Genetic Modifiers Predisposing to Congenital Heart Disease in the Sensitized Down Syndrome Population

• Type of Material: Article
• Authors: Huiqing Li, Johns Hopkins University; Shelia Cherry, Johns Hopkins University; Donna Klinedinst, Johns Hopkins University; Valerie DeLeon, Johns Hopkins University; Jennifer Redig, Oregon Health & Science University; Benjamin Reshey, Oregon Health & Science University; Micheal T. Chin, University of Washington; Stephanie Sherman, Emory University; Cheryl L. Maslen, Oregon Hlth & Sci Univ; Roger H. Reeves, Johns Hopkins University
• Language: English
• Date: 2012-06-01
• Publisher: American Heart Association
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2012 American Heart Association, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1161/CIRCGENETICS.111.960872
• Title of Journal or Parent Work: Circulation: Cardiovascular Genetics
• ISSN: 1942-325X
• Volume: 5
• Issue: 3
• Start Page: 301
• End Page: 308
• Grant/Funding Information: Additional support was from the Oregon Clinical and Translational Research Institute (OCTRI), grant number UL1 RR024140 from the National Center for Research Resources (CLM).; This work was supported in part by Award Number R01HL083300 from the National Heart, Lung, and Blood Institute (RHR, CLM, SLS).
• Keywords: HEY2-MICE; Cardiac & Cardiovascular Systems; Life Sciences & Biomedicine; Down syndrome; CRELD1; Cardiovascular System & Cardiology; congenital heart disease; CHF1/HEY2; MUTATIONS; Genetics & Heredity; genetic modifier; CHROMOSOME-21; MOUSE MODEL; REVEALS; Science & Technology; TRISOMY; ATRIOVENTRICULAR SEPTAL-DEFECTS; SYNDROME PHENOTYPES
• Research Categories: Biology, Genetics; Biology, Physiology; Health Sciences, Medicine and Surgery

Abstract

Background- 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. Methods and Results- We ascertained a group of individuals with DS and complete atrioventricular septal defect and sequenced 2 candidate genes for CHD: CRELD1, which is associated with atrioventricular septal defect in people with or without DS, and HEY2, whose mouse ortholog (Hey2) 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 Creld1 or Hey2 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. Conclusions- 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.