Abstract Details

Title A novel TTN deletion causes Autosomal Dominant Limb-Girdle Muscular Dystrophy with Dilated Cardiomyopathy

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) P5 - Poster Session 5 (5:30 PM-6:30 PM)

Poster/Presentation
Number 12-001

Objective To describe a family with a limb-girdle muscular dystrophy (LGMD) phenotype with facial weakness and dilated cardiomyopathy (DCM), and a de novo and novel TTN deletion.

Background na

Design/Methods Case report.

Results The proband presented with proximal-predominant muscle weakness, facial weakness, and a unique ‘Charlie Chaplin’ gait with profound bilateral hip eversion. Electromyography showed a myopathic process; creatine kinase was normal; bicep muscle biopsy revealed myopathic changes. Testing for FSHD, DM1/2, and alpha-glucosidase was negative. He was diagnosed with idiopathic cardiomyopathy at 42 and heart failure at 57 (ejection fraction [EF] 20%, mild-moderate 4-chamber dilation, meeting DCM criteria). A 35-gene LGMD panel identified one TTN VUS (c.49787T>C, p.L16596P). Further testing via a 204-gene neuromuscular/cardiomyopathy panel identified a likely pathogenic, novel 16.430-kb heterozygous deletion partly spanning TTN’s A-/M-bands (c.96076_107488del, p.I32026Pfs*14; exons 346-362). Targeted testing in nine additional family members identified the deletion in three of the proband’s four children. Clinical evaluation of two sons with the deletion revealed proximal-predominant weakness, distal weakness, and facial weakness. One son’s echocardiogram showed EF 53%, consistent with borderline-low systolic function with left ventricular end-diastolic dimension at the upper limits of normal. Currently, only LGMD2J is known to be caused by pathogenic variants in TTN. LGMD2J is a recessive, early-onset, severe LGMD not known to cause DCM or facial weakness. This family’s condition involves dominant inheritance and childhood-onset of mild muscle weakness, with facial weakness and DCM in later decades.

Conclusions The proband was tested using two different NGS panels and two different commercial laboratories, both included TTN sequencing and yielded inconsistent results. This diagnostic odyssey illustrates challenges associated with NGS technology and variant interpretation in TTN. We suggest that pathogenic variants in TTN may be an under-recognized cause of LGMD phenotypes and should be considered in the genetic differential diagnosis in patients with both skeletal muscle weakness and DCM.

Authors/Disclosures
Kelly Rich, MS, CGC PRESENTER	Ms. Rich has nothing to disclose.
Jennifer A. Roggenbuck, MS, CGC (Ohio State University)	The institution of Ms. Roggenbuck has received research support from Packard Foundation.
Ana Morales	No disclosure on file
	No disclosure on file
	No disclosure on file
Wendy M. King, PT	Ms. King has nothing to disclose.
	No disclosure on file
Thomas L. Winder, PhD, FACMG (Invitae Corp.)	Dr. Winder has nothing to disclose.
Bakri Elsheikh, MD, FAAN (The Ohio State University Wexner Medical Center)	Dr. Elsheikh has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen . Dr. Elsheikh has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Argnex . The institution of Dr. Elsheikh has received research support from Biogen. The institution of Dr. Elsheikh has received research support from Cure SMA.
	No disclosure on file
John T. Kissel, MD, FAAN	Dr. Kissel has nothing to disclose.

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