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Science. 2019 May 31;364(6443):865-870. doi: 10.1126/science.aat5056. Epub 2019 May 30.

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

Author information

1
Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA.
2
Roddenberry Stem Cell Center at Gladstone, San Francisco, CA 94158, USA.
3
Department of Pathology, University of California, San Francisco, San Francisco, CA 94143, USA.
4
Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA.
5
Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA. dsrivastava@gladstone.ucsf.edu.
6
Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143, USA.

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 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.

PMID:
31147515
PMCID:
PMC6557373
[Available on 2019-11-30]
DOI:
10.1126/science.aat5056

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