Mitochondrial MICOS complex genes, implicated in hypoplastic left heart syndrome, maintain cardiac contractility and actomyosin integrity

Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease (CHD) with a likely oligogenic etiology, but our understanding of the genetic complexities and pathogenic mechanisms leading to HLHS is limited. We therefore performed whole genome sequencing (WGS) on a large cohort of HLHS patients and their families to identify candidate genes that were then tested in Drosophila heart model for functional and structural requirements. Bioinformatic analysis of WGS data from an index family comprised of a HLHS proband born to consanguineous parents and postulated to have a homozygous recessive disease etiology, prioritized 9 candidate genes with rare, predicted damaging homozygous variants. Of the candidate HLHS gene homologs tested, cardiac-specific knockdown (KD) of mitochondrial MICOS complex subunit dCHCHD3/6 resulted in drastically compromised heart contractility, diminished levels of sarcomeric actin and myosin, reduced cardiac ATP levels, and mitochondrial fission-fusion ..., Please see the README document (\"README_MICOS.txt\") and the accompanying published article: Katja Birker, Shuchao Ge, Natalie J. Kirkland, Jeanne L. Theis, James Marchant, Zachary C. Fogarty, Maria Azzurra Missinato, Sreehari Kalvakuri, Paul Grossfeld, Adam J. Engler, Karen Ocorr, Timothy J. Nelson, Alexandre R. Colas, Timothy M. Olson, Georg Vogler, and Rolf Bodmer. Mitochondrial MICOS complex genes, implicated in hypoplastic left heart syndrome, maintain cardiac contractility and actomyosin integrity 2022. DOI: https://doi.org/10.1101/2022.06.13.22276366,