iPSC-Based Modeling of Variable Clinical Presentation in Hypertrophic Cardiomyopathy

• Published in: Circulation research Vol. 133; no. 2; pp. 108 - 119
• Main Authors: Escribá, Rubén, Larrañaga-Moreira, José M., Richaud-Patin, Yvonne, Pourchet, Léa, Lazis, Ioannis, Jiménez-Delgado, Senda, Morillas-García, Alba, Ortiz-Genga, Martín, Ochoa, Juan Pablo, Carreras, David, Pérez, Guillermo Javier, de la Pompa, José Luis, Brugada, Ramón, Monserrat, Lorenzo, Barriales-Villa, Roberto, Raya, Angel
• Format: Journal Article
• Language: English
• Published: United States Lippincott Williams & Wilkins 07.07.2023
• Subjects: phenotype; mutation; studies; sibling; energy metabolism
• ISSN: 0009-7330; 1524-4571; 1524-4571
• DOI: 10.1161/CIRCRESAHA.122.321951

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease and a frequent cause of heart failure and sudden cardiac death. Our understanding of the genetic bases and pathogenic mechanisms underlying HCM has improved significantly in the recent past, but the combined effect of various pathogenic gene variants and the influence of genetic modifiers in disease manifestation are very poorly understood. Here, we set out to investigate genotype-phenotype relationships in 2 siblings with an extensive family history of HCM, both carrying a pathogenic truncating variant in the gene (p.Lys600Asnfs*2), but who exhibited highly divergent clinical manifestations. We used a combination of induced pluripotent stem cell (iPSC)-based disease modeling and CRISPR (clustered regularly interspersed short palindromic repeats)/Cas9 (CRISPR-associated protein 9)-mediated genome editing to generate patient-specific cardiomyocytes (iPSC-CMs) and isogenic controls lacking the pathogenic variant. Mutant iPSC-CMs developed impaired mitochondrial bioenergetics, which was dependent on the presence of the mutation. Moreover, we could detect altered excitation-contraction coupling in iPSC-CMs from the severely affected individual. The pathogenic variant was found to be necessary, but not sufficient, to induce iPSC-CM hyperexcitability, suggesting the presence of additional genetic modifiers. Whole-exome sequencing of the mutant carriers identified a variant of unknown significance in the gene (p.Ile1927Phe) uniquely present in the individual with severe HCM. We finally assessed the pathogenicity of this variant of unknown significance by functionally evaluating iPSC-CMs after editing the variant. Our results indicate that the p.Ile1927Phe variant of unknown significance in can be considered as a modifier of HCM expressivity when found in combination with truncating variants in . Overall, our studies show that iPSC-based modeling of clinically discordant subjects provides a unique platform to functionally assess the effect of genetic modifiers.