Double SMCHD1 variants in FSHD2: the synergistic effect of two SMCHD1 variants on D4Z4 hypomethylation and disease penetrance in FSHD2

European Journal of Human Genetics : EJHG
Marlinde L van den BoogaardS van der Maarel

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) predominantly affects the muscles in the face, trunk and upper extremities and is marked by large clinical variability in disease onset and progression. FSHD is associated with partial chromatin relaxation of the D4Z4 repeat array on chromosome 4 and the somatic expression of the D4Z4 encoded DUX4 gene. The most common form, FSHD1, is caused by a contraction of the D4Z4 repeat array on chromosome 4 to a size of 1-10 units. FSHD2, the less common form of FSHD, is most often caused by heterozygous variants in the chromatin modifier SMCHD1, which is involved in the maintenance of D4Z4 methylation. We identified three families in which the proband carries two potentially damaging SMCHD1 variants. We investigated whether these variants were located in cis or in trans and determined their functional consequences by detailed clinical information and D4Z4 methylation studies. In the first family, both variants in trans were shown to act synergistically on D4Z4 hypomethylation and disease penetrance, in the second family both SMCHD1 function-affecting variants were located in cis while in the third family one of the two variants did not affect function. This study demonstrates that having tw...Continue Reading

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Citations

Nov 5, 2019·Journal of Medical Genetics·Remko GoossensSilvère M van der Maarel
Jul 13, 2018·Neurology·Mariëlle WohlgemuthNicol C Voermans
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
Jun 21, 2015·Proceedings of the National Academy of Sciences of the United States of America·Kelan ChenMarnie E Blewitt
Jul 9, 2016·Current Opinion in Neurology·Karlien MulBaziel G M van Engelen
Aug 19, 2021·Neuromuscular Disorders : NMD·N C VoermansUNKNOWN FSHD European Trial Network workshop study group

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