4.8 Article

Oligogenic inheritance of a human heart disease involving a genetic modifier

Journal

SCIENCE
Volume 364, Issue 6443, Pages 865-+

Publisher

AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aat5056

Keywords

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Funding

  1. Damon Runyon Cancer Research Foundation [DRG-2206-14]
  2. Gladstone CIRM [TG2-01160]
  3. NHLBI/NIH [R01 HL057181, U01 HL098179, U01 HL100406, UM1 HL128671]
  4. Roddenberry Foundation
  5. L.K. Whittier Foundation
  6. Younger Family Fund
  7. NIH/NCRR [C06 RR018928]

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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 MKL2, MYH7, and NKX2-5 genes. The MYH7 and MKL2 variants were inherited from the affected, asymptomatic father and the rare NKX2-5 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 NKX2-5 variant's contribution as a genetic modifier.

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