{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T16:44:12Z","timestamp":1791477852551,"version":"4.3.4"},"reference-count":59,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2022,4]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>Whole-genome sequencing in families enables deciphering of congenital heart disease causes. A shared genetic basis for familial bicuspid aortic valve (BAV) and hypoplastic left heart syndrome (HLHS) was postulated.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>Whole-genome sequencing was performed in affected members of 6 multiplex BAV families, an HLHS cohort of 197 probands and 546 relatives, and 813 controls. Data were filtered for rare, predicted-damaging variants that cosegregated with familial BAV and disrupted genes associated with congenital heart disease in humans and mice. Candidate genes were further prioritized by rare variant burden testing in HLHS cases versus controls. Modifier variants in HLHS proband-parent trios were sought to account for the severe developmental phenotype.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              In 5 BAV families, missense variants in 6 ontologically diverse genes for structural (\n              <jats:italic toggle=\"yes\">SPTBN1<\/jats:italic>\n              ,\n              <jats:italic toggle=\"yes\">PAXIP1<\/jats:italic>\n              , and\n              <jats:italic toggle=\"yes\">FBLN1<\/jats:italic>\n              ) and signaling (\n              <jats:italic toggle=\"yes\">CELSR1<\/jats:italic>\n              ,\n              <jats:italic toggle=\"yes\">PLXND1<\/jats:italic>\n              , and\n              <jats:italic toggle=\"yes\">NOS3<\/jats:italic>\n              ) proteins fulfilled filtering metrics.\n              <jats:italic toggle=\"yes\">CELSR1<\/jats:italic>\n              , encoding cadherin epidermal growth factor laminin G seven-pass G-type receptor, was identified as a candidate gene in 2 families and was the only gene demonstrating rare variant enrichment in HLHS probands (\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              =0.003575). HLHS-associated\n              <jats:italic toggle=\"yes\">CELSR1<\/jats:italic>\n              variants included 16 missense, one splice site, and 3 noncoding variants predicted to disrupt canonical transcription factor binding sites, most of which were inherited from a parent without congenital heart disease. Filtering whole-genome sequencing data for rare, predicted-damaging variants inherited from the other parent revealed 2 cases of\n              <jats:italic toggle=\"yes\">CELSR1<\/jats:italic>\n              compound heterozygosity, one case of\n              <jats:italic toggle=\"yes\">CELSR1<\/jats:italic>\n              -\n              <jats:italic toggle=\"yes\">CELSR3<\/jats:italic>\n              synergistic heterozygosity, and 4 cases of\n              <jats:italic toggle=\"yes\">CELSR1<\/jats:italic>\n              -\n              <jats:italic toggle=\"yes\">MYO15A<\/jats:italic>\n              digenic heterozygosity.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              <jats:italic toggle=\"yes\">CELSR1<\/jats:italic>\n              is a susceptibility gene for familial BAV and HLHS, further implicating planar cell polarity pathway perturbation in congenital heart disease.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circgen.121.003523","type":"journal-article","created":{"date-parts":[[2022,2,8]],"date-time":"2022-02-08T10:44:10Z","timestamp":1644317050000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":23,"title":["<i>CELSR1<\/i>\n            Risk Alleles in Familial Bicuspid Aortic Valve and Hypoplastic Left Heart Syndrome"],"prefix":"10.1161","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4494-8683","authenticated-orcid":true,"given":"Jeanne L.","family":"Theis","sequence":"first","affiliation":[{"name":"Cardiovascular Genetics Research Laboratory (J.L.T., R.S.S., T.M.O.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2186-584X","authenticated-orcid":true,"given":"Talha","family":"Niaz","sequence":"additional","affiliation":[{"name":"Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine (T.N., D.J.H., T.M.O.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rhianna S.","family":"Sundsbak","sequence":"additional","affiliation":[{"name":"Cardiovascular Genetics Research Laboratory (J.L.T., R.S.S., T.M.O.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5588-3216","authenticated-orcid":true,"given":"Zachary C.","family":"Fogarty","sequence":"additional","affiliation":[{"name":"Division of Computational Biology, Department of Quantitative Health Sciences (Z.C.F.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2903-1284","authenticated-orcid":true,"given":"William R.","family":"Bamlet","sequence":"additional","affiliation":[{"name":"Division of Clinical Trials and Biostatistics, Department of Quantiative Health Sciences (W.R.B.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0331-3294","authenticated-orcid":true,"given":"Donald J.","family":"Hagler","sequence":"additional","affiliation":[{"name":"Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine (T.N., D.J.H., T.M.O.), Mayo Clinic, Rochester, MN."},{"name":"Department of Cardiovascular Medicine (D.J.H., T.M.O.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2716-9423","authenticated-orcid":true,"given":"Timothy M.","family":"Olson","sequence":"additional","affiliation":[{"name":"Cardiovascular Genetics Research Laboratory (J.L.T., R.S.S., T.M.O.), Mayo Clinic, Rochester, MN."},{"name":"Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine (T.N., D.J.H., T.M.O.), Mayo Clinic, Rochester, MN."},{"name":"Department of Cardiovascular Medicine (D.J.H., 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