Abstract Details

Title FSHD2 Gene May Act as (epi)Genetic Modifier for FSHD1

Topic Muscle Disease/Neuromuscular Junction

Presentation(s) S05 - (-)

Poster/Presentation
Number 002

Objective

Background Autosomal dominant FSHD1 is associated to a contraction of D4Z4 repeated units (RU) < 11 on chromosome 4. In typical cases, the less RU are left, the more the clinical phenotype is severe, but some atypical cases have been described. FSHD2, clinically identical to FSHD1, is not associated to D4Z4 contraction on chromosome 4 but instead to a marked hypomethylation of D4Z4 alleles on both chromosomes 4 and 10. FSHD1 and FSHD2 may share a common pathophysiological pathway since both FSHD1 and FSHD2 myoblasts display a relative chromatin decondensation of the D4Z4 repeat leading to transcriptional derepression of the toxic DUX4 gene.

Design/Methods We analyzed 42 unrelated FSHD1 patients followed in our Center in order to establish a genotype/phenotype correlation between RU number and the severity of clinical phenotype evaluated by Manual Muscle Testing and Brooke and Vignos scales. Methylation studies and complete genotyping of chromosome 4 and 10 D4Z4 loci were performed in atypical cases and in a set of typical patients.

Results A genotype/phenotype correlation was established for all but three FSHD1 patients. These three patients, very severely affected, displayed relatively high number of RU (9). Further analysis confirmed the FSHD1 diagnosis, but uncovered marked hypomethylation of D4Z4 loci on both chromosomes 4 and 10 and mutations in the recently identified FSHD2 gene. Disease segregation studies showed that patients carrying both FSHD1 and FSHD2 had more severe phenotype compared to patients having only FSHD1 or FSHD2 gene defect. Follow up studies in a larger patient cohort identified additional patients with a double diagnosis of FSHD1 and FSHD2, confirming our hypothesis.

Conclusions Our study confirms that FSHD1 and FSHD2 share a common pathophysiological pathway and that the FSHD2 gene may act as a modifier for disease in FSHD1 families.

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.
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Claude J. Desnuelle, MD (CHU De Nice - Hopital Pasteur2)	No disclosure on file
	No disclosure on file

��ɫ��

��ɫ��