title: Contraction of fully expanded FMR1 alleles to the normal range: predisposing haplotype or rare events?
abstract: Fragile X syndrome (FXS), the most common cause of inherited intellectual disability, is due to the expansion over 200 CGGs and methylation of this polymorphic region, in the 5'-UTR (untranslated region) of FMR1 (Xq27.3). We have identified four FXS mosaic males: M1-(CGG)35/(CGG)>200; M2-(CGG)26/(CGG)>200; M3-(CGG)39/(CGG)>200; and M4-(CGG)18/(CGG)125/(CGG)>200. After genotyping their respective mothers, we suggested that normal alleles of these patients resulted from post-zygotic contractions of full expansions. The detection of these four rare independent cases led us to hypothesize the existence of a large-contraction predisposing haplotype in our population. Next, we questioned whether other normal pure CGGs would have arisen through similar contractions from fully expanded alleles. To address these questions, we identified stable single-nucleotide polymorphism (SNP) lineages and related short tandem repeat (STR) haplotypes (DXS998-DXS548-FRAXAC1-FRAXAC2) of the four mosaics, 123 unrelated FXS patients and 212 controls. An extended flanking haplotype (34-44-38-336) shared by mosaics from lineage A suggested a risk lineage-specific haplotype more prone to large contractions. Other normal pure FMR1 alleles from this SNP background also shared phylogenetically close STR haplotypes, although a single (CGG)exp>(CGG)24contraction or the loss of AGG interruptions may explain their origin. In both scenarios, multistep FMR1 mutations involving the gain or loss of several CGGs seem to underlie the evolution of the repeat.
authors: Unidade de Genética Molecular, Centro de Genética Médica Jacinto de Magalhães, Centro Hospitalar do Porto, Porto, Portugal.|Unit for Multidisciplinary Research in Biomedicine, Abel Salazar Institute of Biomedical Sciences, University of Porto-UMIB/ICBAS/UP, Porto, Portugal.
authors: Nuno
authors: http://orcid.org/0000-0003-3274-2474
authors: N
authors: Maia
authors: Unidade de Genética Molecular, Centro de Genética Médica Jacinto de Magalhães, Centro Hospitalar do Porto, Porto, Portugal.
authors: Joana R
authors: JR
authors: Loureiro
authors: Unit for Multidisciplinary Research in Biomedicine, Abel Salazar Institute of Biomedical Sciences, University of Porto-UMIB/ICBAS/UP, Porto, Portugal.|Max-Planck-Institut für Experimentelle Medizin, Klinische Neurowissenschaften, Göttingen, Germany.
authors: Bárbara
authors: B
authors: Oliveira
authors: Unidade de Genética Molecular, Centro de Genética Médica Jacinto de Magalhães, Centro Hospitalar do Porto, Porto, Portugal.|Unit for Multidisciplinary Research in Biomedicine, Abel Salazar Institute of Biomedical Sciences, University of Porto-UMIB/ICBAS/UP, Porto, Portugal.
authors: Isabel
authors: I
authors: Marques
authors: Unidade de Genética Molecular, Centro de Genética Médica Jacinto de Magalhães, Centro Hospitalar do Porto, Porto, Portugal.|Unit for Multidisciplinary Research in Biomedicine, Abel Salazar Institute of Biomedical Sciences, University of Porto-UMIB/ICBAS/UP, Porto, Portugal.
authors: Rosário
authors: R
authors: Santos
authors: Unidade de Genética Molecular, Centro de Genética Médica Jacinto de Magalhães, Centro Hospitalar do Porto, Porto, Portugal.|Unit for Multidisciplinary Research in Biomedicine, Abel Salazar Institute of Biomedical Sciences, University of Porto-UMIB/ICBAS/UP, Porto, Portugal.
authors: Paula
authors: P
authors: Jorge
authors: i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.|IPATIMUP - Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.
authors: Sandra
authors: S
authors: Martins
mesh_terms: D002648:Child; D002675:Child, Preschool; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D005600:Fragile X Syndrome / Q000235:genetics*; D005787:Gene Frequency; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D018911:Trinucleotide Repeats / Q000235:genetics*
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; C497683:FMR1 protein, human