Esther Manor, Azhar Jabareen, Nurit Magal, Arei Kofman, Randi J. Hagerman and Flora Tassone. Prenatal Diagnosis of Fragile X: Can a Full Mutation Allele in the FMR1 Gene Contract to a Normal Size? Front. Genet., 03 November 2017 | https://doi.org/10.3389/fgene.2017.00158
Here we describe a case of a prenatal diagnosis of a male fetus that inherited the unstable allele from his full mutation mosaic mother (29, 160, >200 CGG repeats) reduced to a normal size range (19 CGG repeats). Haplotype analysis showed that the fetus 19 CGG repeats allele derived from the maternal unstable allele which was inherited from his maternal grandmother. No size mosaicism was detected by testing the DNA from in vitro cultured samples, including seventh passage culture as well as from two amniocentesis samples. Sequence analysis confirmed that the allele was 19 CGG repeats long. Methylation assay showed no methylation. Although none of the techniques used in this study can provide with absolute certainty the diagnosis, the results strongly indicate the presence in the fetus of an allele with a CGG repeat number in the normal range. Because this is a prenatal diagnosis case, the crucial question is whether the 19 CGG allele derived from the maternal unstable expanded allele, which contracted to the normal range, became a normal stable allele or a normal unstable allele which could expand in the next generation. It is also possible that allele size mosaicism of the FMR1 gene that went undetected exists. Because this is a prenatal diagnosis case, we cannot with certainty exclude the presence of an undetected expanded allele of the FMR1 gene, in addition to the 19 CGG allele derived from an unstable expanded allele, which contracted to the normal range.
From the article
From the article
The case described here represents a rare case of transmission from a full mutation mother to her offspring with an allele pattern different from what we would have expected in such cases. It is a prenatal diagnosis case of a male fetus that inherited an allele with a CGG repeats number in the normal size range (19 CGG repeats) derived from the unstable expanded maternal allele (160, >200 CGG repeats). 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.
To our knowledge this is the first report of a prenatal diagnosis case showing a pattern of contraction of an expanded FMR1 unstable allele to a normal size allele. Tabolacci et al. (2016) previously described a case of a healthy 10-year-old boy who inherited a contracted unstable FMR1 allele from his mother. The authors described a family with a carrier mother (190 CGG repeats) and her three children. Two of them presented with FXS and had expanded alleles in the full mutation range (265–830 and 430–790 CGG repeats, respectively). In contrast, the healthy boy inherited a contracted allele of 43 CGG repeats. Another study (Maia et al., 2017) described four FXS boys carrying mosaic alleles ranging from the normal (35, 26, 39, and 18 CGG repeats) to the full mutation range (>200 CGG repeats). These studies sharpen the obscure mechanism of expansion of the trinucleotide repeat in the FMR1 gene, indicating that the same allele during the generation might expand or contract and possibly undergo methylation.
Since this is a prenatal diagnosis case, the questions are as follows: Is the unstable allele contracted to the normal range able to become a stable normal allele with no phenotypic consequences? Is it a normal unstable allele that may lead to some clinical involvement? Will it expand during transmission in the following generations? Is it a case of mosaicism through an undetected expanded allele of the FMR1 gene, which may cause features of FXS?
It is of importance to understand the consequence of contraction of high premutation/full mutation FMR1 allele as understanding the mechanism of FMR1 instability can improve genetic counseling of the family…
Although PCR-based approach and the sequencing tests used in the present study have shown to be very reliable, we cannot categorically exclude the presence of an expanded allele. However, the results demonstrate the presence of a normal size allele with no mosaicism, most likely leading to a normal phenotype as the case described by Tabolacci et al. (2016).
Our hypothesis is that the maternal premutation/full mutation allele contracted pre-zygotically either in the mitotic or in the meiotic stage resulting in a normal size allele in the fertilized egg with no syndromic consequence.