Abstract Details

Title Correlating Testing for Rare Genetic Variants with a Broad Clinicopathologic Spectrum of Congenital Myopathies

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) N4 - Neuroscience in the Clinic: Bridging Genetics to the Clinic in Neuromuscular Disease (4:05 PM-4:20 PM)

Poster/Presentation
Number 003

Background CMs are a group of clinically heterogeneous disorders presenting with a range of overlapping findings, making diagnosis challenging. Despite advances in genetic testing, many cases remain undiagnosed.

Objective We report genetic findings from the Beggs laboratory congenital myopathy (CM) cohort, which currently totals over 1,100 individuals and constitutes a robust dataset of existing cases.

Design/Methods Subjects were ascertained based on clinical presentation and pathologic diagnoses suggestive of CM, and solved by a combination of single gene, panel, or genomic sequencing, and/or RNA-Seq.

Results Of 1,219 cases total, 739 (61%) were solved. 605 had mutations in either ACTA1, DNM2, MTM1, NEB, RYR1, SELENON, TPM2, TPM3, or TTN, which are well-known causes of congenital myopathy. While all patients shared a myopathic pattern of weakness and hypotonia, a wide spectrum of clinicopathologic features were appreciated among the cases. The remaining 134 solved cases had mutations in one of 60 different genes, including several rare or novel genes, as well as some more commonly mutated non-CM disease genes in patients who presented atypically for those associated conditions. Among a heterogeneous group of 144 probands with congenital myopathy with nonspecific or no pathology, 43 (30%) had SELENON mutations; 17 (12%) had RYR1 mutations and 8 (6%) had TTN mutations.

Conclusions This analysis of the Beggs laboratory cohort cases, accumulated over roughly 20 years, emphasizes the crucial role of WES/WGS in establishing a molecular genetic diagnosis of CM, as opposed to disease-based gene panels or single-gene testing, which may miss cases where the presentation does not fit the classical description of the disorder, or where multiple genes present with overlapping clinicopathologic diagnoses. Moreover, certain syndromes not known to present predominantly with myopathic symptoms may go undiagnosed if genetic testing is done in a more targeted fashion based on specific clinical symptoms or pathologic diagnosis alone.

Authors/Disclosures
Divya Jayaraman, MD, PhD (Mass General Brigham) PRESENTER	An immediate family member of Dr. Jayaraman has stock in Abbvie, Inc.. An immediate family member of Dr. Jayaraman has stock in Abbott Laboratories. An immediate family member of Dr. Jayaraman has stock in Gilead Sciences. An immediate family member of Dr. Jayaraman has stock in Johnson & Johnson. An immediate family member of Dr. Jayaraman has stock in 3M. An immediate family member of Dr. Jayaraman has stock in Pfizer. An immediate family member of Dr. Jayaraman has stock in Viatris. The institution of Dr. Jayaraman has received research support from NINDS Grant # 5R25NS070682-12 .
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Basil T. Darras, MD (Children'S Hosp Boston Harvard Med School)	The institution of Dr. Darras has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amicus. Dr. Darras has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Amicus. The institution of Dr. Darras has received research support from National Institutes of Health/National Institute of Neurological Disorders and Stroke,. The institution of Dr. Darras has received research support from Slaney Family Fund for SMA. The institution of Dr. Darras has received research support from Spinal Muscular Atrophy Foundation. The institution of Dr. Darras has received research support from CureSMA. The institution of Dr. Darras has received research support from Working on Walking Fund . The institution of Dr. Darras has received research support from CHERISH, CS2/CS12 . The institution of Dr. Darras has received research support from Biogen for CS11. The institution of Dr. Darras has received research support from AveXis. The institution of Dr. Darras has received research support from Sarepta Pharmaceuticals. The institution of Dr. Darras has received research support from PTC Therapeutics. The institution of Dr. Darras has received research support from Roche. The institution of Dr. Darras has received research support from Santhera. The institution of Dr. Darras has received research support from Scholar Rock. The institution of Dr. Darras has received research support from Fibrogen. The institution of Dr. Darras has received research support from Summit. Dr. Darras has received publishing royalties from a publication relating to health care. Dr. Darras has received publishing royalties from a publication relating to health care.
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