{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T11:29:12Z","timestamp":1768476552785,"version":"3.49.0"},"reference-count":36,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Circ Cardiovasc Genet"],"published-print":{"date-parts":[[2012,6]]},"abstract":"<jats:sec>\n            <jats:title>Background\u2014<\/jats:title>\n            <jats:p>About half of people with Down syndrome (DS) exhibit some form of congenital heart disease (CHD); however, trisomy for human chromosome 21 (Hsa21) alone is insufficient to cause CHD, as half of all people with DS have a normal heart, suggesting that genetic modifiers interact with dosage-sensitive gene(s) on Hsa21 to result in CHD. We hypothesize that a threshold exists in both DS and euploid populations for the number of genetic perturbations that can be tolerated before CHD results.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results\u2014<\/jats:title>\n            <jats:p>\n              We ascertained a group of individuals with DS and complete atrioventricular septal defect and sequenced 2 candidate genes for CHD:\n              <jats:italic>CRELD1<\/jats:italic>\n              , which is associated with atrioventricular septal defect in people with or without DS, and\n              <jats:italic>HEY2<\/jats:italic>\n              , whose mouse ortholog (\n              <jats:italic>Hey2<\/jats:italic>\n              ) produces septal defects when mutated. Several deleterious variants were identified, but the frequency of these potential modifiers was low. We crossed mice with mutant forms of these potential modifiers to the Ts65Dn mouse model of DS. Crossing loss-of-function alleles of either\n              <jats:italic>Creld1<\/jats:italic>\n              or\n              <jats:italic>Hey2<\/jats:italic>\n              onto the trisomic background caused a significant increase in the frequency of CHD, demonstrating an interaction between the modifiers and trisomic genes. We showed further that, although each of these mutant modifiers is benign by itself, they interact to affect heart development when inherited together.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>Using mouse models of Down syndrome and of genes associated with congenital heart disease, we demonstrate a biological basis for an interaction that supports a threshold hypothesis for additive effects of genetic modifiers in the sensitized trisomic population.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circgenetics.111.960872","type":"journal-article","created":{"date-parts":[[2012,4,21]],"date-time":"2012-04-21T06:48:51Z","timestamp":1334990931000},"page":"301-308","source":"Crossref","is-referenced-by-count":57,"title":["Genetic Modifiers Predisposing to Congenital Heart Disease in the Sensitized Down Syndrome Population"],"prefix":"10.1161","volume":"5","author":[{"given":"Huiqing","family":"Li","sequence":"first","affiliation":[{"name":"From the Department of Physiology (H.L., S.C., D.K., R.H.R.), Center for Functional Anatomy (V.D.), McKusick-Nathans Institute of Genetic Medicine (R.H.R.), School of Medicine, Johns Hopkins University, Baltimore, MD; Department of Molecular and Medical Genetics (J.R., C.L.M.), Division of Cardiovascular Medicine (B.R., C.L.M.), Oregon Health &amp; Science University Heart Research Center (C.L.M.), Oregon Health &amp; Science University, Portland; Department of Medicine, University of Washington..."}]},{"given":"Sheila","family":"Cherry","sequence":"additional","affiliation":[{"name":"From the Department of Physiology (H.L., S.C., D.K., R.H.R.), Center for Functional Anatomy (V.D.), McKusick-Nathans Institute of Genetic Medicine (R.H.R.), School of Medicine, Johns Hopkins University, Baltimore, MD; Department of Molecular and Medical Genetics (J.R., C.L.M.), Division of Cardiovascular Medicine (B.R., C.L.M.), Oregon Health &amp; Science University Heart Research Center (C.L.M.), Oregon Health &amp; Science University, Portland; Department of Medicine, University of Washington..."}]},{"given":"Donna","family":"Klinedinst","sequence":"additional","affiliation":[{"name":"From the Department of Physiology (H.L., S.C., D.K., R.H.R.), Center for Functional Anatomy (V.D.), McKusick-Nathans Institute of Genetic Medicine (R.H.R.), School of Medicine, Johns Hopkins University, Baltimore, MD; Department of Molecular and Medical Genetics (J.R., C.L.M.), Division of Cardiovascular Medicine (B.R., C.L.M.), Oregon Health &amp; Science University Heart Research Center (C.L.M.), Oregon Health &amp; Science University, Portland; Department of Medicine, University of Washington..."