FXN gene methylation determines carrier status in Friedreich ataxia
© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:60 |
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| Enthalten in: |
Journal of medical genetics - 60(2023), 8 vom: 01. Aug., Seite 797-800 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Lam, Christina [VerfasserIn] |
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| Links: |
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| Themen: |
DNA Methylation |
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| Anmerkungen: |
Date Completed 24.07.2023 Date Revised 15.08.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1136/jmg-2022-108742 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM351460128 |
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| 245 | 1 | 0 | |a FXN gene methylation determines carrier status in Friedreich ataxia |
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| 500 | |a Date Completed 24.07.2023 | ||
| 500 | |a Date Revised 15.08.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a METHODS: FXN DNA methylation was assayed by targeted bisulfite deep sequencing using the Illumina platform | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a DNA Methylation | |
| 650 | 4 | |a DNA Repeat Expansion | |
| 650 | 4 | |a Movement Disorders | |
| 700 | 1 | |a Gilliam, Kaitlyn M |e verfasserin |4 aut | |
| 700 | 1 | |a Rodden, Layne N |e verfasserin |4 aut | |
| 700 | 1 | |a Schadt, Kimberly A |e verfasserin |4 aut | |
| 700 | 1 | |a Lynch, David R |e verfasserin |4 aut | |
| 700 | 1 | |a Bidichandani, Sanjay |e verfasserin |4 aut | |
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