General information

BRWD3-related condition is a syndromic form of X-chromosome linked mild-moderate intellectual disability with complete penetrance but variable expressivity in males. Female carriers to date appear clinically asymptomatic.

The clinical phenotype includes early hypotonia (9/9), marked early language delay (9/9), behavioural features (7/9), macrocephaly (7/9) and behavioural disturbance including temper tantrums and shyness (7/9). The facial phenotype seems to be consistent across all cases and includes a prominent forehead, pointed chin, deep-set eyes and large prominent ears.

Additional supportive features include obesity in some cases, evidence of pubertal delay and skewed X inactivation in female carriers (only one family tested).

To date, clinical information is available on 9 individuals, from 4 families, with loss of function mutations, including truncating mutations, splice site mutations and a partial BRWD3 gene deletion. However, it is likely more individuals will be diagnosed as genomic testing is more commonly used for undiagnosed intellectual disability.

A unique missense mutation has also been shown to segregate in one pedigree including 5 affected males with mild intellectual disability without other clinical features. The significance of missense mutations remains uncertain.

BRWD3 (bromodomain and WD repeat domain containing 3) is a 41 exon gene located at Xq21.1. It is named after its function domains (two bromodomains and eight WD40). The bromodomains suggest a potential chromatin binding function and possible transcriptional regulation role. It is a binding partner of CUL4B and has a role in protein ubiquitylation and degradation.

The gene may be screened as part of an exome panel.