{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T22:13:37Z","timestamp":1793312017568,"version":"4.5.0"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2021,2]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>\n              Hypoplastic left heart syndrome (HLHS) with risk of poor outcome has been linked to\n              <jats:italic>MYH6<\/jats:italic>\n              variants, implicating overlap in genetic etiologies of structural and myopathic heart disease.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>Whole genome sequencing was performed in 197 probands with HLHS, 43 family members, and 813 controls. Data were filtered for rare, segregating variants in 3 index families comprised of an HLHS proband and relative(s) with cardiomyopathy. Whole genome sequencing data from cases and controls were compared for rare variant burden across 56 cardiomyopathy genes utilizing a weighted burden test approach, accounting for multiple testing using a Bonferroni correction.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              A pathogenic\n              <jats:italic>MYBPC3<\/jats:italic>\n              nonsense variant was identified in the first proband who underwent cardiac transplantation for diastolic heart failure, her father with left ventricular noncompaction, and 2 fourth-degree relatives with hypertrophic cardiomyopathy. A likely pathogenic\n              <jats:italic>RYR2<\/jats:italic>\n              missense variant was identified in the second proband, a second-degree relative with aortic dilation, and a fourth-degree relative with dilated cardiomyopathy. A pathogenic\n              <jats:italic>RYR2<\/jats:italic>\n              exon 3 in-frame deletion was identified in the third proband diagnosed with catecholaminergic polymorphic ventricular tachycardia and his father with left ventricular noncompaction and catecholaminergic polymorphic ventricular tachycardia. To further investigate HLHS-cardiomyopathy gene associations in cases versus controls, rare variant burden testing of 56 genes revealed enrichment in\n              <jats:italic>MYH6<\/jats:italic>\n              (\n              <jats:italic>P<\/jats:italic>\n              =0.000068). Rare, predicted-damaging\n              <jats:italic>MYH6<\/jats:italic>\n              variants were identified in 10% of probands in our cohort\u20144 with familial congenital heart disease, 4 with compound heterozygosity (3 with systolic ventricular dysfunction), and 4 with\n              <jats:italic>MYH6<\/jats:italic>\n              \u2013\n              <jats:italic>FLNC<\/jats:italic>\n              synergistic heterozygosity.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>Whole genome sequencing in multiplex families, proband-parent trios, and case-control cohorts revealed defects in cardiomyopathy-associated genes in patients with HLHS, which may portend impaired functional reserve of the single-ventricle circulation.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circgen.120.003126","type":"journal-article","created":{"date-parts":[[2020,12,16]],"date-time":"2020-12-16T17:07:37Z","timestamp":1608138457000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":47,"title":["Genetic Association Between Hypoplastic Left Heart Syndrome and Cardiomyopathies"],"prefix":"10.1161","volume":"14","author":[{"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\/0000-0003-3810-8933","authenticated-orcid":true,"given":"Jessie J.","family":"Hu","sequence":"additional","affiliation":[{"name":"Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine (J.J.H., M.Y.Q., P.W.O., 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"}]},{"given":"Jared M.","family":"Evans","sequence":"additional","affiliation":[{"name":"Division of Biomedical Statistics and Informatics, Department of Health Sciences Research (J.M.E., W.R.B.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William R.","family":"Bamlet","sequence":"additional","affiliation":[{"name":"Division of Biomedical Statistics and Informatics, Department of Health Sciences Research (J.M.E., W.R.B.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9898-2318","authenticated-orcid":true,"given":"M. Yasir","family":"Qureshi","sequence":"additional","affiliation":[{"name":"Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine (J.J.H., M.Y.Q., P.W.O., T.M.O.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick W.","family":"O\u2019Leary","sequence":"additional","affiliation":[{"name":"Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine (J.J.H., M.Y.Q., P.W.O., T.M.O.), Mayo Clinic, Rochester, MN."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3810-8933","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 (J.J.H., M.Y.Q., P.W.O., T.M.O.), Mayo Clinic, Rochester, 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