This is a follow-up of the layman’s article that GEITP previously shared on Aug 3 [from The New York Times, see below]. To reiterate, autosomal dominant mutations are inherited (from parent to child) as a single copy of a defective gene, thereby producing the full-blown affliction in the offspring. The mutated MYBPC3 gene causes hypertrophic cardiomyopathy (HCM); because of its delayed manifestation, this mutation escapes natural selection and is virtually always transmitted to the next generation. Consequently, the frequency of such a founder mutation in particular human populations is very high. For example, the MYBPC3 mutation is found at frequencies ranging from 2% to 8% in major Indian populations.
HCM is a myocardial disease characterized by left ventricular hypertrophy, myofibrillar disarray and myocardial stiffness; it has an estimated prevalence of 1:500 in adults and manifests clinically with heart failure. HCM is the commonest cause of sudden death in otherwise healthy young athletes. HCM, while not a uniformly fatal condition, has a tremendous impact on the lives of individuals, including physiological (heart failure and arrhythmias), psychological (limited activity and fear of sudden death), and genealogical concerns. MYBPC3 mutations account for approximately 40% of all genetic defects causing HCM and are also responsible for a large fraction of other inherited cardiomyopathies –– including dilated cardiomyopathy and left ventricular non-compaction. In the attached article and editorial, authors describe correction of the heterozygous MYBPC3 mutation in human preimplantation embryos, using precise CRISPR–Cas9-based targeting accuracy and high homology-directed repair efficiency by activating an endogenous, germline-specific DNA repair response.
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. By modulating the cell cycle stage at which the DSB was induced, authors 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. 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. However, much remains to be considered before clinical applications –– including reproducibility of the technique with other heterozygous mutations.
Nature 24 Aug 2o17; 548: 413-419 [full article] and pp 398-400 [News’N’Views editorial]
Subject: Scientists Edit a Dangerous Mutation from Genes in Human Embryos
The day of “editing severe mutations out of the fertilized egg (zygote)” is here. The CRISPR/Cas9 editing must be done before the zygote divides beyond the eight- or sixteen-cell stage (after which differentiation into specialized cell types and tissues begins). This article (from New York Times) precedes the scientific article that will appear soon in Nature.
For clinical geneticists wondering which gene has been edited –– the detrimental mutation “repaired” is a defective variant allele of MYBPC3 (myosin-binding protein C3, cardiac), and it is inherited as an autosomal dominant trait, meaning that one out of two children from parents one of whom carries this mutation will be affected with a serious life-threatening disease called hypertrophic cardiomyopathy. DwN