TY - JOUR T1 - <em>FXN</em> gene methylation determines carrier status in Friedreich ataxia JF - Journal of Medical Genetics JO - J Med Genet DO - 10.1136/jmg-2022-108742 SP - jmedgenet-2022-108742 AU - Christina Lam AU - Kaitlyn M Gilliam AU - Layne N Rodden AU - Kimberly A Schadt AU - David R Lynch AU - Sanjay Bidichandani Y1 - 2023/01/12 UR - http://jmg.bmj.com/content/early/2023/01/11/jmg-2022-108742.abstract N2 - Background Friedreich ataxia (FRDA) is typically caused by homozygosity for an expanded GAA triplet-repeat (GAA-TRE) in intron 1 of the FXN gene. Some patients are compound heterozygous for the GAA-TRE and another FXN pathogenic variant. Detection of the GAA-TRE in the heterozygous state, occasionally technically challenging, is essential for diagnosing compound heterozygotes and asymptomatic carriers.Objective We explored if the FRDA differentially methylated region (FRDA-DMR) in intron 1, which is hypermethylated in cis with the GAA-TRE, effectively detects heterozygous GAA-TRE.Methods FXN DNA methylation was assayed by targeted bisulfite deep sequencing using the Illumina platform.Results FRDA-DMR methylation effectively identified a cohort of known heterozygous carriers of the GAA-TRE. In an individual with clinical features of FRDA, commercial testing showed a paternally inherited pathogenic FXN initiation codon variant but no GAA-TRE. Methylation in the FRDA-DMR effectively identified the proband, his mother and various maternal relatives as heterozygous carriers of the GAA-TRE, thus confirming the diagnosis of FRDA.Conclusion FXN DNA methylation reliably detects the GAA-TRE in the heterozygous state and offers a robust alternative strategy to diagnose FRDA due to compound heterozygosity and to identify asymptomatic heterozygous carriers of the GAA-TRE. ER -