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Moreover, there are also predominantly monogenic heart defects, such as cardiomyopathies, with known disease genes for the majority of cases. In this study, we identified mutations in myomesin 2 (MYOM2) in patients with Tetralogy of Fallot (TOF), the most common cyanotic heart malformation, as well as in patients with hypertrophic cardiomyopathy (HCM), who do not exhibit any mutations in the known disease genes. MYOM2 is a major component of the myofibrillar M-band of the sarcomere, and a hub gene within interactions of sarcomere genes. We show that patient-derived cardiomyocytes exhibit myofibrillar disarray and reduced passive force with increasing sarcomere lengths. Moreover, our comprehensive functional analyses in the Drosophila animal model reveal that the so far uncharacterized fly gene CG14964 [herein referred to as Drosophila myomesin and myosin binding protein (dMnM)] may be an ortholog of MYOM2, as well as other myosin binding proteins. Its partial loss of function or moderate cardiac knockdown results in cardiac dilation, whereas more severely reduced function causes a constricted phenotype and an increase in sarcomere myosin protein. Moreover, compound heterozygous combinations of CG14964 and the sarcomere gene Mhc (MYH6\/7) exhibited synergistic genetic interactions. In summary, our results suggest that MYOM2 not only plays a critical role in maintaining robust heart function but may also be a candidate gene for heart diseases such as HCM and TOF, as it is clearly involved in the development of the heart.<\/jats:p>\n                  <jats:p>This article has an associated First Person interview with Emilie Auxerre-Planti\u00e9 and Tanja Nielsen, joint first authors of the paper.<\/jats:p>","DOI":"10.1242\/dmm.045377","type":"journal-article","created":{"date-parts":[[2020,10,8]],"date-time":"2020-10-08T17:05:52Z","timestamp":1602176752000},"source":"Crossref","is-referenced-by-count":37,"title":["Identification of\n                    <i>MYOM2<\/i>\n                    as a candidate gene in hypertrophic cardiomyopathy and Tetralogy of Fallot, and its functional evaluation in the\n                    <i>Drosophila<\/i>\n                    heart"],"prefix":"10.1242","volume":"13","author":[{"given":"Emilie","family":"Auxerre-Planti\u00e9","sequence":"first","affiliation":[{"name":"Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin 1 Cardiovascular Genetics , , 13125 Berlin , Germany"},{"name":"Berlin Institute of Health (BIH) 2 , Berlin , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2389-7514","authenticated-orcid":false,"given":"Tanja","family":"Nielsen","sequence":"additional","affiliation":[{"name":"Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin 1 Cardiovascular Genetics , , 13125 Berlin , Germany"},{"name":"Berlin Institute of Health (BIH) 2 , Berlin , Germany"},{"name":"DZHK (German Centre for Cardiovascular Research) 3 , partner site Berlin, Berlin , Germany"},{"name":"Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute 4 , La Jolla, CA 92037 , USA"},{"name":"Freie Universit\u00e4t Berlin 5 Department of 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