title: Chromosome fragility at FRAXA in human cleavage stage embryos at risk for fragile X syndrome.
abstract: Fragile X syndrome (FXS), the most common inherited intellectual disability syndrome, is caused by expansion and hypermethylation of the CGG repeat in the 5' UTR of the FMR1 gene. This expanded repeat, also known as the rare fragile site FRAXA, causes X chromosome fragility in cultured cells from patients but only when induced by perturbing pyrimidine synthesis. We performed preimplantation genetic diagnosis (PGD) on 595 blastomeres biopsied from 442 cleavage stage embryos at risk for FXS using short tandem repeat (STR) markers. In six blastomeres, from five embryos an incomplete haplotype was observed with loss of all alleles telomeric to the CGG repeat. In all five embryos, the incomplete haplotype corresponded to the haplotype carrying the CGG repeat expansion. Subsequent analysis of additional blastomeres from three embryos by array comparative genomic hybridization (aCGH) confirmed the presence of a terminal deletion with a breakpoint close to the CGG repeat in two blastomeres from one embryo. A blastomere from another embryo showed the complementary duplication. We conclude that a CGG repeat expansion at FRAXA causes X chromosome fragility in early human IVF embryos at risk for FXS.
authors.affiliation: Centre for Medical Genetics, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Brussel, België
authors.forename: Pieter
authors.initials: P
authors.lastname: Verdyck
authors.affiliation: Centre for Medical Genetics, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Brussel, België
authors.forename: Veerle
authors.initials: V
authors.lastname: Berckmoes
authors.affiliation: Centre for Reproductive Medicine, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Brussel, België
authors.forename: Anick
authors.initials: A
authors.lastname: De Vos
authors.affiliation: Centre for Reproductive Medicine, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Brussel, België
authors.forename: Willem
authors.initials: W
authors.lastname: Verpoest
authors.affiliation: Centre for Medical Genetics, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Brussel, België
authors.forename: Inge
authors.initials: I
authors.lastname: Liebaers
authors.affiliation: Centre for Medical Genetics, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Brussel, België
authors.forename: Maryse
authors.initials: M
authors.lastname: Bonduelle
authors.affiliation: Centre for Medical Genetics, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Brussel, België
authors.forename: Martine
authors.initials: M
authors.lastname: De Rycke
mesh_terms: D001757:Blastomeres / Q000378:metabolism / Q000473:pathology; D043283:Chromosome Fragile Sites; D002873:Chromosome Fragility; D055028:Comparative Genomic Hybridization; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000378:metabolism*; D005260:Female; D005307:Fertilization in Vitro; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D005600:Fragile X Syndrome / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D015870:Gene Expression; D005819:Genetic Markers; D006239:Haplotypes; D006801:Humans; D008297:Male; D011247:Pregnancy; D019836:Preimplantation Diagnosis; D019680:Trinucleotide Repeat Expansion
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D005819:Genetic Markers; C497683:FMR1 protein, human
keywords: FRAXA; double-stranded DNA break; fragile X syndrome; preimplantation genetic diagnosis