Genomic mosaicism in the pathogenesis and inheritance of a Rett syndrome cohort
Qingping ZhangXiaoxu YangJiaping WangJiarui LiQixi WuYongxin WenYing ZhaoXiaoying ZhangYao HeXiru WuShujie YuLiping WeiXinhua Bao
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Abstract:
To determine the role of mosaicism in the pathogenesis and inheritance of Rett and Rett-like disorders.We 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.Pathogenic 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.This 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.Keywords:
Rett Syndrome
Pathogenesis
Inheritance
Multifactorial Inheritance
Polygene
Inheritance
Mendelian inheritance
Family-based QTL mapping
Major gene
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Some of the more common descriptions of inheritance, and particularly multiple inheritance are analysed; these are frequently unclear and even contradictory in much of the published literature. Using abstract data types to provide examples, it is shown how a consistent basis for inheritance and multiple inheritance may be built up, which helps to clarify the true meaning of inheritance.
Inheritance
Multiple inheritance
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MeCP2
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Rett syndrome (RTT) is a rare genetic neurodevelopmental disarray in which children are mostly effected with relapse of previously acquired skills after a period of normal development. Rett syndrome is usually identified in children age between 6to 18 months as they begin to lose the abilities they gained.it is caused by the mutation on the x chromosome on a gene MECP2.There are about 900 different mutations found on MECP2 gene. It is not a degenerative disorder. The course and severity of Rett syndrome is determined by the location, type and severity of the mutation and X-inactivation. In more than 99 percent of people with Rett syndrome, there is no history of the disorder in their family.
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MeCP2
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A rare case of a 40 month old girl has been diagnosed clinically to be that of the Rett syndrome, i.e. demonstrating regression in the development, repetitive handwringing movements and inability to speak. There were no specific laboratory findings.
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Rett syndrome (RTT) has been described in its classic form only in females. Although the majority of cases are sporadic, familial cases give valuable insight into the genetic basis and phenotypic variability of the disorder. The exclusive occurrence of classic Rett syndrome in females led to the hypothesis that the Rett syndrome locus is likely to be X-linked and mutations are lethal in hemizygous males. We identified two boys in families with recurrent Rett syndrome who had encephalopathies with neonatal onset and who may represent the phenotype of males harboring Rett syndrome muta tions. The difference in severity of disease in these males and their female relatives supports the location of Rett syndrome locus on the X-chromosome. (J Child Neurol 1998;13:229-231).
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About human monogenic diseases,there are many kinds of inheritance patterns.they are autosomal dominant inheritance,autosomal recessive inheriance,x-linked dominant inheritance,x-linked recessive inheritance,holandric inheritance,that is Y-linked inheritance,sex-influenced inheritance,sex-limited inheritance,and etc.in this paper,we described the characters of these inheritance patterns in detail,and compared briefly the differences and similarities between them.
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Atypical Rett syndrome (atypical RTT) is a neurodevelopmental disorder that is diagnosed when a child presents with a Rett-like syndrome but does not fulfill all the diagnostic criteria for typical Rett syndrome (classic/typical RTT; see this term).
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