Abstract 20402: Exome Genotyping of Dallas Heart Study Reveals Putative Cardiac Disease-Causing Mutations: Disconnect Between Genotype and Phenotype
Next generation sequencing has increased the scope and availability of exome sequencing to clinical practice. A major challenge of using the new technology is handling incidental findings. The American Society of Medical Genetics (ACMG) recommends that mutations in 56 genes, including 20 genes that cause heart disease, be reported to patients, regardless of the indication for sequencing. The implications of applying these recommendations to clinical practice are unclear. Here we screened participants of the Dallas Heart Study (n=4928), with the Illumina HumanExome BeadChip array. A total of 46 sequence variants in 6 of the ACMG cardiac genes were identified. Six pathogenic variants were found in 36 participants (0.7% of the cohort). Those with the putative pathologic variants in cardiac genes were not more likely to have a positive family history for cardiac disease or sudden death (69% vs 65%; p=0.81) or an elevated serum cardiac troponin (33% vs 22%; p=0.41] when compared to carriers of benign or low frequency variants of unknown significance (VUS) in the same genes (25 variants in 78 participants). No difference in median (interquartile range) of BNP [7.1 pg/ml (0.7-47 pg/ml) vs 4.9 pg/ml (0-20 pg/ml); p=0.34), ejection fraction [70% (63-76%) vs 71% (69-77%); p=0.41] or LV mass [151 g (115-190 g) vs 143 g (99-176 g); p=0.52] were identified between the two groups who had variants in GLA, MYBPC3, and TNNT2. The QTc interval was similar in those with putative pathogenic KCNQ1 variants and benign/VUS variants [416 ms (406-437 ms) vs 410 ms (401-427ms)]. Our data indicate that cardiac incidental findings will be identified in >1% of the population and that a significant proportion of these individuals will not have clinically significant heart disease.
Author Disclosures: D. Stoller: None. J. Cohen: Research Grant; Significant; NIH. Speakers Bureau; Modest; Merck, Regeneron, Pfizer, Roche. Honoraria; Modest; Merck, Regeneron, Pfizer, Roche. H. Hobbs: Research Grant; Significant; NIH, HHMI. Consultant/Advisory Board; Significant; Pfizer Board of Directors.
- © 2014 by American Heart Association, Inc.