Oligogenic inheritance of a human heart disease involving a genetic modifier.

Abstract

Complex genetic mechanisms are thought to underlie many human diseases, yet experimental proof of this model has been elusive. Here, we show that a human cardiac anomaly can be caused by a combination of rare, inherited heterozygous mutations. Whole-exome sequencing of a nuclear family revealed that three offspring with childhood-onset cardiomyopathy had inherited three missense single-nucleotide variants in the <i>MKL2</i>, <i>MYH7</i>, and <i>NKX2-5</i> genes. The <i>MYH7</i> and <i>MKL2</i> variants were inherited from the affected, asymptomatic father and the rare <i>NKX2-5</i> variant (minor allele frequency, 0.0012) from the unaffected mother. We used CRISPR-Cas9 to generate mice encoding the orthologous variants and found that compound heterozygosity for all three variants recapitulated the human disease phenotype. Analysis of murine hearts and human induced pluripotent stem cell-derived cardiomyocytes provided histologic and molecular evidence for the <i>NKX2-5</i> variant's contribution as a genetic modifier.