A case of compound mutations in the MYBPC3 gene associated with biventricular hypertrophy and neonatal death

Hypertrophic cardiomyopathy (HCM) is a familial, genetically determined, primary cardiomyopathy caused by mutations in genes coding for proteins of the sarcomere, or, less frequently, genes involved in storage diseases. In pediatric settings, pure HCM has an estimated incidence of 4.7 per million children. The disease is often sub-clinical and goes unrecognized mainly because most patients with HCM have only mild symptoms, if any. However, sudden cardiac death, the most dramatic clinical occurrence and the primary concern for patients and physicians alike, may be the first manifestation of the disease. We describe a case of compound heterozygosity in the MYBPC3 gene (p.Glu258Lys and IVS25-1G>A) associated with biventricular hypertrophy, atrial enlargement and subsequent neonatal death 33 days postpartum. Other studies have reported compound and/or double heterozygosis in the same or different sarcomeric genes during childhood and adulthood, and neonatal presentations have also been described. Our observations show that the combination of a missense (p.Glu258Lys) and a splice-site mutation (IVS25-1G>A) profoundly affects the clinical course. In families in which parental mutations are known, preimplantation (where ethically and legally feasible) or prenatal genetic screening should be adopted because: (1) neonatal HCM in genetic heterozygosity is potentially lethal and (2) heart disease is the most common developmental malformation and the leading cause of neonatal mortality and morbidity.