PO25 A Novel MYH7-Related Restrictive Cardiomyopathy with LV Non-Compaction Requiring Heart Transplantation

Introduction The MYH7 gene encodes the beta-cardiac myosin heavy chain subunit, a key protein primarily expressed in the cardiac and skeletal muscles. Mutations in MYH7 are most often associated with hypertrophic cardiomyopathy (HCM) and laing early-onset distal myopathy. Nonetheless, MYH7 variants may underline other cardiac phenotypes. Case Presentation An 18-year-old female patient with a history of suspected primary cardiomyopathy has been followed since the age of 13. Other than pre-diabetes mellitus (unrelated to autoimmunity), she has no other known disease. Her family has no known cardiovascular or hereditary illnesses. The patient was receiving bisoprolol 2.5mg twice daily, started years ago. Initially, she presented with recurrent unexplained syncope – no arrhythmic events were ever recorded, namely on implantable loop recorder. Over the last couple of years, she complained of increasing dyspnea and fatigue on effort (Ross/NYHA III). Her physical examination was unremarkable, with normal body mass index, absent dysmorphic features and no skin pigmentation disorders. The ECG showed sinus rhythm, incomplete right bundle branch block and ST depression with biphasic T waves in V2-V3. The stress test, stopped at 3 minutes, displayed transient complete AV block on peak effort – thus, beta-blockade was stopped. On repeat testing, there was normal AV conduction on maximal effort (RQ 1.12) and severely reduced pVO2 (10,2mL/min/m2). The transthoracic echocardiography (TTE) was remarkable for a non-dilated left ventricle (LV) without LV hypertrophy, reduced LV ejection fraction (50%) and global longitudinal strain (GLS -12.7%), restrictive physiology, bi-atrial dilatation and formal (Jenni) criteria for LV non-compaction. Cardiac MRI confirmed the morphological changes on TTE, and showed myocardial crypts (with positive late gadolinium enhancement at these sites) plus apical papillary muscle displacement (figure). Genetic testing identified a novel mutation in the MYH7 gene (c.1358G>C, p.(Arg453Pro)), located in the motor domain of myosin, classified as a variant of uncertain significance (VUS). This variant fills criteria for a HOT VUS (i.e., same residue of another missense pathogenic variant, mutation in a hotspot and deleterious protein function in biogenetic models). This was followed with cascade family screening that was negative for both parents and sister. During follow-up the patient worsened her symptoms, displaying advanced heart failure and received an heart transplant that ocurred without complications. Conclusion We here described the case of a young patient with a novel MYH7-related cardiac disease presenting mainly with a restrictive cardiomyopathy phenotype, presence of morphological features for sarcomeric cardiomyopathy, and LV non-compaction. This finding has led to specific follow-up and subsequent heart transplant and cascade screening in the family.