Prenatal Diagnosis of Fragile X Syndrome in a Twin Pregnancy Complicated by a Complete Retraction.

Fragile X syndrome (FXS) is usually associated with a CGG repeat expansion >200 repeats within the <italic>FMR1</italic> gene, known as a full mutation (FM). FM alleles produce abnormal methylation of the <italic>FMR1</italic> promoter with reduction or silencing of <italic>FMR1</italic> gene expression. Furthermore, premutation (PM: 55–199 CGGs) and full mutation alleles usually expand in size when maternally transmitted to progeny. This study describes a PM allele carried by the mother decreasing to a normal sized allele in a male from a dichorionic diamniotic (DCDA) twin pregnancy, with the female twin inheriting FM (200–790 CGGs), PM (130 CGGs) and normal-sized (39 CGGs) alleles. Further evidence of instability of the maternal PM allele was shown by a male proband (older brother) mosaic for PM (CGG 78 and 150 CGGs) and FM (200–813 CGGs), and a high level of <italic>FMR1</italic> promoter methylation, between 50 and 70%, in multiple tissues. The fully-retracted, normal-sized allele was identified by PCR CGG sizing in the male twin, with no evidence of a FM allele identified using Southern blot analysis in multiple tissues collected postnatally and prenatally. Consistent with this, prenatal PCR sizing (35 CGGs) showed inconsistent inheritance of the maternal normal allele (30 CGGs), with single-nucleotide polymorphism (SNP) linkage analysis confirming that the abnormal <italic>FMR1</italic> chromosome had been inherited from the mother’s PM chromosome. Importantly, the male twin showed no significant hypermethylation of the <italic>FMR1</italic> promoter in all pre and postnatal tissues tested, as well as normal levels of <italic>FMR1</italic> mRNA in blood. In summary, this report demonstrates the first postnatal follow up of a prenatal case in which <italic>FMR1</italic> mRNA levels were approaching normal, with normal levels of <italic>FMR1</italic> promoter methylation and normal CGG size in multiple pre and postnatally collected tissues. [ABSTRACT FROM AUTHOR]