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

Abstract

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.

Compound heterozygous or homozygous truncating MYBPC3 mutations cause lethal cardiomyopathy with features of noncompaction and septal defects

“…14,31-35 A homozygous truncating pathogenic splice site variant c.3330+2T4G in MYBPC3 was reported in three neonates with severe HCM who all died at an average age of 3-4 months in a consanguineous Old Order Amish pedigree with severe HCM. 31 This variant was also reported in another cohort of 10 neonates with severe infantile HCM of Old Order Amish descent, suggesting a founder effect. 33 Of note, several of the affected Amish neonates with homozygous MYBPC3 truncating variants also presented with septal defects including apical muscular VSD, ASD, and patent ductus arteriosus.…”

“…Different congenital heart malformations (septal defects, patent ductus arteriosus, aortic aneurysm, and Ebstein anomaly) have been reported in families with pathogenic mutations in sarcomeric protein genes, including MYBPC3, MYH6, MYH7, MYH11, and ACTC1. 31,[36][37][38] In children with noncompaction cardiomyopathy, Tsai et al 39 showed that 78% had a congenital heart defect. These data suggest that sarcomeric cardiac muscle proteins are not only involved in cardiomyopathies but also in congenital heart malformations.…”

Mybpc3 gene therapy for neonatal cardiomyopathy enables long-term disease prevention in mice

“…First, it showed prevention of a disease phenotype, but no rescue. Yet, we believe that prevention is the more realistic scenario in the patient group we would like to target with the gene therapy approach, namely infants with severe homozygous or compound heterozygous mutations who quickly develop a therapy-resistant form of systolic heart failure 14,[16][17][18][19][20] . Second, mouse models including our KI model clearly differ from human HCM in that they show a much milder phenotype, generally only at the homozygous state 8,40,41 .…”

“…Whereas the mean life expectancy of patients who survived into young adulthood does not markedly differ from that of the normal population 12 , sudden cardiac death is common in young adults with HCM, particularly athletes 13 , and some patients develop severe systolic dysfunction and heart failure. Less known is that neonatal forms of HCM rapidly evolve into systolic heart failure and death within the first year of life [14][15][16][17][18][19][20] . Some of these infants have homozygous or compound heterozygous frameshift MYBPC3 mutations 14,[16][17][18][19][20] , expected to result in low level or absence of mutant cMyBP-C.…”

“…Less known is that neonatal forms of HCM rapidly evolve into systolic heart failure and death within the first year of life [14][15][16][17][18][19][20] . Some of these infants have homozygous or compound heterozygous frameshift MYBPC3 mutations 14,[16][17][18][19][20] , expected to result in low level or absence of mutant cMyBP-C. Here we tested the easily generalizable idea to prevent the disease phenotype by adding full-length Mybpc3 by gene therapy in a Mybpc3-targeted knock-in (KI) mouse model 21,22 that genetically mimics the severe neonatal HCM cases 21,22 .…”