}]},{"given":"Valerie","family":"DeLeon","sequence":"additional","affiliation":[{"name":"From the Department of Physiology (H.L., S.C., D.K., R.H.R.), Center for Functional Anatomy (V.D.), McKusick-Nathans Institute of Genetic Medicine (R.H.R.), School of Medicine, Johns Hopkins University, Baltimore, MD; Department of Molecular and Medical Genetics (J.R., C.L.M.), Division of Cardiovascular Medicine (B.R., C.L.M.), Oregon Health &amp; Science University Heart Research Center (C.L.M.), Oregon Health &amp; Science University, Portland; Department of Medicine, University of Washington..."}]},{"given":"Jennifer","family":"Redig","sequence":"additional","affiliation":[{"name":"From the Department of Physiology (H.L., S.C., D.K., R.H.R.), Center for Functional Anatomy (V.D.), McKusick-Nathans Institute of Genetic Medicine (R.H.R.), School of Medicine, Johns Hopkins University, Baltimore, MD; Department of Molecular and Medical Genetics (J.R., C.L.M.), Division of Cardiovascular Medicine (B.R., C.L.M.), Oregon Health &amp; Science University Heart Research Center (C.L.M.), Oregon Health &amp; Science University, Portland; Department of Medicine, University of Washington..."}]},{"given":"Benjamin","family":"Reshey","sequence":"additional","affiliation":[{"name":"From the Department of Physiology (H.L., S.C., D.K., R.H.R.), Center for Functional Anatomy (V.D.), McKusick-Nathans Institute of Genetic Medicine (R.H.R.), School of Medicine, Johns Hopkins University, Baltimore, MD; Department of Molecular and Medical Genetics (J.R., C.L.M.), Division of Cardiovascular Medicine (B.R., C.L.M.), Oregon Health &amp; Science University Heart Research Center (C.L.M.), Oregon Health &amp; Science University, Portland; Department of Medicine, University of Washington..."}]},{"given":"Michael T.","family":"Chin","sequence":"additional","affiliation":[{"name":"From the Department of Physiology (H.L., S.C., D.K., R.H.R.), Center for Functional Anatomy (V.D.), McKusick-Nathans Institute of Genetic Medicine (R.H.R.), School of Medicine, Johns Hopkins University, Baltimore, MD; Department of Molecular and Medical Genetics (J.R., C.L.M.), Division of Cardiovascular Medicine (B.R., C.L.M.), Oregon Health &amp; Science University Heart Research Center (C.L.M.), Oregon Health &amp; Science University, Portland; Department of Medicine, University of Washington..."}]},{"given":"Stephanie L.","family":"Sherman","sequence":"additional","affiliation":[{"name":"From the Department of Physiology (H.L., S.C., D.K., R.H.R.), Center for Functional Anatomy (V.D.), McKusick-Nathans Institute of Genetic Medicine (R.H.R.), School of Medicine, Johns Hopkins University, Baltimore, MD; Department of Molecular and Medical Genetics (J.R., C.L.M.), Division of Cardiovascular Medicine (B.R., C.L.M.), Oregon Health &amp; Science University Heart Research Center (C.L.M.), Oregon Health &amp; Science University, Portland; Department of Medicine, University of Washington..."}]},{"given":"Cheryl L.","family":"Maslen","sequence":"additional","affiliation":[{"name":"From the Department of Physiology (H.L., S.C., D.K., R.H.R.), Center for Functional Anatomy (V.D.), McKusick-Nathans Institute of Genetic Medicine (R.H.R.), School of Medicine, Johns Hopkins University, Baltimore, MD; Department of Molecular and Medical Genetics (J.R., C.L.M.), Division of Cardiovascular Medicine (B.R., C.L.M.), Oregon Health &amp; Science University Heart Research Center (C.L.M.), Oregon Health &amp; Science University, Portland; Department of Medicine, University of Washington..."}]},{"given":"Roger H.","family":"Reeves","sequence":"additional","affiliation":[{"name":"From the Department of Physiology (H.L., S.C., D.K., R.H.R.), Center for Functional Anatomy (V.D.), McKusick-Nathans Institute of Genetic Medicine (R.H.R.), School of Medicine, Johns Hopkins University, Baltimore, MD; Department of Molecular and Medical Genetics (J.R., C.L.M.), Division of Cardiovascular Medicine (B.R., C.L.M.), Oregon Health &amp; Science University Heart Research Center (C.L.M.), Oregon Health &amp; Science University, Portland; Department of Medicine, University of Washington..."}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/0735-1097(89)90122-8"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.31494"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0813248106"},{"key":"e_1_3_4_5_2","first-page":"294","article-title":"Down syndrome: molecular mapping of the congenital heart disease and duodenal stenosis","volume":"50","author":"Korenberg JR","year":"1992","unstructured":"Korenberg JR, Bradley C, Disteche CM. 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