Mutations in the BRWD3 Gene Cause X-Linked Mental Retardation Associated with Macrocephaly

Field, Michael; Tarpey, Patrick; Smith, Raffaella; Edkins, Sarah; O’Meara, Sarah; Stevens, C; Tofts, Calli; Teague, Jon W.; Butler, Adam; Dicks, Ed; Barthorpe, Syd; Buck, Gemma; Cole, Jennifer; Gray, Kristian; Halliday, Kelly; Hills, Katy; Jenkinson, Andy; Jones, David R.; Menzies, Andrew; Mironenko, Tatiana; Perry, Janet; Raine, Keiran; Richardson, David; Shepherd, Rebecca; Small, Alex; Varian, Jennifer; West, Sofie; Widaa, Sara; Mallya, Uma; Wooster, Richard; Moon, Jennifer A.; Luo, Ying; Hughes, Helen E.; Shaw, Marie; Friend, Kathryn; Corbett, Mark; Turner, Gillian; Partington, M. W.; Mulley, John C.; Bobrow, Martin; Schwartz, Charles E.; Stevenson, Roger E.; Gécz, Jozef; Stratton, Michael R.; Futreal, P. Andrew; Raymond, F. Lucy

doi:10.1086/520677

Cited by 81 publications

(75 citation statements)

References 22 publications

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“…For example, Brwd3, which was associated with XLMR by another group during the course of our study (Field et al 2007), has lacZ reporter expression in the brain and neural tube. Expression does not have to be restricted; an example of this from our screen is Dlg3, where in humans mutations in DLG3 are associated with mental retardation (Tarpey et al 2004).…”

Section: Discussionmentioning

confidence: 63%

Phenotypic annotation of the mouse X chromosome

Cox

Vollmer

Tamplin³

et al. 2010

Genome Res.

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Mutational screens are an effective means used in the functional annotation of a genome. We present a method for a mutational screen of the mouse X chromosome using gene trap technologies. This method has the potential to screen all of the genes on the X chromosome without establishing mutant animals, as all gene-trapped embryonic stem (ES) cell lines are hemizygous null for mutations on the X chromosome. Based on this method, embryonic morphological phenotypes and expression patterns for 58 genes were assessed, ∼10% of all human and mouse syntenic genes on the X chromosome. Of these, 17 are novel embryonic lethal mutations and nine are mutant mouse models of genes associated with genetic disease in humans, including BCOR and PORCN. The rate of lethal mutations is similar to previous mutagenic screens of the autosomes. Interestingly, some genes associated with X-linked mental retardation (XLMR) in humans show lethal phenotypes in mice, suggesting that null mutations cannot be responsible for all cases of XLMR. The entire data set is available via the publicly accessible website (http://xlinkedgenes.ibme.utoronto.ca/).

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Section: Discussionmentioning

confidence: 63%

Phenotypic annotation of the mouse X chromosome

Cox

Vollmer

Tamplin³

et al. 2010

Genome Res.

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“…Secondly, BRWD3 is another gene possibly related to our patient’s phenotype, because loss of function mutations were identified in 4 male patients with X-linked mental retardation, macrocephaly and dysmorphic features [25]. Interestingly, one of them also showed tall stature (>+1.9 SDS) and his affected uncle was tall with a final height of +1.3 SDS.…”

Section: Discussionmentioning

confidence: 98%

Genome-Wide SNP Array Analysis in Patients with Features of Sotos Syndrome

Visser¹,

Gijsbers

Ruivenkamp

et al. 2010

Horm Res Paediatr

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Background: Sotos syndrome is characterized by overgrowth, facial dysmorphism and learning impairment. Haploinsufficiency of NSD1 accounts for approximately 60–90% of the patients. Consequently, a considerable number of patients with features of Sotos syndrome remain without a molecular diagnosis. To date, target-gene approaches in these patients have not been successful. Methods: Twenty-six Sotos syndrome-like patients were analyzed with a high-resolution whole-genome SNP array, and segregation was studied in the parents. Results: Four possible pathogenic copy-number variants including deletions of 10p12.32-p12.31, 14q13.1, Xq21.1-q21.31 and a duplication of 15q11.2-q13.1 were detected. They varied in size from 155 kb to 13.36 Mb. The 10p12.32-p12.31 deletion revealed a candidate gene (PLXDC2) for overgrowth. The 14q13.1 deletion affected only the NPAS3 gene and the patient carrying this deletion displayed mental retardation as the main feature. The Xq21.1-q21.31 deletion and the 15q11.2-q13.1 duplication encompassed multiple genes of which several could be associated with phenotypic expression. Conclusion: The high-resolution genome-wide SNP array approach resulted in a detection rate of 15% of novel abnormalities and is therefore a powerful method to attain a molecular diagnosis in Sotos syndrome-like patients. Identified candidate genes provide directions for future screening of larger patient cohorts.

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“…Furthermore, UBE3A is localized to dendrites and spines, and its absence leads to reduced spine density and length [65]. In addition to PARK2 and UBE3A, an increasing number of E3 genes are linked to neurogenetic disorders, including UBR1 (Johanson-Blizzard syndrome) [66], NHLRC1 (Lafora's disease) [67], and CUL4B [68], BRWD3 [69] and HUWE1 [70].…”

Section: Ups Functionality Increases In Prion-associated Diseasementioning

confidence: 99%