Electronic health record phenotype in subjects with genetic variants associated with arrhythmogenic right ventricular cardiomyopathy: a study of 30,716 subjects with exome sequencing

Abstract

Purpose Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart disease. Clinical follow-up of incidental findings in ARVC-associated genes is recommended. We aimed to determine the prevalence of disease thus ascertained. Methods 30,716 individuals underwent exome sequencing. Variants in PKP2, DSG2, DSC2, DSP, JUP, TMEM43, or TGFβ3 that were database-listed as pathogenic or likely pathogenic were identified and evidence-reviewed. For subjects with putative loss-of-function (pLOF) variants or variants of uncertain significance (VUS), electronic health records (EHR) were reviewed for ARVC diagnosis, diagnostic criteria, and International Classification of Diseases (ICD-9) codes. Results 18 subjects had pLOF variants; none had an EHR diagnosis of ARVC. Of 14 patients with an electrocardiogram (ECG), one had a minor diagnostic criterion, 13 were normal. 184 subjects had VUSs; none had an ARVC diagnosis. In subjects with VUSs, there was no difference in the proportion with major (4%) or minor (13%) ECG diagnostic criteria compared to variant-negative controls. ICD-9 codes showed no difference in defibrillator utilization, electrophysiologic abnormalities or non-ischemic cardiomyopathies in patients with pLOF or VUSs compared to controls. Conclusion pLOF variants in an unselected cohort were not associated with ARVC phenotypes based on EHR review. The negative predictive value of EHR review remains uncertain.

Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy

“…Further, we observed that expression of desmin and α-ac- mental Figure 8). A direct interaction of AnkB and β-catenin was further confirmed by in vitro binding assays, in which GST-AnkB MBD, but not GST, was associated with recombinant 35 [S]-Met β-catenin (Supplemental Figure 8). Our findings illustrate a specific and direct interaction of the AnkB MBD and the C-terminal domain (CTD) of β-catenin (residues 697-781).…”

“…This concept is further supported by the allele frequencies of many ANK2 variants identified being too common to be causative in isolation, coupled with the frequent lack of family history in cases. Although potentially viewed as a limitation, this phenomenon is probably operative in the majority of genetic ACM subtypes, in which the importance of polygenic drivers and gene dosage is becoming increasingly apparent (33)(34)(35)(36). Indeed, the notion of ACM being a polygenic disease dependent on multiple "hits" will almost certainly be the rule rather than the exception for the vast majority of remaining ACM genotype-negative cases that are overwhelmingly sporadic (37).…”

A Model for Genome-First Care: Returning Secondary Genomic Findings to Participants and Their Healthcare Providers in a Large Research Cohort

“…This is particularly vexing given the uncertainty regarding disease penetrance in genotypically identified individuals. [20, 21] However, evidence generation in the context of the program, a key element of a LHS, will accrue knowledge that can then be applied to future participants with secondary genomic findings identified through clinical genomic sequencing—a problem that already exists and for which no evidence based recommendations exist.…”

Clinotator: analyzing ClinVar variation reports to prioritize reclassification efforts

“…Clinical assertions based on insufficient evidence can persist in public databases and consequently seed misinformation into future interpretations 9, 15 . Recently, in the field of cardiovascular disease, there have been several high-profile instances of cardiovascular variants deemed to be highly pathogenic, yet not segregating with disease 9, 16, 17 . This unfortunate outcome is inevitable owing to the aforementioned reasons and illustrates a key issue: the continual need to share and reconcile new information with old data and reclassify clinical assertions as appropriate on a regular basis 6, 8 .…”