Mutations in the BRWD3 gene cause X-linked mental retardation associated with macrocephaly.
Field M., Tarpey PS., Smith R., Edkins S., O'Meara S., Stevens C., Tofts C., Teague J., Butler A., Dicks E., Barthorpe S., Buck G., Cole J., Gray K., Halliday K., Hills K., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Varian J., West S., Widaa S., Mallya U., Wooster R., Moon J., Luo Y., Hughes H., Shaw M., Friend KL., Corbett M., Turner G., Partington M., Mulley J., Bobrow M., Schwartz C., Stevenson R., Gecz J., Stratton MR., Futreal PA., Raymond FL.
In the course of systematic screening of the X-chromosome coding sequences in 250 families with nonsyndromic X-linked mental retardation (XLMR), two families were identified with truncating mutations in BRWD3, a gene encoding a bromodomain and WD-repeat domain-containing protein. In both families, the mutation segregates with the phenotype in affected males. Affected males have macrocephaly with a prominent forehead, large cupped ears, and mild-to-moderate intellectual disability. No truncating variants were found in 520 control X chromosomes. BRWD3 is therefore a new gene implicated in the etiology of XLMR associated with macrocephaly and may cause disease by altering intracellular signaling pathways affecting cellular proliferation.