Format

Send to

Choose Destination
Circ Cardiovasc Genet. 2017 Feb;10(1). pii: e001573. doi: 10.1161/CIRCGENETICS.116.001573.

Application of Whole Exome Sequencing in the Clinical Diagnosis and Management of Inherited Cardiovascular Diseases in Adults.

Author information

1
From the Division of Cardiovascular Medicine (S.B.S., E.S., L.S., M.D.A.Z., B.A., J.G.A., M.M., D.J., A.M.), Yale Program for Cardiovascular Genetics (S.B.S., E.S., L.S., F.H.-S., A.M.), Department of Genetics, Yale School of Medicine, New Haven, CT (D.D., A.E.B., R.P.L., A.M.); Division of Cardiovascular Medicine, Department of Radiology (S.B.S.) and Division of Cardiac Imaging (S.B.S.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; and Key Laboratory of Clinical Trail Research in Cardiovascular Drugs, Ministry of Health Cardiovascular Institute, Fu Wai Hospital, CAMS and PUMC, Beijing, China (Y.J.).
2
From the Division of Cardiovascular Medicine (S.B.S., E.S., L.S., M.D.A.Z., B.A., J.G.A., M.M., D.J., A.M.), Yale Program for Cardiovascular Genetics (S.B.S., E.S., L.S., F.H.-S., A.M.), Department of Genetics, Yale School of Medicine, New Haven, CT (D.D., A.E.B., R.P.L., A.M.); Division of Cardiovascular Medicine, Department of Radiology (S.B.S.) and Division of Cardiac Imaging (S.B.S.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; and Key Laboratory of Clinical Trail Research in Cardiovascular Drugs, Ministry of Health Cardiovascular Institute, Fu Wai Hospital, CAMS and PUMC, Beijing, China (Y.J.). arya.mani@yale.edu.

Abstract

BACKGROUND:

With the advent of high throughput sequencing, the identification of genetic causes of cardiovascular disease (CVD) has become an integral part of medical diagnosis and management and at the forefront of personalized medicine in this field. The use of whole exome sequencing for clinical diagnosis, risk stratification, and management of inherited CVD has not been previously evaluated.

METHODS AND RESULTS:

We analyzed the results of whole exome sequencing in first 200 adult patients with inherited CVD, who underwent genetic testing at the Yale Program for Cardiovascular Genetics. Genetic diagnosis was reached and reported with a success rate of 26.5% (53 of 200 patients). This compares to 18% (36 of 200) that would have been diagnosed using commercially available genetic panels (P=0.04). Whole exome sequencing was particularly useful for clinical diagnosis in patients with aborted sudden cardiac death, in whom the primary insult for the presence of both depressed cardiac function and prolonged QT had remained unknown. The analysis of the remaining cases using genome annotation and disease segregation led to the discovery of novel candidate genes in another 14% of the cases.

CONCLUSIONS:

Whole exome sequencing is an exceptionally valuable screening tool for its capability to establish the clinical diagnosis of inherited CVDs, particularly for poorly defined cases of sudden cardiac death. By presenting novel candidate genes and their potential disease associations, we also provide evidence for the use of this genetic tool for the identification of novel CVD genes. Creation and sharing of exome databases across centers of care should facilitate the discovery of unknown CVD genes.

KEYWORDS:

arrhythmia; cardiomyopathy; genetics; sudden cardiac death

PMID:
28087566
PMCID:
PMC5245580
DOI:
10.1161/CIRCGENETICS.116.001573
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Atypon Icon for PubMed Central
Loading ...
Support Center