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)/(CGG); M2-(CGG)/(CGG); M3-(CGG)/(CGG); and M4-(CGG)/(CGG)/(CGG). 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)>(CGG) 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.

Reversion to Normal of FMR1 Expanded Alleles: A Rare Event in Two Independent Fragile X Syndrome Families

“…Similar reverted and non-mosaic alleles have been described in FXS families both in unaffected females [19,22] and in unaffected males [23,24]. Contracted alleles in the range of normality have also been detected along with expanded ones in FXS mosaic males, such as in the four affected boys reported by Maia et al [25], who inherited the normal allele by their FM or PM mother, or as in a monozygous male twin, who derived the normal allele from his PM mother [26]. These latter cases are probably due to somatic instability of the CGG expansions in the range of PM or FM, which is well documented [27,28], while information regarding unstable normal alleles is limited [29].…”

Mutational mechanism for DAB1 (ATTTC) n insertion in SCA37: ATTTT repeat lengthening and nucleotide substitution

“…Microsatellite repetitive tracts are often interrupted by other nucleotide motifs that result from nucleotide substitutions (Ananda et al, 2014). In some diseases, as SCA1 (MIM# 164400), SCA2 (MIM# 183090), fragile-X syndrome (MIM# 300624), myotonic dystrophy type 2 (DM2; MIM# 602668), and Friedrich ataxia (FRDA; MIM# 229300), nonpathogenic alleles are more likely to be interrupted than expanded alleles, whereas in SCA8 (MIM# 608768), SCA10 (MIM# 603516), and DM1 (MIM# 160900) interruptions are more expected in expanded alleles (Braida et al, 2010;Chung et al, 1993;Hu et al, 2017;Imbert et al, 1996;Landrian et al, 2017;Liquori et al, 2003;Maia et al, 2017;Martins et al, 2005;Menon et al, 2013;Montermini et al, 1997;Moseley et al, 2000;Musova et al, 2009;Ramos et al, 2010;Yrigollen et al, 2014;Zuhlke et al, 2002). Depending on the gene, interruptions in the repetitive tract may be randomly positioned, as in ATXN2, ATXN8OS, and ATXN10, or follow a pattern (Chung et al, 1993;Landrian et al, 2017;Yrigollen et al, 2014).…”

On the wrong DNA track: Molecular mechanisms of repeat-mediated genome instability

“…For example, single common ancestors had a pathogenic amplification of ATTCT repeats in SCA10 (55)(56)(57), CCTG repeats in DM2 (58), and TTTTA/TTTCA repeats in FAME3 (32). Contrastingly, de novo repeat expansions were reported for the CAG repeat in HD (59), the CGG repeat in fragile X syndrome (60), and the GCN repeat in hand-foot-genital (HFG) syndrome (61). Last, the mechanisms of repeat toxicity vary among different repeats and include both a loss and gain of function.…”