ArticleCirculation. Cardiovascular genetics2012
Genetic modifiers predisposing to congenital heart disease in the sensitized Down syndrome population.
Article in Circulation. Cardiovascular genetics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
37 citing papers in PubMed, 1 synthesis or guideline pooled it, 67 citations in OpenAlex.
- Gender differences in the prevalence of congenital heart disease in Down's syndrome: a brief meta-analysis.BMC medical genetics · 2017Pooled it
- Cardiac Organoids for Modeling Congenital Heart Disease: From Genetic Discovery to Therapeutic Screening.Current cardiology reports · 2026Review
- A Researcher's guide to rodent models of Down syndrome: Recent insights and translational perspectives.STAR protocols · 2026Review
- Promoting Research Excellence in Down Syndrome: Proceedings of the 5th International Conference of the Trisomy 21 Research Society.Neuromolecular medicine · 2026Article
- Biallelic CRELD1 variants cause a multisystem syndrome, including neurodevelopmental phenotypes, cardiac dysrhythmias, and frequent infections.Genetics in medicine : official journal of the American College of Medical Genetics · 2024Article
- Human Genetics of Atrioventricular Septal Defect.Advances in experimental medicine and biology · 2024Review
- CRELD1 variants are associated with bicuspid aortic valve in Turner syndrome.Human genetics · 2023Article
- Genetics and Molecular Basis of Congenital Heart Defects in Down Syndrome: Role of Extracellular Matrix Regulation.International journal of molecular sciences · 2023Review
- CRELD2, endoplasmic reticulum stress, and human diseases.Frontiers in endocrinology · 2023Review
- Pulmonary Hypertension in the Population with Down Syndrome.Cardiology and therapy · 2022Review
- Novel insights from fetal and placental phenotyping in 3 mouse models of Down syndrome.American journal of obstetrics and gynecology · 2021Article
- Review
- New Molecular and Organelle Alterations Linked to Down Syndrome Heart Disease.Frontiers in genetics · 2021Review
- Opportunities, barriers, and recommendations in down syndrome research.Translational science of rare diseases · 2021Article
- A non-mosaic transchromosomic mouse model of down syndrome carrying the long arm of human chromosome 21.eLife · 2020Article
- Genetics of atrioventricular canal defects.Italian journal of pediatrics · 2020Review
- Influence of allelic differences in Down syndrome.Progress in brain research · 2020Review
- Survey of Human Chromosome 21 Gene Expression Effects on Early Development inG3 (Bethesda, Md.) · 2018Article
- Genetic backgrounds and hidden trait complexity in natural populations.Current opinion in genetics & development · 2017Review
- Modifying Mendel Redux: Unbiased Approaches Can Find Modifiers.Circulation. Cardiovascular genetics · 2017Article
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundAbout 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
resultsWe 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.
conclusionsUsing 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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.