Hierarchical Bayes model for random haplotype and family effects in the transmission of fragile‐X

Huggins, Richard; Loesch, Danuta Z.; Qian, Guoqi; Bui, Minh; Mitchell, R.J.; Dobson, Melanie J.; Taylor, Annette K.

doi:10.1002/gepi.10316

Cited by 1 publication

(1 citation statement)

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“…The major modifying factor is the sex of a parent, where, as described above, the risk of expansion of PM alleles is limited to the mothers but for the GZ alleles, it is relatively higher for the fathers than from the mothers. 89 In addition, the data from large pedigrees suggested that the sex of offspring might be another modifying factor, with male offspring manifesting higher rate of large expansions from the parent than female offspring; 91,92 however this concept still remains controversial. 78,93 …”

Section: Small Cgg Expansion Alleles As the Source Of The Full Mutatimentioning

confidence: 99%

Unstable Mutations in the FMR1 Gene and the Phenotypes

Loesch

Hagerman

2012

Advances in Experimental Medicine and Biology

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Fragile X syndrome (FXS), a severe neurodevelopmental anomaly, and one of the earliest disorders linked to an unstable ('dynamic') mutation, is caused by the large (>200) CGG repeat expansions in the noncoding portion of the FMR1 (Fragile X Mental Retardation-1) gene. These expansions, termed full mutations, normally silence this gene's promoter through methylation, leading to a gross deficit of the Fragile X Mental Retardation Protein (FMRP) that is essential for normal brain development. Rare individuals with the expansion but with an unmethylated promoter (and thus, FMRP production), present a much less severe form of FXS.However, a unique feature of the relationship between the different sizes of CGG expanded tract and phenotypic changes is that smaller expansions (<200) generate a series of different clinical manifestations and/or neuropsychological changes. The major part of this chapter is devoted to those FMR1 alleles with small (55-200) CGG expansions, termed 'premutations', which have the potential for generating the full mutation alleles on mother-offspring transmission, on the one hand, and are associated with some phenotypic changes, on the other. Thus, the role of several factors known to determine the rate of CGG expansion in the premutation alleles is discussed first. Then, an account of various neurodevelopmental, congnitive, behavioural and physical changes reported in carriers of these small expansions is given, and possible association of these conditions with a toxicity of the elevated FMR1 gene's transcript (mRNA) is discussed.The next two sections are devoted to major and well defined clinical conditions associated with the premutation alleles. The first one is the late onset neurodegenerative disorder termed fragile Xassociated tremor ataxia syndrome (FXTAS). The wide range of clinical and neuropsychological manifestations of this syndrome, and their relevance to elevated levels of the FMR1 mRNA, are described. Another distinct disorder linked to the CGG repeat expansions within the premutation range is fragile X-associated primary ovarian insufficiency (FXPOI) in females, and an account of the spectrum of manifestations of this disorder, together with the latest findings suggesting an early onset of the ovarian changes, is given.In the following section, the most recent findings concerning the possible contribution of FMR1 'grey zone' alleles (those with the smallest repeat expansions overlapping with the normal range

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Section: Small Cgg Expansion Alleles As the Source Of The Full Mutatimentioning

confidence: 99%