Research
Print page Print page
Switch language
Rigshospitalet - a part of Copenhagen University Hospital
Published

Analysis of 60 706 Exomes Questions the Role of De Novo Variants Previously Implicated in Cardiac Disease

Research output: Contribution to journalJournal articleResearchpeer-review

  1. Genomic Triangulation in Sudden Unexplained Death in the Young: The Way to Go?

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Fabry Disease in Families With Hypertrophic Cardiomyopathy: Clinical Manifestations in the Classic and Later-Onset Phenotypes

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. CPT1A Missense Mutation Associated With Fatty Acid Metabolism and Reduced Height in Greenlanders

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. New Blood Pressure-Associated Loci Identified in Meta-Analyses of 475 000 Individuals

    Research output: Contribution to journalJournal articleResearchpeer-review

  5. SCARB1 Gene Variants Are Associated With the Phenotype of Combined High High-Density Lipoprotein Cholesterol and High Lipoprotein (a)

    Research output: Contribution to journalJournal articleResearchpeer-review

  1. Renal 123I-MIBG Uptake before and after Live-Donor Kidney Transplantation

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Defibrillators for prevention from sudden cardiac death: is it that easy?-Authors' reply

    Research output: Contribution to journalComment/debateResearchpeer-review

View graph of relations

BACKGROUND: De novo variants in the exome occur at a rate of 1 per individual per generation, and because of the low reproductive fitness for de novo variants causing severe disease, the likelihood of finding these as standing variations in the general population is low. Therefore, this study sought to evaluate the pathogenicity of de novo variants previously associated with cardiac disease based on a large population-representative exome database.

METHODS AND RESULTS: We performed a literature search for previous publications on de novo variants associated with severe arrhythmias and structural heart diseases and investigated whether these variants were present in the Exome Aggregation Consortium (ExAC) database (n=60 706). We identified monogenic variants in single case reports and smaller studies (≤200 subjects) and variants considered to increase susceptibility of disease in 3 larger trio studies (>1000 subjects). Of the monogenic variants, 11% (23/211) were present in ExAC, whereas 26% (802/3050) variants believed to increase susceptibility of disease were identified in ExAC. Monogenic de novo variants in ExAC had a total allele count of 109 and with ≈844 expected cases in ExAC, these variants would account for 13% of all cases in the studied diseases if truly monogenetic.

CONCLUSIONS: We observed numerous de novo variants associated with cardiac disease as standing variation in ExAC, thus these variants are less likely monogenetic causes or major risk contributors for cardiac disease. This highlights the importance of investigating the pathogenicity of de novo variants because they are not as exclusive and pathogenically evident as presumed previously.

Original languageEnglish
JournalCirculation. Cardiovascular genetics
Volume10
Issue number6
Pages (from-to)e001878
ISSN1942-325X
DOIs
Publication statusPublished - Dec 2017

    Research areas

  • Journal Article

ID: 52569019