BRWD3 |
- 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)
Haploinsufficiency (HI) Score Details
- X-linked intellectual disability Monarch
-
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.
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
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.