Novel KLHL26 variant associated with a familial case of Ebstein's anomaly and left ventricular noncompaction.

BACKGROUND: Ebstein's anomaly (EA) is a rare congenital heart disease of the tricuspid valve and right ventricle. Patients with EA often manifest with left ventricular noncompaction (LVNC), a cardiomyopathy. Despite implication of cardiac sarcomere genes in some cases, very little is understood regarding the genetic etiology of EA/LVNC. Our study describes a multigenerational family with at least 10 of 17 members affected by EA/LVNC. METHODS: We performed echocardiography on all family members and conducted exome sequencing of six individuals. After identifying candidate variants using two different bioinformatic strategies, we confirmed segregation with phenotype using Sanger sequencing. We investigated structural implications of candidate variants using protein prediction models. RESULTS: Exome sequencing analysis of four affected and two unaffected members identified a novel, rare, and damaging coding variant in the Kelch-like family member 26 (KLHL26) gene located on chromosome 19 at position 237 of the protein (GRCh37). This variant region was confirmed by Sanger sequencing in the remaining family members. KLHL26 (c.709C > T p.R237C) segregates only with EA/LVNC-affected individuals (FBAT p < .05). Investigating structural implications of the candidate variant using protein prediction models suggested that the KLHL26 variant disrupts electrostatic interactions when binding to part of the ubiquitin proteasome, specifically Cullin3 (CUL3), a component of E3 ubiquitin ligase. CONCLUSION: In this familial case of EA/LVNC, we have identified a candidate gene variant, KLHL26 (p.R237C), which may have an important role in ubiquitin-mediated protein degradation during cardiac development.

Chronic Arrhythmias in the Setting of Heterotaxy: Differences between Right and Left Isomerism.

So-called heterotaxy affects lateralization of the thoracic and abdominal organs. Congenital malformations may be present in one of several organ systems. Cardiac involvement includes both structural and conduction abnormalities. Data regarding arrhythmias in heterotaxy come from case reports and small case series. We pooled available data to further characterize arrhythmias in heterotaxy. A systematic review of the literature for manuscripts describing arrhythmias in heterotaxy patients was conducted. Databases including PubMed, EMBASE, and Ovid were searched. Studies describing arrhythmias in patients with heterotaxy were included if they were in English and presented characteristics of the arrhythmias. Arrhythmia characteristics were abstracted and are presented as pooled data. Freedom from arrhythmia by age was then analyzed using Kaplan-Meier analysis. A total of 19 studies with 121 patients were included in the pooled analysis. Those with right isomerism were found to be more likely to have atrial flutter, atrial tachycardia, junctional tachycardia, and ventricular tachycardia. Those with left isomerism were more likely to have atrioventricular block, intraventricular conduction delay, sick sinus syndrome, and atrioventricular nodal reentry tachycardia. Median age of onset for all arrhythmias was 4 years with no difference by specific arrhythmia or isomerism. Those with right and left isomerism are at risk for different arrhythmias but are likely to develop arrhythmias at the same age. Those with left isomerism are more likely to require pacemaker placement due to atrioventricular block. Understanding these differences allows for focused surveillance of development of these arrhythmias.