Contraction of a Maternal Fragile X Mental Retardation 1 Premutation Allele

Abstract

Fragile X syndrome (FXS) is mainly caused by an expansion of a cytosine-guanine-guanine (CGG) trinucleotide repeat (greater than 200) in the 5' untranslated region of the fragile X mental retardation 1 (FMR1) gene resulting in gene silencing, methylation, and absence of FMRP. FXS involves a wide spectrum of phenotypes including intellectual disabilities, autism spectrum disorder (ASD), maladaptive behaviors or symptoms, social anxiety, mood disorders and physical features. Carriers of premutation alleles (55 -200 CGG repeats) can manifest with neurodevelopmental phenotypes and are at risk for the neurodegenerative fragile X-associated tremor/ataxia syndrome (FX-TAS) and about 20% of women with a premutation develop fragile Xassociated primary ovarian insufficiency (FXPOI). These phenotypes are believed to be caused by a distinct molecular mechanism involving increased FMR1 mRNA production and toxicity. Premutation alleles are unstable and depending on the CGG length and the presence of AGG interruptions have the potential to expand to larger premutation or full mutation alleles during transmission from mothers to their children. The contraction of a CGG repeat allele, although rare, has been observed. Here, we report the case of a three-generation family, who was identified as part of a pilot study of newborn screening for FXS. Specifically, the maternal grandmother carried a premutation allele (109 CGG repeats), which contracted to an intermediate size allele (52 CGG repeats) in her son, the father of a newborn girl (proband). This allele expanded to a premutation allele of 59 CGG repeats in the proband newborn. A premutation allele of 61 CGG repeats was detected in the proband's sister who demonstrated social phobia but normal cognition. The proband newborn showed some fragile X associated physical stigmata but normal cognition. Intriguingly, all FMR1 CGG expanded allele showed no AGG interruptions. This case shows a remarkable instability of premutation alleles throughout the three generations likely arising from different mechanisms.

FXS-Like Phenotype in Two Unrelated Patients Carrying a Methylated Premutation of the FMR1 Gene

“…We cannot exclude the possibility that the pattern of premutation alleles could result from a contraction of the full-mutation unstable allele and that both alleles coexist in the same tissue. Although this is a genetic event rarely described, few cases of contraction of a maternal high premutation/full mutation FMR1 allele during transmission have been reported ( Yrigollen et al, 2014 ; Miranda et al, 2015 ; Maia et al, 2017 ). More unique it is the case of contraction of an expanded FMR1 unstable allele to a normal size, recently reported ( Manor et al, 2017 ).…”

Prenatal Diagnosis of Fragile X: Can a Full Mutation Allele in the FMR1 Gene Contract to a Normal Size?

“…It is well known that the majority (near to 100%) of the male fetuses that inherited unstable FMR1 allele from mosaic mothers are expected to inherit a full mutation allele. Contraction of a maternal high premutation (>100 CGG repeats)/full mutation FMR1 allele during transmission has been rarely described ( Yrigollen et al, 2014 ; Miranda et al, 2015 ; Tabolacci et al, 2016 ; Maia et al, 2017 ).…”