Prenatal diagnosis of fragile X syndrome in a twin pregnancy complicated by a complete retraction

Yael Prawer, Matthew Hunter, Sara Cronin, Ling Ling, Solange Aliaga Vera, Michael Fahey, Nikki Gelfand, Ralph Oertel, Essra Bartlett, David Francis, David Godler

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number287
Number of pages11
JournalGenes
Volume9
Issue number6
DOIs
Publication statusPublished - 7 Jun 2018

Keywords

  • Expansion
  • FMR1 gene
  • Fragile-X syndrome
  • Methylation
  • Mosaicism
  • Retraction

Cite this

Prawer, Yael ; Hunter, Matthew ; Cronin, Sara ; Ling, Ling ; Vera, Solange Aliaga ; Fahey, Michael ; Gelfand, Nikki ; Oertel, Ralph ; Bartlett, Essra ; Francis, David ; Godler, David. / Prenatal diagnosis of fragile X syndrome in a twin pregnancy complicated by a complete retraction. In: Genes. 2018 ; Vol. 9, No. 6.
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title = "Prenatal diagnosis of fragile X syndrome in a twin pregnancy complicated by a complete retraction",
abstract = "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.",
keywords = "Expansion, FMR1 gene, Fragile-X syndrome, Methylation, Mosaicism, Retraction",
author = "Yael Prawer and Matthew Hunter and Sara Cronin and Ling Ling and Vera, {Solange Aliaga} and Michael Fahey and Nikki Gelfand and Ralph Oertel and Essra Bartlett and David Francis and David Godler",
year = "2018",
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Prawer, Y, Hunter, M, Cronin, S, Ling, L, Vera, SA, Fahey, M, Gelfand, N, Oertel, R, Bartlett, E, Francis, D & Godler, D 2018, 'Prenatal diagnosis of fragile X syndrome in a twin pregnancy complicated by a complete retraction', Genes, vol. 9, no. 6, 287. https://doi.org/10.3390/genes9060287

Prenatal diagnosis of fragile X syndrome in a twin pregnancy complicated by a complete retraction. / Prawer, Yael; Hunter, Matthew; Cronin, Sara; Ling, Ling; Vera, Solange Aliaga; Fahey, Michael; Gelfand, Nikki; Oertel, Ralph; Bartlett, Essra; Francis, David; Godler, David.

In: Genes, Vol. 9, No. 6, 287, 07.06.2018.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Prenatal diagnosis of fragile X syndrome in a twin pregnancy complicated by a complete retraction

AU - Prawer, Yael

AU - Hunter, Matthew

AU - Cronin, Sara

AU - Ling, Ling

AU - Vera, Solange Aliaga

AU - Fahey, Michael

AU - Gelfand, Nikki

AU - Oertel, Ralph

AU - Bartlett, Essra

AU - Francis, David

AU - Godler, David

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Y1 - 2018/6/7

N2 - 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.

AB - 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.

KW - Expansion

KW - FMR1 gene

KW - Fragile-X syndrome

KW - Methylation

KW - Mosaicism

KW - Retraction

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U2 - 10.3390/genes9060287

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