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We performed whole genome sequencing (WGS) on 183 HLHS patient-parent trios to identify candidate genes, which were functionally tested in the\n                    <jats:italic>Drosophila<\/jats:italic>\n                    heart model. Bioinformatic analysis of WGS data from an index family of a HLHS proband born to consanguineous parents prioritized 9 candidate genes with rare, predicted damaging homozygous variants. Of them, cardiac-specific knockdown (KD) of mitochondrial MICOS complex subunit\n                    <jats:italic>dCHCHD3\/6<\/jats:italic>\n                    resulted in drastically compromised heart contractility, diminished levels of sarcomeric actin and myosin, reduced cardiac ATP levels, and mitochondrial fission-fusion defects. These defects were similar to those inflicted by cardiac KD of ATP synthase subunits of the electron transport chain (ETC), consistent with the MICOS complex\u2019s role in maintaining cristae morphology and ETC assembly. Five additional HLHS probands harbored rare, predicted damaging variants in\n                    <jats:italic>CHCHD3<\/jats:italic>\n                    or\n                    <jats:italic>CHCHD6<\/jats:italic>\n                    . Hypothesizing an oligogenic basis for HLHS, we tested 60 additional prioritized candidate genes from these patients for genetic interactions with\n                    <jats:italic>CHCHD3\/6<\/jats:italic>\n                    in sensitized fly hearts. Moderate KD of\n                    <jats:italic>CHCHD3\/6<\/jats:italic>\n                    in combination with\n                    <jats:italic>Cdk12<\/jats:italic>\n                    (activator of RNA polymerase II),\n                    <jats:italic>RNF149<\/jats:italic>\n                    (\n                    <jats:italic>goliath<\/jats:italic>\n                    , E3 ubiquitin ligase), or\n                    <jats:italic>SPTBN1<\/jats:italic>\n                    (\n                    <jats:italic>\u03b2-Spectrin,<\/jats:italic>\n                    scaffolding protein) caused synergistic heart defects, suggesting the likely involvement of diverse pathways in HLHS. Further elucidation of novel candidate genes and genetic interactions of potentially disease-contributing pathways is expected to lead to a better understanding of HLHS and other CHDs.\n                  <\/jats:p>","DOI":"10.7554\/elife.83385","type":"journal-article","created":{"date-parts":[[2023,7,5]],"date-time":"2023-07-05T08:55:25Z","timestamp":1688547325000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.83385","source":"Crossref","is-referenced-by-count":20,"title":["Mitochondrial MICOS complex genes, implicated in hypoplastic left heart syndrome, maintain cardiac contractility and actomyosin integrity"],"prefix":"10.7554","volume":"12","author":[{"given":"Katja","family":"Birker","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03m1g2s55","id-type":"ROR","asserted-by":"publisher"}],"name":"Development, Aging and Regeneration Program, Center for Genetic Disorders & Aging Research, Sanford Burnham Prebys Medical Discovery Institute","place":["San Diego, 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