Both cis and trans-acting genetic factors drive somatic instability in female carriers of the FMR1 premutation

Hwang, Yehyun, Hayward, Bruce, Zafarullah, Marwa, Kumar, Jay, Durbin Johnson, Blythe, Holmans, Peter ORCID: https://orcid.org/0000-0003-0870-9412, Usdin, Karen and Tassone, Flora 2022. Both cis and trans-acting genetic factors drive somatic instability in female carriers of the FMR1 premutation. Scientific Reports 12 , 10419. 10.1038/s41598-022-14183-0

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Abstract

The fragile X mental retardation (FMR1) gene contains an expansion-prone CGG repeat within its 5′ UTR. Alleles with 55–200 repeats are known as premutation (PM) alleles and confer risk for one or more of the FMR1 premutation (PM) disorders that include Fragile X-associated Tremor/Ataxia Syndrome (FXTAS), Fragile X-associated Primary Ovarian Insufficiency (FXPOI), and Fragile X-Associated Neuropsychiatric Disorders (FXAND). PM alleles expand on intergenerational transmission, with the children of PM mothers being at risk of inheriting alleles with > 200 CGG repeats (full mutation FM) alleles) and thus developing Fragile X Syndrome (FXS). PM alleles can be somatically unstable. This can lead to individuals being mosaic for multiple size alleles. Here, we describe a detailed evaluation of somatic mosaicism in a large cohort of female PM carriers and show that 94% display some evidence of somatic instability with the presence of a series of expanded alleles that differ from the next allele by a single repeat unit. Using two different metrics for instability that we have developed, we show that, as with intergenerational instability, there is a direct relationship between the extent of somatic expansion and the number of CGG repeats in the originally inherited allele and an inverse relationship with the number of AGG interruptions. Expansions are progressive as evidenced by a positive correlation with age and by examination of blood samples from the same individual taken at different time points. Our data also suggests the existence of other genetic or environmental factors that affect the extent of somatic expansion. Importantly, the analysis of candidate single nucleotide polymorphisms (SNPs) suggests that two DNA repair factors, FAN1 and MSH3, may be modifiers of somatic expansion risk in the PM population as observed in other repeat expansion disorders.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Additional Information:	Tis article is licensed under a Creative Commons Attribution 4.0 International License
Publisher:	Nature Research
ISSN:	2045-2322
Date of First Compliant Deposit:	23 May 2022
Date of Acceptance:	18 May 2022
Last Modified:	24 May 2023 00:44
URI:	https://orca.cardiff.ac.uk/id/eprint/149945

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