{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T22:13:33Z","timestamp":1793312013259,"version":"4.5.0"},"reference-count":29,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2011,4,25]],"date-time":"2011-04-25T00:00:00Z","timestamp":1303689600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2012,6]]},"abstract":"<jats:p>Iascone M, Ciccone R, Galletti L, Marchetti D, Seddio F, Lincesso AR, Pezzoli L, Vetro A, Barachetti D, Boni L, Federici D, Soto AM, Comas JV, Ferrazzi P, Zuffardi O. Identification of <jats:italic>de novo<\/jats:italic> mutations and rare variants in hypoplastic left heart syndrome.<\/jats:p><jats:p>Hypoplastic left heart syndrome (HLHS) is one of the most severe congenital heart malformations, characterized by underdevelopment of the structures in the left heart\u2013aorta complex. The majority of cases are sporadic. Although multiple genetic loci have been tentatively implicated in HLHS, no gene or pathway seems to be specifically associated with the disease. To elucidate the genetic basis of HLHS, we analyzed 53 well\u2010characterized patients with isolated HLHS using an integrated genomic approach that combined DNA sequencing of five candidate genes (<jats:italic>NKX2\u20105<\/jats:italic>, <jats:italic>NOTCH1<\/jats:italic>, <jats:italic>HAND1<\/jats:italic>, <jats:italic>FOXC2<\/jats:italic> and <jats:italic>FOXL1<\/jats:italic>) and genome\u2010wide screening by high\u2010resolution array comparative genomic hybridization. In 30 patients, we identified two novel <jats:italic>de novo<\/jats:italic> mutations in <jats:italic>NOTCH1<\/jats:italic>, 23 rare patients inherited gene variants in <jats:italic>NOTCH1<\/jats:italic>, <jats:italic>FOXC2<\/jats:italic> and <jats:italic>FOXL1<\/jats:italic>, and 33 rare patients mostly inherited copy\u2010number variants. Some of the identified variations coexisted in the same patient. The biological significance of such rare variations is unknown, but our findings strengthen the role of NOTCH pathway in cardiac valve development, indicating that HLHS is, at least in part, a \u2018valve\u2019 disease. This is the first report of <jats:italic>de novo<\/jats:italic> mutations associated with isolated HLHS. Moreover, the coexistence of multiple rare variants suggests in some cases a cumulative effect, as shown for other complex disease.<\/jats:p>","DOI":"10.1111\/j.1399-0004.2011.01674.x","type":"journal-article","created":{"date-parts":[[2011,4,1]],"date-time":"2011-04-01T18:15:47Z","timestamp":1301681747000},"page":"542-554","source":"Crossref","is-referenced-by-count":101,"title":["Identification of <i>de novo<\/i> mutations and rare variants in hypoplastic left heart 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