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Open AccessCase Report

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

Monash Genetics, Monash Health, Clayton, 3168 Victoria, Australia
Department of Paediatrics, Monash University, Clayton, 3168 Victoria, Australia
Cyto-Molecular Diagnostic Research Laboratory, Victorian Clinical Genetics Services and Murdoch Childrens Research Institute, Royal Children’s Hospital, Parkville, 3052 Victoria, Australia
Dentistry and Health Sciences, Department of Paediatrics, Faculty of Medicine, University of Melbourne, Parkville, 3052 Victoria, Australia
Author to whom correspondence should be addressed.
Genes 2018, 9(6), 287;
Received: 20 April 2018 / Revised: 31 May 2018 / Accepted: 4 June 2018 / Published: 7 June 2018
(This article belongs to the Section Human Genomics and Genetic Diseases)
Fragile X syndrome (FXS) is usually associated with a CGG repeat expansion >200 repeats within the FMR1 gene, known as a full mutation (FM). FM alleles produce abnormal methylation of the FMR1 promoter with reduction or silencing of FMR1 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 FMR1 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 FMR1 chromosome had been inherited from the mother’s PM chromosome. Importantly, the male twin showed no significant hypermethylation of the FMR1 promoter in all pre and postnatal tissues tested, as well as normal levels of FMR1 mRNA in blood. In summary, this report demonstrates the first postnatal follow up of a prenatal case in which FMR1 mRNA levels were approaching normal, with normal levels of FMR1 promoter methylation and normal CGG size in multiple pre and postnatally collected tissues. View Full-Text
Keywords: fragile-X syndrome; FMR1 gene; methylation; mosaicism; expansion; retraction fragile-X syndrome; FMR1 gene; methylation; mosaicism; expansion; retraction
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Prawer, Y.; Hunter, M.; Cronin, S.; Ling, L.; Aliaga Vera, S.; Fahey, M.; Gelfand, N.; Oertel, R.; Bartlett, E.; Francis, D.; Godler, D. Prenatal Diagnosis of Fragile X Syndrome in a Twin Pregnancy Complicated by a Complete Retraction. Genes 2018, 9, 287.

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