Abstract 16899: Exome Sequencing for Genetic Etiology in Families With Sudden Cardiac Death or Arrest
Introduction: Sudden cardiac arrest/death (SCA/D) is an uncommon, but tragic occurrence in youth. Causes include inherited structural, functional, and electrical cardiac abnormalities, with more than 100 known associated genes. A proactive family screening approach is important to provide life-saving treatment and to help identify other affected members due to the high association of genetic causes.
Hypothesis: Exome sequencing (ES) can be used to identify genetic causes of SCA/D.
Methods: Our objective was to use ES to identify definite and potential causes in families affected with SCA/D. Our study population included 41 probands with clinical symptoms or signs ± family history of SCA/D or SCA/D-associated conditions (affected), but without known molecular etiologies for SCA/D. Additional samples were obtained from 127 family members (parents/siblings/grandparents: 40 clinically affected and 87 unaffected). Samples were analyzed following exome capture and sequencing at an average read depth of 100X. Reads were mapped to human genome GRCh37 using Novoalign, and post-processing and analysis was done using Picard and GATK. A total of 103 genes (2,190 exons) related to SCA/D were used as a primary filter; 100 random variants within the targeted genes were evaluated for depth of sequencing and coverage. The majority of exons (97.6%) were captured and fully covered on average at minimum of 20x sequencing depth.
Results: Analysis of the 41 SCA/D probands revealed a definitive diagnostic answer in 11/41 (26.8%). Variants of uncertain significance (VUS), potential causes of SCA-associated cardiac conditions, were found in 15/41 (36.6%) cases, and 15/41 (36.6%) cases were negative. Of the 11 gene positive probands, 14/42 (33.3%) family members were positive for the deleterious gene. Other medically actionable pathogenic gene mutations, not related to the primary cardiac conditions, were identified in 3/41 probands (7.3%).
Conclusions: Exome sequencing is a helpful diagnostic tool for SCA/D, given its potential to successfully identify a molecular diagnosis, but clinicians should be aware of the limitations including incomplete knowledge of disease genes, uncertainty resulting from identification of VUS, and incomplete coverage of known genes.
Author Disclosures: V.L. Vetter: None. N.P. Dugan: None. S. Biswas: None. M. Li: None. M.C. Dulik: None. V. Jayaraman: None. L.K. Conlin: None. B. Devkota: None. E.J. Romasko: None. J. Abrudan: None. N.B. Spinner: None. I.D. Krantz: None.
- © 2016 by American Heart Association, Inc.