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

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.

Figure 1

Pipeline to assess the pathogenicity of genetic variants identified in an Adult Cardiovascular Disease Genetics Clinic.

Figure 2

Pedigrees for discussed cases are shown. Circles represent females; squares represent males and symbols with a slash through them indicate deceased subjects. An arrow indicates the proband/person who had exome sequencing. (A) Pedigree of case 1 (patient 6). Individuals with hypermobility are indicated by black symbols; individuals not investigated for hypermobility are indicated by a black dot; individuals with aneurysm are indicated by a vertical purple line; individuals with scoliosis are indicated by a yellow vertical line; individuals with pectus are indicated with two blue vertical lines; individuals with periventricular heterotopia are indicated with red diagonal lines. Genotypes of COL5A1, COL5A2, and FLNA are shown below those individuals who underwent genetic testing. (B) Representative electrocardiogram (EKG) of case 4 (patient 152). Heart rate is 36 beat per minute and her corrected QTC was 630 msec. (C) Pedigree of case 4 (patient 152). Individuals with both torsade des pointes and congenital hearing loss are indicated by filled symbols; individuals reported to have permanent pacemakers are indicated by half-filled symbols. (D) Pedigree of case 5 (patient 97). Individuals with myocardial infarction and surgical intervention (i.e. CABG, PCI, etc.) are indicated with filled symbols; individuals with DVT are indicated by blue horizontal lines; individual with PE are indicated by red diagonal lines.