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HLHS segregates with other left ventricular outflow tract (LVOT) malformations in families, and can present as either an isolated phenotype or as a feature of a larger genetic disorder. The multifactorial etiology of HLHS makes it difficult to interpret the clinical significance of genetic variants. Specific genes have been implicated in HLHS, including rare, predicted damaging MYH6 variants that are present in &gt;10% of HLHS patients, and which have been shown to be associated with decreased transplant-free survival in our previous studies. MYH6 (\u03b1-myosin heavy chain, \u03b1-MHC) variants have been reported in HLHS and numerous other CHDs, including LVOT malformations, and may provide a genetic link to these disorders. In this paper, we outline the MYH6 variants that have been identified, discuss how bioinformatic and functional studies can inform clinical decision making, and highlight the importance of genetic testing in HLHS.<\/jats:p>","DOI":"10.3390\/jcdd9050144","type":"journal-article","created":{"date-parts":[[2022,5,3]],"date-time":"2022-05-03T08:26:35Z","timestamp":1651566395000},"page":"144","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Significance of \u03b1-Myosin Heavy Chain (MYH6) Variants in Hypoplastic Left Heart Syndrome and Related Cardiovascular Diseases"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9878-4223","authenticated-orcid":false,"given":"Melissa","family":"Anfinson","sequence":"first","affiliation":[{"name":"Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA"},{"name":"Herma Heart Institute, Children\u2019s Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert H.","family":"Fitts","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Marquette University, Milwaukee, WI 53233, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John W.","family":"Lough","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeanne M.","family":"James","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children\u2019s Mercy, Kansas City, MO 64108, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pippa M.","family":"Simpson","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Quantitative Health Sciences, Medical College of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie S.","family":"Handler","sequence":"additional","affiliation":[{"name":"Herma Heart Institute, Children\u2019s Wisconsin, Milwaukee, WI 53226, USA"},{"name":"Department of Pediatrics, Division of Pediatric Cardiology, Children\u2019s Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael E.","family":"Mitchell","sequence":"additional","affiliation":[{"name":"Herma Heart Institute, Children\u2019s Wisconsin, Milwaukee, WI 53226, USA"},{"name":"Department of Surgery, Division of Congenital Heart Surgery, Children\u2019s Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aoy","family":"Tomita-Mitchell","sequence":"additional","affiliation":[{"name":"Herma Heart Institute, Children\u2019s Wisconsin, Milwaukee, WI 53226, USA"},{"name":"Department of Surgery, Division of Congenital Heart Surgery, Children\u2019s Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S170","DOI":"10.1016\/S0003-4975(99)01283-7","article-title":"Congenital Heart Surgery Nomenclature and Database Project: Hypoplastic left heart syndrome","volume":"69","author":"Tchervenkov","year":"2000","journal-title":"Ann. 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