Interpreting Secondary Cardiac Disease Variants in an Exome Cohort

Abstract

Background Massively parallel sequencing to identify rare variants is widely practiced in medical research and in the clinic. Genome and exome sequencing can identify the genetic cause of a disease (primary results), but can also identify pathogenic variants underlying diseases that are not being sought (secondary or incidental results). A major controversy has developed surrounding the return of secondary results to research participants. We have piloted a method to analyze exomes to identify participants at-risk for cardiac arrhythmias, cardiomyopathies or sudden death. Methods and Results Exome sequencing was performed on 870 participants not selected for arrhythmia, cardiomyopathy, or a family history of sudden death. Exome data from 22 cardiac arrhythmia and 41 cardiomyopathy-associated genes were analyzed using an algorithm that filtered results on genotype quality, frequency, and database information. We identified 1367 variants in the cardiomyopathy genes and 360 variants in the arrhythmia genes. Six participants had pathogenic variants associated with dilated cardiomyopathy (n=1), hypertrophic cardiomyopathy (n=2), left ventricular noncompaction (n=1) or long QT syndrome (n=2). Two of these participants had evidence of cardiomyopathy and one had left ventricular noncompaction on ECHO. Three participants with likely pathogenic variants had prolonged QTc. Family history included unexplained sudden death among relatives. Conclusions Approximately 0.5% of participants in this study had pathogenic variants in known cardiomyopathy or arrhythmia genes. This high frequency may be due to self-selection, false positives, or underestimation of the prevalence of these conditions. We conclude that clinically important cardiomyopathy and dysrhythmia secondary variants can be identified in unselected exomes.

Mutation Analysis of the Main Hypertrophic Cardiomyopathy Genes Using Multiplex Amplification and Semiconductor Next-Generation Sequencing

“…6, 9 The Exome Sequencing project found rare variants (ESP database, http:// evs.gs.washington.edu) previously identified in HCM patients, a fact that has questioned the pathogenicity of some missense nucleotide changes previously considered as mutations. 26, 27 At this stage, the present procedure would facilitate rapid and cost-effective sequencing of the main HCM-associated genes in large sets of individuals.…”

Fatality and Severity of Firearm Injuries in a Denver Trauma Center, 2000-2013

“…Previously, criteria for reporting secondary variants in these genes were developed that required a MAF no higher than that for the disease overall and either 3 independent reports of pathogenicity or 2 such reports and supporting evidence (typically functional data) with no conflicting benign data. 2 Applying more restrictive criteria to the 127 variants identified by Van Driest and colleagues would likely identify few as pathogenic. Van Driest and colleagues 1 overinterpreted their data in concluding, "These findings raise questions about the implications of notifying patients of incidental genetic findings."…”

“…To devise appropriate prevention efforts, investigations of the severity and prognosis of both fatal and nonfatal gunshot wounds (GSW) are pivotal, yet they remain scarce. [1][2][3] We studied temporal patterns of GSW-associated severity and mortality in a Colorado urban trauma center and of all trauma deaths occurring in its catchment area from 2000 to 2013.…”

Enhancing the Incidental Pipeline in Genomic Sequencing

“…However, the most rapidly evolving algorithms will not be helpful if the benefits cannot be returned to patients [Johnston et al, 2012;Ng et al, 2013]. The channel for continued contact should stay open to allow for ongoing medical involvement and communication.…”

“…A person who undergoes sequencing to help understand, for example, the cause of their child's condition, must be aware of the ramifications relating to incidental medical information. These ramifications include genetic information that may be important for their own health as well as that of additional relatives who may share the same genetic variant [Johnston et al, 2012;Ng et al, 2013].…”