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Contraction of fully expanded FMR1 alleles to the normal range: predisposing haplotype or rare events?

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Title: Contraction of fully expanded FMR1 alleles to the normal range: predisposing haplotype or rare events?
Authors: Rosário Santos, Paula Jorge, Bárbara Oliveira, Nuno Maia, Sandra Martins, Joana R. Loureiro, Isabel Marques
Contributors: Instituto de Investigação e Inovação em Saúde
Source: Journal of Human Genetics. 62:269-275
Publisher Information: Springer Science and Business Media LLC, 2016.
Publication Year: 2016
Subject Terms: Male, 0301 basic medicine, 0303 health sciences, Trinucleotide Repeats/genetics, Haplotypes/genetics, Microsatellite Repeats/genetics, Middle Aged, Polymorphism, Single Nucleotide/genetics, Polymorphism, Single Nucleotide, 3. Good health, Fragile X Mental Retardation Protein, 03 medical and health sciences, Fragile X Syndrome/genetics, Gene Frequency, Haplotypes, Trinucleotide Repeats, Child, Preschool, Fragile X Syndrome, Humans, Child, Fragile X Mental Retardation Protein/genetics, Microsatellite Repeats
Description: 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)24 contraction 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.
Document Type: Article
File Description: application/pdf
Language: English
ISSN: 1435-232X
1434-5161
DOI: 10.1038/jhg.2016.122
Access URL: https://repositorio-aberto.up.pt/bitstream/10216/114492/1/SMartins_FMR1.pdf
https://pubmed.ncbi.nlm.nih.gov/27784894
https://nature.com/articles/jhg2016122
https://www.ncbi.nlm.nih.gov/pubmed/27784894
https://www.nature.com/articles/jhg2016122.pdf
https://pubmed.ncbi.nlm.nih.gov/27784894/
https://pure.mpg.de/pubman/faces/ViewItemOverviewPage.jsp?itemId=item_2416919
https://europepmc.org/abstract/MED/27784894
http://hdl.handle.net/10216/114492
Rights: Springer TDM
Accession Number: edsair.doi.dedup.....3f679d60231b14dba93e562fb5a1cb8c
Database: OpenAIRE
Description
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)24 contraction 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.
ISSN:1435232X
14345161
DOI:10.1038/jhg.2016.122