Familial cases and male cases with <i>MECP2</i> mutations

Zhang, Qingping; Zhao, Ying; Bao, Xinhua; Luo, Jin Jun; Zhang, Xiaoying; Li, Jiarui; Wei, Liping; Wu, Xiru

doi:10.1002/ajmg.b.32534

Cited by 18 publications

(18 citation statements)

References 36 publications

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“…Several studies, including ours, have shown that male patients who had variants causing typical RTT in females usually presented with severe neonatal encephalopathy and early death. 15,29 Male patients with somatic mosaic variants may have milder phenotypes in comparison with those of female patients with the same variants and a heterozygous genotype primarily because of differences between their MAFs. However, the correlation between MAFs and the severity of the disease, as well as the minimum threshold of MAFs, requires further investigation in a larger cohort.…”

Section: Discussionmentioning

confidence: 99%

Genomic mosaicism in the pathogenesis and inheritance of a Rett syndrome cohort

Zhang

Yang

Wang

et al. 2019

Genetics in Medicine

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PurposeTo determine the role of mosaicism in the pathogenesis and inheritance of Rett and Rett-like disorders.MethodsWe recruited 471 Rett and Rett-like patients. Panel-sequencing targeting MECP2, CDKL5, and FOXG1 was performed. Mosaicism was quantified in 147 patients by a Bayesian genotyper. Candidates were validated by amplicon sequencing and digital PCR. Germline mosaicism of 21 fathers with daughters carrying pathogenic MECP2 variants was further quantified.ResultsPathogenic variants of MECP2/CDKL5/FOXG1 were found in 324/471 (68.7%) patients. Somatic MECP2 mosaicism was confirmed in 5/471 (1.1%) patients, including 3/18 males (16.7%) and 2/453 females (0.4%). Three of the five patients with somatic MECP2 mosaicism had mosaicism at MECP2-Arg106. Germline MECP2 mosaicism was detected in 5/21 (23.8%) fathers.ConclusionThis is the first systematic screening of somatic and paternal germline MECP2 mosaicism at a cohort level. Our findings indicate that somatic MECP2 mosaicism contributes directly to the pathogenicity of Rett syndrome, especially in male patients. MECP2-Arg106 might be a mosaic hotspot. The high proportion of paternal germline MECP2 mosaicism indicates an underestimated mechanism underlying the paternal origin bias of MECP2 variants. Finally, this study provides an empirical foundation for future studies of genetic disorders caused by de novo variations of strong paternal origin.

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Section: Discussionmentioning

confidence: 99%

Genomic mosaicism in the pathogenesis and inheritance of a Rett syndrome cohort

Zhang

Yang

Wang

et al. 2019

Genetics in Medicine

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“…Accordingly, MECP2 mutations have been demonstrated to cause various clinical conditions (HGMD), such as Rett syndrome (678 different mutations), MECP2 duplication syndrome (85), X-linked ID (52), neurodevelopmental delay (35), brain abnormalities (26), atypical Rett syndrome (22), and psychomotor developmental delay (14). It has been observed that a majority of patients with MECP2-caused RTT are sporadic [7,20] because most pathogenic mutations in MECP2 are de novo mutations [21]. In many cases, DNMs are likely derived from the X chromosome in male sperms [22,23].…”

Section: Discussionmentioning

confidence: 99%

Three intellectual disability-associated de novo mutations in MECP2 identified by trio-WES analysis

Xiang

Zhu

et al. 2020

BMC Med Genet

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Background: To date, at least 746 genes have been identified to cause intellectual disability (ID). Among them, mutations in the Methyl CpG binding protein 2 (MECP2) gene are the leading cause of Rett syndrome and associated ID. Methods: Considering the large number of ID-associated genes, we applied trio-based whole-exome sequencing (trio-WES) and in silico analysis for genetic diagnosis of 294 children with ID. Results: Three de novo heterozygous mutations [NM_004992.3: c.502C > T, p.(Arg168*), c.916C > T, p.(Arg306Cys), and c.879C > G, p.(Ile293Met)] in MECP2 were identified in three unrelated girls. The first two mutations were detected in two patients who were diagnosed as typical Rett syndrome, X-linked ID and psychomotor retardation. The third mutation (c.879C > G), a previously unreported, was found in a 6-year-old girl with ID, microcephaly, severe underweight and psychomotor retardation. Particularly, this extremely rare de novo mutation (DNM) is located in the transcriptional repression domain (TRD) of MECP2, where at least 62 different causal mutations are identified. Conclusions: We identified three DNMs in MECP2 in a cohort of 294 individuals with ID. The novel c.879C > G mutation, as a likely pathogenic allele, may become a risk factor associated with X-linked ID, microcephaly and psychomotor retardation.

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“…Variant type and location do not adequately explain phenotypic variability, as individuals with the same pathogenic variant have clinical presentations varying from ASD, ID, and RTT ( Figure 1 ), and XCI has been proposed to be an important factor in the onset and severity of RTT [ 78 , 79 ]. Phenotypic variation ranging from classical RTT to normal individuals with protective skewing of the X chromosome have been reported [ 78 ].…”

Section: Mecp2mentioning

confidence: 99%

The Impact of X-Chromosome Inactivation on Phenotypic Expression of X-Linked Neurodevelopmental Disorders

2021

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Nearly 20% of genes located on the X chromosome are associated with neurodevelopmental disorders (NDD) due to their expression and role in brain functioning. Given their location, several of these genes are either subject to or can escape X-chromosome inactivation (XCI). The degree to which genes are subject to XCI can influence the NDD phenotype between males and females. We provide a general review of X-linked NDD genes in the context of XCI and detailed discussion of the sex-based differences related to MECP2 and FMR1, two common X-linked causes of NDD that are subject to XCI. Understanding the effects of XCI on phenotypic expression of NDD genes may guide the development of stratification biomarkers in X-linked disorders.

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Familial cases and male cases with MECP2 mutations

Cited by 18 publications

References 36 publications

Genomic mosaicism in the pathogenesis and inheritance of a Rett syndrome cohort

Genomic mosaicism in the pathogenesis and inheritance of a Rett syndrome cohort

Three intellectual disability-associated de novo mutations in MECP2 identified by trio-WES analysis

The Impact of X-Chromosome Inactivation on Phenotypic Expression of X-Linked Neurodevelopmental Disorders

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