Novel KLHL26 Variant Associated with a Familial Case of Ebstein's Anomaly and Left Ventricular Noncompaction

Overview

Journal Mol Genet Genomic Med

Specialty Genetics

Date 2020 Jan 28

PMID 31985165

Citations 8

Authors

Sai Suma K Samudrala

Lauren M North

Karl D Stamm

Michael G Earing

Michele A Frommelt

Richard Willes

Swarnendu Tripathi

Nikita R Dsouza

Michael T Zimmermann

Donna K Mahnke

Huan Ling Liang

Michael Lund

Chien-Wei Lin

Gabrielle C Geddes

Michael E Mitchell

Aoy Tomita-Mitchell

Affiliations

Soon will be listed here.

Abstract

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.

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