Why the study?
Many diseases are hypothesized to arise from co-inheritance of rare genetic variants that are benign individually but harmful in combination, but this has been difficult to validate functionally.
Does the co-inheritance of three specific genetic variants cause early-onset heart disease?
Does the co-inheritance of three specific genetic variants cause early-onset heart disease?
This study provides functional validation of oligogenic inheritance in human heart disease by recreating the disease phenotype in a mouse model using gene editing.
Supports oligogenic inheritance in a mouse model; leaves open causal confirmation in humans.
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
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Gifford et al. (2019) studied this question.
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