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

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. Disclosure: Dr. Rich has nothing to disclose. Dr. Roggenbuck has nothing to disclose. Dr. Morales has nothing to disclose. Dr. Tan has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Invitae Corp. Dr. Eck has nothing to disclose. Dr. King has nothing to disclose. Dr. Vatta has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Invitae Corp. Dr. Winder has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Invitae. Dr. Elsheikh has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Stealth Bio-therapeutics, Biogen. Dr. Elsheikh has received research support from Cure SMA, Biogen. Dr. Hershberger has nothing to disclose. Dr. Kissel has nothing to disclose.