Abstract Details

Title Identification of the Epigenetic Modifier of the D4Z4 Epiallele in FSHD2

Topic Muscle Disease/Neuromuscular Junction

Presentation(s) S05 - (-)

Poster/Presentation
Number 001

Objective

Background Facioscapulohumeral muscular dystrophy (FSHD) is associated with chromatin decondensation of the D4Z4 macrosatellite array on chromosome 4 and ectopic expression of the D4Z4-encoded germ line transcription factor DUX4 in skeletal muscle. Two genetic variants of chromosome 4 have been identified of which only one is permissive to DUX4 expression. In most patients, D4Z4 chromatin decondensation is caused by contraction of the D4Z4 array (FSHD1) and is inherited as a dominant trait. In some patients D4Z4 decondensation occurs on normal sized arrays (FSHD2) of both chromosomes 4q and 10q and show a more complex inheritance pattern. In both FSHD1 and FSHD2, the chromatin relaxation is associated with a loss of CpG methylation and a loss of repressive histone modifications at D4Z4.

Design/Methods We applied exome sequencing in FSHD2 families in which D4Z4 hypomethylation segregated as a dominant trait with the objective to identify the chromatin modifier responsible for D4Z4 hypomethylation.

Results Here we show that rare, normally benign variants in a chromatin modifier segregate with genome-wide D4Z4 CpG hypomethylation. FSHD2 patients inherited both mutations in this epigenetic modifier and normal-sized D4Z4 arrays permissive for DUX4 expression. Mutations in this chromatin modifier explain approximately 80% of FSHD2 patients.

Conclusions We identified an epigenetic modifier of the D4Z4 epiallele that is underlying FSHD2 and possibly other human diseases subject to epigenetic regulation. It may also act as a modifier in FSHD1.

Authors/Disclosures
Sabrina Sacconi, MD PRESENTER	Dr. Sacconi has received personal compensation in the range of $500-$4,999 for serving as a Consultant for LUPIN. Dr. Sacconi has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for SANOFI. Dr. Sacconi has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for BIOGEN. Dr. Sacconi has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for AMICUS. Dr. Sacconi has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for UCB Pharma. Dr. Sacconi has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for ALEXION. Dr. Sacconi has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for FULCRUM THERAPEUTICS. Dr. Sacconi has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for AXELYS. Dr. Sacconi has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for OLOGY. The institution of Dr. Sacconi has received research support from Solve FSHD.
	No disclosure on file
Alrabi Tawil, MD, FAAN (University of Rochester Medical Center)	Dr. Tawil has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Kate Therapeutics. Dr. Tawil has received personal compensation in the range of $500-$4,999 for serving as a Consultant for meRicule. The institution of Dr. Tawil has received research support from Friends of FSH Research. The institution of Dr. Tawil has received research support from FSH Society. The institution of Dr. Tawil has received research support from NIH. The institution of Dr. Tawil has received research support from Fulcrum. Dr. Tawil has received intellectual property interests from a discovery or technology relating to health care.
Kimberly Vanover, PhD	No disclosure on file
George W. Padberg, MD, PhD, FAAN	No disclosure on file
Claude J. Desnuelle, MD (CHU De Nice - Hopital Pasteur2)	No disclosure on file
Stephen J. Tapscott, MD, PhD (Fred Hutchinson Cancer Research Center)	Dr. Tapscott has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Avidity. Dr. Tapscott has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Fulcrum Therapeutics. Dr. Tapscott has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Kate Therapeutics. Dr. Tapscott has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for miRecule. Dr. Tapscott has received intellectual property interests from a discovery or technology relating to health care.
	No disclosure on file
	No disclosure on file
	No disclosure on file

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