Fragile X syndrome in a male with methylated premutation alleles and no detectable methylated full mutation alleles. Issue 10 (29th July 2019)

• Record Type: Journal Article
• Authors: Hayward, Bruce; Loutaev, Inna; Ding, Xiaohua; Nolin, Sarah L.; Thurm, Audrey; Usdin, Karen; Smith, Carolyn B.
• Is Part Of: American journal of medical genetics. Volume 179:Issue 10(2019)
• Page Start: 2132
• Page End: 2137
• Publication Date: 2019-07-29
• Subjects: FMR1 -- fragile X syndrome -- gene methylation -- premutation allele; Medical genetics -- Periodicals; 616.14205
• DOI: 10.1002/ajmg.a.61286
• Languages: English
• ISSNs: 1552-4825

Abstract

Abstract: Most cases of fragile X syndrome (FXS) result from aberrant methylation of the FMR1 gene. Methylation occurs when the number of tandemly arranged cytosine guanine guanine (CGG)‐repeats in the 5′ end of the transcriptional unit of FMR1 exceeds a certain critical threshold, thought to be between 200 and 400 repeats. Such alleles are referred to as full mutation (FM) alleles. Premutation (PM) alleles, alleles with 55–200 repeats, are generally not aberrantly methylated and in fact may have hyperexpression of the FMR1 mRNA. We describe here a male who meets the diagnostic criteria for FXS, who is highly mosaic with a mixture of multiple PM and FM alleles and 50% methylation. However, the methylated alleles are limited to two alleles in the PM range, ~165 and ~175 repeats respectively, with the FM alleles being unmethylated. This finding has implications for FXS diagnosis as well as for efforts to delete the repeat in individuals with FXS using a CRISPR‐Cas9 approach.