Paternal retraction of a fragile X allele to normal size, showing normal function over two generations

Abstract

The FMR1 premutation (PM:55-199 CGG) is associated with fragile X-associated tremor/ataxia syndrome (FXTAS) and when maternally transmitted is at risk of expansion to a hypermethylated full mutation (FM: ≥ 200 CGG) that causes fragile X syndrome (FXS). We describe a maternally transmitted PM (77 CGG) that was passed to a son (103 CGG), and to a daughter (220-1822 CGG), who were affected with FXTAS and FXS, respectively. The male with the PM showed low-level mosaicism for normal size of 30 and 37 CGG. This male had two offspring: one female mosaic for PM and FM (56, 157, >200 CGG) and another with only a 37 CGG allele detected in multiple tissues, neither with a clinical phenotype. The female with the 37 CGG allele showed normal levels of FMR1 methylation and mRNA and passed this 37 CGG allele to one of her daughters, who was also unaffected. These findings show that postzygotic paternal retraction can lead to low-level mosaicism for normal size alleles, with these normal alleles being functional when passed over two generations.

The polyG diseases: a new disease entity

“…Clinical and genetic anticipation are typical features in most STR-related diseases, while anticipation have not observed in patients with polyG diseases currently. Nucleotide repeat instability and unstable transmission of CGG repeats between parents and offspring have been reported in individual FXTAS, NIID, and OPDM families [ 5 , 20 ]. These characteristics suggest that polyG diseases may have different molecular genetic mechanisms compared to polyQ diseases.…”

“…Although polyG diseases are reported to be autosomal dominant [ 21 ], the hereditary mode is uncertain due to random expansion or contraction of the repeats [ 52 ]. For example, offspring of FXTAS patients can be unaffected or suffer from FXS [ 5 ]. Unexpectedly, males carrying large CGG repeat expansions (up to 300) in NOTCH2NLC seem to be asymptomatic, though NOTCH2NLC mRNA levels decrease as a consequence of hypermethylation around the CGG repeats, displaying a strikingly different prognosis in contrast to FXS patients with full mutation alleles of FMR1 [ 133 ].…”