Consequently, the frequency of some of these founder mutations in particular human populations is very high. Because of their delayed manifestation, these mutations escape natural selection and are often transmitted to the next generation. Genes in which dominant mutations manifest as late-onset adult disorders include BRCA1 and BRCA2, which are associated with a high risk of breast and ovarian cancers 1, and MYBPC3, mutation of which causes hypertrophic cardiomyopathy (HCM) 2. Among these are autosomal dominant mutations, where inheritance of a single copy of a defective gene can result in clinical symptoms. More than 10,000 monogenic inherited disorders have been identified, affecting millions of people worldwide. However, much remains to be considered before clinical applications, including the reproducibility of the technique with other heterozygous mutations. The efficiency, accuracy and safety of the approach presented suggest that it has potential to be used for the correction of heritable mutations in human embryos by complementing preimplantation genetic diagnosis. ![]() By modulating the cell cycle stage at which the DSB was induced, we were able to avoid mosaicism in cleaving embryos and achieve a high yield of homozygous embryos carrying the wild-type MYBPC3 gene without evidence of off-target mutations. ![]() Induced double-strand breaks (DSBs) at the mutant paternal allele were predominantly repaired using the homologous wild-type maternal gene instead of a synthetic DNA template. Here we describe the correction of the heterozygous MYBPC3 mutation in human preimplantation embryos with precise CRISPR–Cas9-based targeting accuracy and high homology-directed repair efficiency by activating an endogenous, germline-specific DNA repair response. Genome editing has potential for the targeted correction of germline mutations.
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