Sequential Defects in Cardiac Lineage Commitment and Maturation Cause Hypoplastic Left Heart Syndrome

Markus Krane, Martina Dreßen, Gianluca Santamaria, Ilaria My, Christine M. Schneider, Tatjana Dorn, Svenja Laue, Elisa Mastantuono, Riccardo Berutti, Hilansi Rawat, Ralf Gilsbach, Pedro Schneider, Harald Lahm, Sascha Schwarz, Stefanie A. Doppler, Sharon Paige, Nazan Puluca, Sophia Doll, Irina Neb, Thomas BradeZhong Zhang, Claudia Abou-Ajram, Bernd Northoff, Lesca M. Holdt, Stefanie Sudhop, Makoto Sahara, Alexander Goedel, Andreas Dendorfer, Fleur V.Y. Tjong, Maria E. Rijlaarsdam, Julie Cleuziou, Nora Lang, Christian Kupatt, Connie Bezzina, Rüdiger Lange, Neil E. Bowles, Matthias Mann, Bruce D. Gelb, Lia Crotti, Lutz Hein, Thomas Meitinger, Sean Wu, Daniel Sinnecker, Peter J. Gruber, Karl Ludwig Laugwitz, Alessandra Moretti

Research output: Contribution to journalArticlepeer-review

29 Scopus citations


Background: Complex molecular programs in specific cell lineages govern human heart development. Hypoplastic left heart syndrome (HLHS) is the most common and severe manifestation within the spectrum of left ventricular outflow tract obstruction defects occurring in association with ventricular hypoplasia. The pathogenesis of HLHS is unknown, but hemodynamic disturbances are assumed to play a prominent role. Methods: To identify perturbations in gene programs controlling ventricular muscle lineage development in HLHS, we performed whole-exome sequencing of 87 HLHS parent-offspring trios, nuclear transcriptomics of cardiomyocytes from ventricles of 4 patients with HLHS and 15 controls at different stages of heart development, single cell RNA sequencing, and 3D modeling in induced pluripotent stem cells from 3 patients with HLHS and 3 controls. Results: Gene set enrichment and protein network analyses of damaging de novo mutations and dysregulated genes from ventricles of patients with HLHS suggested alterations in specific gene programs and cellular processes critical during fetal ventricular cardiogenesis, including cell cycle and cardiomyocyte maturation. Single-cell and 3D modeling with induced pluripotent stem cells demonstrated intrinsic defects in the cell cycle/unfolded protein response/autophagy hub resulting in disrupted differentiation of early cardiac progenitor lineages leading to defective cardiomyocyte subtype differentiation/maturation in HLHS. Premature cell cycle exit of ventricular cardiomyocytes from patients with HLHS prevented normal tissue responses to developmental signals for growth, leading to multinucleation/polyploidy, accumulation of DNA damage, and exacerbated apoptosis, all potential drivers of left ventricular hypoplasia in absence of hemodynamic cues. Conclusions: Our results highlight that despite genetic heterogeneity in HLHS, many mutations converge on sequential cellular processes primarily driving cardiac myogenesis, suggesting novel therapeutic approaches.

Original languageEnglish
Pages (from-to)1409-1428
Number of pages20
Issue number17
StatePublished - 26 Oct 2021


  • autophagy
  • cell cycle
  • heart defects, congenital
  • hypoplastic left heart syndrome
  • induced pluripotent stem cells
  • unfolded protein response
  • whole exome sequencing


Dive into the research topics of 'Sequential Defects in Cardiac Lineage Commitment and Maturation Cause Hypoplastic Left Heart Syndrome'. Together they form a unique fingerprint.

Cite this