Key result
CRISPR/Cas9 corrects the MYH7 p.Met659Ile variant to generate two normal, pluripotent patient-specific iPSC lines.
Why the study?
The clinical significance of approximately 40% of genetic variants in inherited cardiovascular diseases is uncertain, requiring new tools such as CRISPR/Cas9-edited iPSCs to clarify pathogenicity.
Answers are grounded in this paper and cite their sources.
The generation of isogenic iPSC lines with a corrected MYH7 variant provides a valuable tool for studying the pathogenetic mechanisms of hypertrophic cardiomyopathy.
The problem of interpretation of the genetic data from patients with inherited cardiovascular diseases still remains relevant. To date, the clinical significance of approximately 40 % of variants in genes associated with inherited cardiovascular diseases is uncertain, which requires new approaches to the assessment of their pathogenetic contribution. A combination of the induced pluripotent stem cell (iPSC) technology and editing the iPSC genome with CRISPR/Cas9 is thought to be the most promising tool for clarifying variant pathogenicity. A variant of unknown significance in MYH7, p.Met659Ile (c.1977G>A), was previously identified in several genetic screenings of hypertrophic cardiomyopathy patients. In this study, the single nucleotide substitution was corrected with CRISPR/Cas9 in iPSCs generated from a carrier of the variant. As a result, two iPSC lines (ICGi019-B-1 and ICGi019-B-2) were generated and characterized using a standard set of methods. The iPSC lines with the corrected p.Met659Ile (c.1977G>A) variant in MYH7 possessed a morphology characteristic of human pluripotent cells, expressed markers of the pluripotent state (the OCT4, SOX2, NANOG transcription factors and SSEA-4 surface antigen), were able to give rise to derivatives of three germ layers during spontaneous differentiation, and retained a normal karyotype (46,XY). No CRISPR/Cas9 off-target activity was found in the ICGi019-B-1 and ICGi019-B-2 iPSC lines. The maintenance of the pluripotent state and normal karyotype and the absence of CRISPR/Cas9 off-target activity in the iPSC lines with the corrected p.Met659Ile (c.1977G>A) variant in MYH7 allow using the iPSC lines as an isogenic control for further studies of the variant pathogenicity and its impact on the hypertrophic cardiomyopathy development.
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Shulgina et al. (2025) studied Hypertrophic cardiomyopathy (n=1). CRISPR/Cas9 correction of MYH7 p.Met659Ile variant vs. Uncorrected patient-specific iPSC line was evaluated on Generation of corrected iPSC lines. CRISPR/Cas9 correction of the p.Met659Ile variant in MYH7 in patient-specific iPSCs successfully generated two isogenic iPSC lines that maintained pluripotency and a normal karyotype.
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