Research Article

Oligogenic inheritance of a human heart disease involving a genetic modifier

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Science  31 May 2019:
Vol. 364, Issue 6443, pp. 865-870
DOI: 10.1126/science.aat5056

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Three rights can make a wrong

Many diseases are thought to arise from co-inheritance of rare genetic variants that are benign on their own but harmful in combination. This hypothesis has been difficult to validate by functional experiments. Gifford et al. sequenced the genomes of two parents who were asymptomatic and their three children, all of whom had early-onset heart disease. They identified three likely culprit genetic variants, two in transcription factor genes linked to heart development and one in a gene encoding a muscle structural protein. When they introduced these three variants together into mice by gene editing, the mice developed heart disease resembling that seen in the children.

Science, this issue p. 865


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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