TY - JOUR
T1 - Distinguishing hypertrophic cardiomyopathy-associated mutations from background genetic noise
AU - Kapplinger, Jamie D.
AU - Landstrom, Andrew P.
AU - Bos, J. Martijn
AU - Salisbury, Benjamin A.
AU - Callis, Thomas E.
AU - Ackerman, Michael J.
N1 - Funding Information:
Acknowledgments J.D.K. is supported by the NIH grant GM72474-08 and thanks the Mayo Clinic MSTP for fostering an outstanding environment for physician-scientist training. This project was supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program (MJA).
PY - 2014/4
Y1 - 2014/4
N2 - Despite the significant progress that has been made in identifying disease-associated mutations, the utility of the hypertrophic cardiomyopathy (HCM) genetic test is limited by a lack of understanding of the background genetic variation inherent to these sarcomeric genes in seemingly healthy subjects. This study represents the first comprehensive analysis of genetic variation in 427 ostensibly healthy individuals for the HCM genetic test using the "gold standard" Sanger sequencing method validating the background rate identified in the publically available exomes. While mutations are clearly overrepresented in disease, a background rate as high as ∼5 % among healthy individuals prevents diagnostic certainty. To this end, we have identified a number of estimated predictive value-based associations including gene-specific, topology, and conservation methods generating an algorithm aiding in the probabilistic interpretation of an HCM genetic test.
AB - Despite the significant progress that has been made in identifying disease-associated mutations, the utility of the hypertrophic cardiomyopathy (HCM) genetic test is limited by a lack of understanding of the background genetic variation inherent to these sarcomeric genes in seemingly healthy subjects. This study represents the first comprehensive analysis of genetic variation in 427 ostensibly healthy individuals for the HCM genetic test using the "gold standard" Sanger sequencing method validating the background rate identified in the publically available exomes. While mutations are clearly overrepresented in disease, a background rate as high as ∼5 % among healthy individuals prevents diagnostic certainty. To this end, we have identified a number of estimated predictive value-based associations including gene-specific, topology, and conservation methods generating an algorithm aiding in the probabilistic interpretation of an HCM genetic test.
KW - Diagnosis
KW - Genetic test
KW - Hypertrophic cardiomyopathy
KW - Mutation
KW - Polymorphism
UR - http://www.scopus.com/inward/record.url?scp=84899407958&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84899407958&partnerID=8YFLogxK
U2 - 10.1007/s12265-014-9542-z
DO - 10.1007/s12265-014-9542-z
M3 - Article
C2 - 24510615
AN - SCOPUS:84899407958
SN - 1937-5387
VL - 7
SP - 347
EP - 361
JO - Journal of cardiovascular translational research
JF - Journal of cardiovascular translational research
IS - 3
ER -