Analysis of 60 706 Exomes Questions the Role of De Novo Variants Previously Implicated in Cardiac Disease
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Standard
Analysis of 60 706 Exomes Questions the Role of De Novo Variants Previously Implicated in Cardiac Disease. / Paludan-Müller, Christian; Ahlberg, Gustav; Ghouse, Jonas; Svendsen, Jesper H; Haunsø, Stig; Olesen, Morten S.
I: Circulation. Cardiovascular genetics, Bind 10, Nr. 6, e001878, 2017.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Analysis of 60 706 Exomes Questions the Role of De Novo Variants Previously Implicated in Cardiac Disease
AU - Paludan-Müller, Christian
AU - Ahlberg, Gustav
AU - Ghouse, Jonas
AU - Svendsen, Jesper H
AU - Haunsø, Stig
AU - Olesen, Morten S
N1 - © 2017 American Heart Association, Inc.
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
U2 - 10.1161/CIRCGENETICS.117.001878
DO - 10.1161/CIRCGENETICS.117.001878
M3 - Journal article
C2 - 29237690
VL - 10
JO - Circulation: Cardiovascular Genetics
JF - Circulation: Cardiovascular Genetics
SN - 1942-325X
IS - 6
M1 - e001878
ER -
ID: 194518261