Open AccessNovel KLHL26 variant associated with a familial case of Ebstein’s anomaly and left ventricular noncompaction
Author(s) -
Samudrala Sai Suma K.,
North Lauren M.,
Stamm Karl D.,
Earing Michael G.,
Frommelt Michele A.,
Willes Richard,
Tripathi Swarnendu,
Dsouza Nikita R.,
Zimmermann Michael T.,
Mahnke Donna K.,
Liang Huan Ling,
Lund Michael,
Lin ChienWei,
Geddes Gabrielle C.,
Mitchell Michael E.,
TomitaMitchell Aoy
Publication year - 2020
Publication title -
molecular genetics and genomic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.765
H-Index - 29
ISSN - 2324-9269
DOI - 10.1002/mgg3.1152
Subject(s) - left ventricular noncompaction , sanger sequencing , exome sequencing , candidate gene , genetics , exome , cardiomyopathy , biology , ubiquitin ligase , phenotype , mutation , gene , medicine , cardiology , heart failure , ubiquitin
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.