MRX93 syndrome (BRWD3 gene): five new patients with novel mutations

Abstract

Overgrowth syndromes (OGS) comprise a heterogeneous group of disorders whose main characteristic is that either the weight, height, or head circumference are above the 97th centile or 2 to 3 SD above the mean for age and sex. Additional features, such as facial dysmorphism, developmental delay or intellectual disability (ID), congenital anomalies, neurological problems and an increased risk of neoplasia are usually associated with OGS. Genetic analysis in patients with overlapping clinical features is essential, to distinguish between two or more similar conditions, and to provide appropriate genetic counseling and recommendations for follow up. In the present paper, we report five new patients (from four unrelated families) with an X‐linked mental retardation syndrome with overgrowth (XMR93 syndrome), also known as XLID‐BRWD3‐related syndrome. The main features of these patients include ID, macrocephaly and dysmorphic facial features. XMR93 syndrome is a recently described disorder caused by mutations in the Bromodomain and WD‐repeat domain‐containing protein 3 (BRWD3) gene. This article underscores the importance of genetic screening by exome sequencing for patients with OGS and ID with unclear clinical diagnosis, and expands the number of reported individuals with XMR93 syndrome, highlighting the clinical features of this unusual disease.

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

“…It is over a decade since BRWD3 disruption was first shown to cause an intellectual disability syndrome in males (Field et al, 2007). However, with only three clinical reports, we know surprisingly little about the BRWD3 phenotype (Field et al, 2007; F o r P e e r R e v i e w Grotto et al, 2014;Tenorio et al, 2019 Relatively little is known about the biology of the BRWD3 phenotype, and to our knowledge, there have been no reports of knockout models or functional studies in mammalian models. However, a possible mechanism of pathogenesis of the OGID phenotype is suggested by experiments in Drosophila, which found that loss of the BRWD3 homologue leads to increased histone H3.3 levels and wide-ranging effects on gene transcription mediated through histone-dependent chromatin regulation (Chen et al, 2015).…”

Further definition of the proximal 19p13.3 microdeletion/microduplication syndrome and implication of PIAS4 as the major contributor

“…An in‐house bioinformatic pipeline was developed to analyze the raw data. This pipeline consists of base calling, alignment, local realignment, duplicate removal, quality recalibration, data merging, variant detection, genotyping and annotation was described in previous reports . In parallel to analysis process, an exhaustive quality control of the sequenced samples was performed according a custom pipeline .…”

“…This pipeline consists of base calling, alignment, local realignment, duplicate removal, quality recalibration, data merging, variant detection, genotyping and annotation was described in previous reports . In parallel to analysis process, an exhaustive quality control of the sequenced samples was performed according a custom pipeline . Review, classification and interpretation of the variants were made according to the American College of Medical Genetics and Genomics (ACMG) guidelines …”

“…17 In parallel to analysis process, an exhaustive quality control of the sequenced samples was performed according a custom pipeline. 17 Review, classification and interpretation of the variants were made according to the American College of Medical Genetics and Genomics (ACMG) guidelines. 18…”

Integrative Networks by BRWD3 Regulates Cytoskeleton Organization and Cell Motility

“…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].…”