Abstract Details

Title Exome sequencing reveals novel candidate genes and potential oligogenic inheritance in patients with the complex trait arthrogryposis

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) P2 - Poster Session 2 (5:30 PM-6:30 PM)

Poster/Presentation
Number 12-041

Objective Delineating the molecular etiology of arthrogryposis using exome sequencing studies

Background Arthrogryposis is a clinical finding described as congenital contractures in nonconsecutive joints. Over 400 disorders are found to have arthrogryposis as a finding and more than 300 genes have been linked with this condition. Clinical and genetic heterogeneity makes the molecular diagnosis challenging and the underlying molecular etiology remains largely unknown.

Design/Methods Exome sequencing (ES) was implemented in 115 families with the clinical sign of arthrogryposis including two families identified through GeneMatcher. Variants of interest underwent Sanger PCR confirmation/segregation. Array Comparative Genomic Hybridization (aCGH) and Droplet Digital PCR (ddPCR) were performed accordingly in individuals who were found to have copy number variants (CNV) and mosaicism, respectively.

Results A molecular diagnosis was identified in 73% (83/113) when including both known and candidate genes. Of the 83 solved families, 65 of which revealed mutations in 45 distinct known genes, further documenting extensive genetic heterogeneity. CHRNG and ECEL1 were the most commonly mutated genes (22%) in this population. Novel candidate genes were elucidated in 23 families. Multilocus pathogenic rare variation including two or even three genes with pathogenic variation was observed in ~21% (18/83) of families, likely driven by absence of heterozygosity (AOH) regions. RYR3, MYOM2, ERGIC1, and SPTBN4 are novel arthrogryposis genes identified in two or more families. We found de novoCNVs in 3 families likely contributing to the disease phenotype. We also show evidence for monoallelic and biallelic variants in the same gene in association with either clinically similar or distinct syndromes.

Conclusions We performed a comprehensive ES study to delineate the molecular etiology of arthrogryposis. We propose several novel candidate genes and to explore the potential role for oligogenic models in arthrogryposis patients.

Authors/Disclosures
Davut Pehlivan, MD PRESENTER	Dr. Pehlivan has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ionis Pharmaceuticals.
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
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	No disclosure on file
James R. Lupski, MD, PhD (Baylor College of Medicine)	Dr. Lupski has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novartis. Dr. Lupski has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Regeneron Genetics Center.

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