Null variants and deletions in <i>BRWD3</i> cause an X‐linked syndrome of mild–moderate intellectual disability, macrocephaly, and obesity: A series of 17 patients

Ostrowski, Philip J.; Zachariou, Anna; Loveday, Chey; Baralle, Diana; Blair, Edward; Douzgou, Sofia; Field, Michael; Foster, Alison; Kyle, Claire; Lachlan, Katherine; Mansour, Sahar; Naik, Swati; Rea, Gillian; Smithson, Sarah; Sznajer, Yves; Cole, Trevor; Tatton‐Brown, Katrina

doi:10.1002/ajmg.c.31750

Cited by 9 publications

(9 citation statements)

References 10 publications

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“…These include genes functioning in histone modification and chromatin re‐modeling like NSD1 , EZH2 , EED2 , DNMT3A , SETD2 , SUZ12 , CHD8 (Cyrus et al, 2019; Marzin et al, 2019; Ostrowski, Zachariou, Loveday, Beleza‐Meireles, et al, 2019; Tatton‐Brown et al, 2017). Transcription factors including nuclear factor one (NFI) DNA binding proteins like NFIA , NFIB , and NFIX (Zenker et al, 2019); BRWD3 (Ostrowski, Zachariou, Loveday, Baralle, et al, 2019) and the nucleosome remodeling and deacetylase complex genes like CHD3 , CHD4 , GATAD2B also cause neurodevelopmental disorders with overgrowth, mainly macrocephaly (Pierson et al, 2019). Another group of proteins which regulate growth is the PI3K‐AKT signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

“…She had multiple facial nevi and freckles, café au lait spots, and hypopigmented patches all over the body. Marked BRWD3 (Ostrowski, Zachariou, Loveday, Baralle, et al, 2019) and the nucleosome remodeling and deacetylase complex genes like CHD3, CHD4, GATAD2B also cause neurodevelopmental disorders with overgrowth, mainly macrocephaly (Pierson et al, 2019). Another group of proteins which regulate growth is the PI3K-AKT signaling pathway.…”

Section: Tsc2 (Omim*191092)mentioning

confidence: 99%

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Genetic heterogeneity of disorders with overgrowth and intellectual disability: Experience from a center in North India

Moirangthem

Mandal

Saxena

et al. 2021

American J of Med Genetics Pt A

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Overgrowth, defined as height and/or OFC ≥ +2SD, characterizes a subset of patients with syndromic intellectual disability (ID). Many of the disorders with overgrowth and ID (OGID) are rare and the full phenotypic and genotypic spectra have not been unraveled. This study was undertaken to characterize the phenotypic and genotypic profile of patients with OGID. Patients with OGID were ascertained from the cohort of patients who underwent cytogenetic microarray (CMA) and/or exome sequencing (ES) at our center over a period of 6 years. Thirty-one subjects (six females) formed the study group with ages between 3.5 months and 13 years. CMA identified pathogenic deletions in two patients. In another 11 patients, a disease causing variant was detected by ES. The spectrum of disorders encompassed aberrations in genes involved in the two main pathways associated with OGID. These were genes involved in epigenetic regulation like NSD1, NFIX, FOXP1, and those in the PI3K-AKT pathway like PTEN, AKT3, TSC2, PPP2R5D. Five novel pathogenic variants were added by this study. NSD1-related Sotos syndrome was the most common disorder, seen in five patients. A causative variant was identified in 61.5% of patients who underwent only ES compared to the low yield of 11.1% in the CMA group. The molecular etiology could be confirmed in 13 subjects with OGID giving a diagnostic yield of 42%. The major burden was formed by autosomal dominant monogenic disorders. Hence, ES maybe a better first-tier genomic test rather than CMA in OGID.

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Section: Discussionmentioning

confidence: 99%

Section: Tsc2 (Omim*191092)mentioning

confidence: 99%

Genetic heterogeneity of disorders with overgrowth and intellectual disability: Experience from a center in North India

Moirangthem

Mandal

Saxena

et al. 2021

American J of Med Genetics Pt A

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“…Previously, 32 mutations have been reported, including 21 destructive mutations (nine nonsense mutations, six frame shift mutations, three splice site mutations, and three gross deletions), seven missense mutations, one intronic mutation, and three gross duplications. 1,[11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] Their clinical and molecular details were listed in Appendix S1 (Table S1). Further analysis demonstrated that all individuals who carrying destructive mutations were associated with intellectual disability.…”

