668385; 27959697). Additional evidence: PMID: 27959697 - Posey et al. (2017) reported a female (Patient no.59) with a de novo nonsense variant in BRWD3 (p.R190*) identified by exome sequencing [Supplementary Table S5]. Phenotypes were not provided. No mention of X-inactivation studies. PMID: 35266334 - Wang et al. (2022) reported a male with a de novo nonsense variant in BRWD3 (p.R1240*) identified by exome sequencing (Patient ID: UDP11). Reported phenotypes included intellectual disability (borderline), delayed speech and language development, ADHD, macrocephaly, poor fine motor coordination, dilation of lateral ventricles, long face and cupped ears. PMID: 34429528 - Hyder et al (2021) reported a male with de novo nonsense variant in BRWD3 (p.Q1338*) [Table 1]. Reported phenotypes included specific learning disability, Arnold-Chiari malformation, right unilambdoid synostosis, bronchomalacia, periventricular leukomalacia and hypospadias. PMID: 28152038 - La Duca et al. (2017) include a case with a truncating variant in BRWD3 (p.I617Yfs*14). Inheritance and phenotypes were not provided. PMID: 26350204 - Grozeva et al. (2015) used targeted sequencing of a cohort of 986 individuals with moderate to severe intellectual disability (ID), to identify two males with novel truncating variants in BRWD3 (p.Tyr232* and p.Ser1264Ilefs*13). Inheritance and phenotypes (beyond ID) were not provided. PMID:17666407 - de Smith et al (2007) studied 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.
NOTE:

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 (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)
TS Evidence Comments:
No evidence supporting or refuting triplosensitivity for this gene found.
NOTE:

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.

Genomic View

Select assembly: (NC_000023.10) (NC_000023.11)