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Fragile X syndrome in a male with methylated premutation alleles and no detectable methylated full mutation alleles
Author(s) -
Hayward Bruce,
Loutaev Inna,
Ding Xiaohua,
Nolin Sarah L.,
Thurm Audrey,
Usdin Karen,
Smith Carolyn B.
Publication year - 2019
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.61286
Subject(s) - allele , genetics , biology , fragile x syndrome , mutation , gene
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.