Section: Genotype-phenotype Correlation Of Brwd3 Variantsmentioning

confidence: 99%

Variants in BRWD3 associated with X‐linked partial epilepsy without intellectual disability

et al. 2022

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Aims Etiology of the majority patients with idiopathic partial epilepsy (IPE) remains elusive. We thus screened the potential disease‐associated variants in the patients with IPE. Methods Trios‐based whole exome sequencing was performed in a cohort of 320 patients with IPE. Frequency and molecular effects of variants were predicted. Results Three novel BRWD3 variants were identified in five unrelated cases with IPE, which were four male cases and one female case. The variants included two recurrent missense variants (c.836C>T/p.Thr279Ile and c.4234A>C/p.Ile1412Leu) and one intronic variant close to splice site (c.2475 + 6A>G). The two missense variants were located in WD40 repeat domain and bromodomain, respectively. They were predicted to be damaging by silico tools and change hydrogen bonds with surrounding amino acids. The frequency of mutant alleles in this cohort was significantly higher than that in the controls of East Asian and all population of gnomAD. All these variants were inherited from the asymptomatic mothers. Four male cases presented frequent seizures at onset, while the female case only had two fever‐triggered seizures. They showed good responses to valproate and lamotrigine, then finally became seizure free. All the cases had no intellectual disability. Further analysis demonstrated that all previously reported destructive variants of BRWD3 caused intellectual disability, while missense variants located in WD40 repeat domains and bromodomains of BRWD3 were associated with epilepsy. Conclusion BRWD3 gene is potentially associated with X‐linked partial epilepsy without intellectual disability. The genotypes and locations of BRWD3 variants may explain for their phenotypic variation.

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“…Mutant dBRWD3 (also named as ramshackle in Drosophila) leads to dying earlier during the development [8,9] or to disrupt dendritic morphogenesis and sensory organ differentiation [10]. In human, abnormal BRWD3 expression causes intellectual disability [11][12][13][14][15][16][17][18][19], leukemia [20], breast cancer [21] and head & neck cancer [22]. The human BRWD3 containing several WD repeats and 2 bromodomain (BRD) repeats, belongs to bromodomain-contain proteins (BCPs) family [12].…”

Section: Brwd3 (Bromodomain and Wd Repeat Domain Containing 3)mentioning

confidence: 99%

Integrative Networks by BRWD3 Regulates Cytoskeleton Organization and Cell Motility

Li¹,

Wang²,

Cui³

et al. 2020

Preprint

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BackgroundEukaryotic cytoskeleton forms and keeps cell shape, transports intracellular particles and organelles, determines cell motility and other important cellular events. A large number of regulators of cytoskeleton organization have been identified, but the detailed regulatory mechanism still remains obscure. Previous reports suggest that BRWD3 may be a regulator of cytoskeleton organization in Drosophila melanogaster, and influences cell shape. Therefore, we investigated the molecular network of BRWD3 regulating cytoskeleton organization.ResultsIn this study, we observed the alteration of cell shape, cell motility, and proliferation when BRWD3 was knocked down in MCF-7 and MDA-MB-231 cell lines. The cells were rounded, cell motility decreased when BRWD3 was knocked down. Using chromatin immunoprecipitation combining with sequencing, we found that BRWD3 influenced the cytoskeleton organization, cell shape, and cell motility through regulating expression of the cytoskeleton associative genes including ARF1, ABI2, ARPC3, ARPC1A, RHOC, MEF2C, and VIM.ConclusionsA molecular network by BRWD3 is sketched to elucidate that BRWD3 may not only regulate actin filament but also regulate microtubule and intermediate filament-based cytoskeleton organization. These efforts provide an overview of a BRWD3 network regulating cytoskeleton organization, cell shape and motility, and allow a better understanding of cytoskeleton (re)organization and pathogenesis of mental retardation X-linked 93 and relative carcinomas.

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Null variants and deletions in BRWD3 cause an X‐linked syndrome of mild–moderate intellectual disability, macrocephaly, and obesity: A series of 17 patients

Cited by 9 publications

References 10 publications

Genetic heterogeneity of disorders with overgrowth and intellectual disability: Experience from a center in North India

Genetic heterogeneity of disorders with overgrowth and intellectual disability: Experience from a center in North India

Variants in BRWD3 associated with X‐linked partial epilepsy without intellectual disability

Integrative Networks by BRWD3 Regulates Cytoskeleton Organization and Cell Motility

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