Homozygosity for a novel splice site mutation in the cardiac myosin-binding protein C gene causes severe neonatal hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy is typically inherited in an autosomal dominant pattern and has a variable age of onset and prognosis. Mutations in the myosin-binding protein C (MYBPC3) gene are one of the most frequent genetic causes of the disease. Patients with MYBPC3 mutations generally have a late onset and a relatively good prognosis. We report here more than 20 Old Order Amish children with severe neonatal hypertrophic cardiomyopathy caused by a novel homozygous splice site mutation in the MYBPC3 gene. The affected children typically presented with signs and symptoms of congestive heart failure during the first 3 weeks of life. Echocardiography revealed hypertrophic non-obstructive cardiomyopathy. These children had a life span averaging 3-4 months. All patients died from heart failure before 1 year of age unless they received a heart transplant. A genome-wide mapping study was performed in three patients. The disease related gene was localized to a 4.6 Mb region on chromosome 11p11.2-p11.12. This homozygous block contained MYBPC3, a previously identified cardiomyopathy related gene. We identified a novel homozygous mutation, c.3330 + 2T > G, in the splice-donor site of MYBPC3 intron 30. The mutation resulted in skipping of the 140-bp exon 30, which led to a frame shift and premature stop codon in exon 31 (p.Asp1064GlyfsX38). We have found a substantial incidence of this phenotype in Old Order Amish communities. It is also concerning that many unidentified heterozygous individuals who are at risk for development of hypertrophic cardiomyopathy do not receive proper medical attention in the communities.