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

Essra Bartlett; Alison D Archibald; David Francis; Ling Ling; Rob Thomas; Gabrielle Chandler; Lisa Ward; Gemma O'Farrell; Alison Pandelache; Martin B Delatycki; Bruce H Bennetts; Gladys Ho; Katrina Fisk; Emma K Baker; David J Amor; David E Godler

doi:10.1002/ajmg.a.62500

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

Am J Med Genet A. 2022 Jan;188(1):304-309. doi: 10.1002/ajmg.a.62500. Epub 2021 Sep 21.

Authors

Essra Bartlett¹, Alison D Archibald^{1

2

3}, David Francis¹, Ling Ling⁴, Rob Thomas¹, Gabrielle Chandler¹, Lisa Ward¹, Gemma O'Farrell¹, Alison Pandelache¹, Martin B Delatycki^{1

2

3}, Bruce H Bennetts^{5

6}, Gladys Ho^{5

6}, Katrina Fisk⁵, Emma K Baker^{4

2

7}, David J Amor^{1

2

8}, David E Godler^{4

2}

Affiliations

¹ Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia.
² Faculty of Medicine, Dentistry and Health Sciences, Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia.
³ Bruce Lefroy Centre, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia.
⁴ Diagnosis and Development, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia.
⁵ Sydney Genome Diagnostics-Molecular Genetics, Children's Hospital at Westmead, Sydney, New South Wales, Australia.
⁶ Discipline of Genetic Medicine, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
⁷ School of Psychology and Public Health, La Trobe University, Melbourne, Victoria, Australia.
⁸ Neurodisability and Rehabilitation, Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia.

PMID: 34545686
DOI: 10.1002/ajmg.a.62500

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 post-zygotic paternal retraction can lead to low-level mosaicism for normal size alleles, with these normal alleles being functional when passed over two generations.

Keywords: CGG; FMR1; fragile X syndrome; mosaicism; premutation.

Publication types

Case Reports
Research Support, Non-U.S. Gov't

MeSH terms

Alleles
DNA Methylation
Female
Fragile X Mental Retardation Protein* / genetics
Fragile X Syndrome* / diagnosis
Fragile X Syndrome* / genetics
Humans
Male
Mutation
Trinucleotide Repeat Expansion

Substances

FMR1 protein, human
Fragile X Mental Retardation Protein