Allele-specific DNA hypomethylation characterises FSHD1 and FSHD2

Journal of Medical Genetics
Patrizia CalandraGiancarlo Deidda

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is associated with an epigenetic defect on 4qter. Two clinically indistinguishable forms of FSHD are known, FSHD1 and FSHD2. FSHD1 is caused by contraction of the highly polymorphic D4Z4 macrosatellite repeat array on chromosome 4q35. FSHD2 is caused by pathogenic mutations of the SMCHD1 gene.Both genetic defects lead to D4Z4 DNA hypomethylation. In the presence of a polymorphic polyadenylation signal (PAS), DNA hypomethylation leads to inappropriate expression of the D4Z4-encoded DUX4 transcription factor in skeletal muscle. Currently, hypomethylation is not diagnostic per se because of the interference of non-pathogenic arrays and the lack of information about the presence of DUX4-PAS. We investigated, by bisulfite sequencing, the DNA methylation levels of the region distal to the D4Z4 array selectively in PAS-positive alleles. Comparison of FSHD1, FSHD2 and Control subjects showed a highly significant difference of methylation levels in all CpGs tested. Importantly, using a cohort of 112 samples, one of these CpGs (CpG6) is able to discriminate the affected individuals with a sensitivity of 0.95 supporting this assay potential for FSHD diagnosis. Moreover, our study showed a rela...Continue Reading

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Citations

May 25, 2016·Current Neurology and Neuroscience Reports·Leo H Wang, Rabi Tawil
Dec 28, 2017·Human Molecular Genetics·Jessica C de GreefSilvère M van der Maarel
Nov 23, 2017·European Journal of Human Genetics : EJHG·Richard Jlf LemmersSilvère M van der Maarel
Feb 23, 2020·Clinical Genetics·Anna GrecoSilvère M van der Maarel
Mar 4, 2020·Genes·Valentina SalsiRossella Tupler
Jul 23, 2020·European Journal of Neurology : the Official Journal of the European Federation of Neurological Societies·Giulia GiacomucciGiorgio Tasca
Jun 25, 2020·The Journal of Pharmacology and Experimental Therapeutics·L Alejandro RojasOwen Wallace
Mar 7, 2017·The Journal of Clinical Investigation·Emanuela TeveroniFabiola Moretti
Apr 25, 2019·Annual Review of Genomics and Human Genetics·Charis L Himeda, Peter L Jones
Apr 16, 2020·International Journal of Molecular Sciences·Ana NikolicRossella Tupler
Oct 3, 2020·Skeletal Muscle·Linde F BouwmanJessica C de Greef
Mar 15, 2020·Journal of Medical Genetics·Liangliang QiuZhiqiang Wang
Jan 14, 2021·Journal of Medical Genetics·Richard J L F LemmersSilvère M van der Maarel

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