A New Congenital Multicores Titinopathy with Myosin deficiency (4032)

Objective: To report on TTN gene aberrations leading to a congenital myopathy with cardiac involvement in a brother (P1, age 18), and a sister (P2, age 10) of healthy Italian parents. Background: Congenital titinopathies is a group of myopathies with variable cardiac involvement and heterogeneous muscle biopsy features. Design/Methods: Clinic, histopathologic, MRI, NGS and titin protein studies were performed in a brother (P1, age 18), and a sister (P2, age 10) of healthy Italian parents. Results: Onset was congenital with hypotonia, retarded motor milestones, and diffuses muscle weakness. P1 had prominent hyperlaxity and hyperkeratosis pilaris. Cardiac involvement consisted of right branch block and mitral valve prolapsus in P1 and neonatal onset bradycardia and syncopal episodes in P2. Muscle MRIs showed diffuse and symmetric muscle involvement with variable fatty replacement and atrophy. Muscle biopsies showed multicores, type 1 uniformity, and absence of fast myosin 2A heavy chain. Myosin degradation was observed on electron microscopy. NGS identified one TTN frameshift pathogenic variant, c.79683dupA; p. (Arg26562Thrfs*12), inherited from the mother, and two missense variants, c.94015A>G; p.(Thr31339Ala), and c.18970A>C; p. (Thr6324Pro) inherited from the father. The c.79683dupA is predicted to produce a stop codon at position 26574 and a truncated protein lacking Cter including myosin interacting domains. The c.18970A>C and c.94015A>G are localized at actin and myosin interacting sites. Western blot studies in muscles from P1 revealed complete absence of myosin heavy chain fast isoform (MyHC2). Conclusions: We fully describe a novel congenital multicores titinopathy with cardiac involvement and secondary loss of myosin heavy chain. We suggest that myosin loss could play an important role in muscle weakness and cardiac dysfunction development in titinopathies. Disclosure: Dr. Perrin has nothing to disclose. Dr. Metay has nothing to disclose. Dr. Villanova has nothing to disclose. Dr. Carlier has nothing to disclose. Dr. Pegoraro has nothing to disclose. Dr. Juntas-Morales has nothing to disclose. Dr. Stojkovic has nothing to disclose. Dr. Richard has nothing to disclose. Dr. Richard has nothing to disclose. Dr. Granzier has nothing to disclose. Dr. Koenig has nothing to disclose. Dr. Cossee has nothing to disclose. Dr. Malfatti has nothing to disclose.