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...

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Vydáno v:	Molecular genetics & genomic medicine Ročník 8; číslo 4; s. e1152 - n/a
Hlavní autoři:	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, Chien‐Wei, Geddes, Gabrielle C., Mitchell, Michael E., Tomita‐Mitchell, Aoy
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States John Wiley & Sons, Inc 01.04.2020 John Wiley and Sons Inc Wiley
Témata:	Adult Age Binding Sites Biodegradation Cardiomyopathy Cardiovascular diseases Child Child, Preschool Children & youth Chromosome 19 Chromosomes congenital heart defects Coronary artery disease Cullin Proteins - metabolism Ebstein Anomaly - genetics Ebstein Anomaly - pathology Ebstein's anomaly Echocardiography Electrostatic properties Etiology Families & family life Female Genes Genetic Testing Heart Defects, Congenital - genetics Heart Defects, Congenital - pathology Heart diseases Humans Infant, Newborn Kelch‐like family member 26 left‐ventricular noncompaction Loss of Function Mutation Male Middle Aged Original Pedigree Phenotypes Prediction models Premature birth Proteasomes Protein Binding Proteins Rheumatic heart disease Sequence analysis Transcription factors Tricuspid valve Ubiquitin ubiquitin proteasome Ubiquitin-protein ligase Ventricle United States > US Wisconsin Kelch-like family member 26 left-ventricular noncompaction Ebstein's anomaly ubiquitin proteasome congenital heart defects
ISSN:	2324-9269, 2324-9269
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Shrnutí:	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. Patient's Ebstein's anomaly (EA), a rare congenital heart disease of the tricuspid valve and right ventricle often manifest with left ventricular noncompaction (LVNC), a cardiomyopathy. Our study identifies a novel, rare, and damaging coding variant c.709C > T (p.R237C) in the Kelch‐like family member 26 (KLHL26) gene with 10 affected out of 17 affected members using Sanger sequencing. Through structural modeling, we show that the KLHL26 variant may affect protein binding to Cullin3 (CUL3), a component of E3 ubiquitin ligase in the ubiquitin‐mediated protein degradation.
Bibliografie:	Funding information This work was supported by National Heart, Lung, and Blood Institute 5T35HL072483‐32 (L.N) and 5T35HL072483‐34 (S.S.), the Wolfe Family Foundation, the Little Hearts for Life Foundation, the Medical College of Wisconsin's Department of Surgery, and the Children's Hospital of Wisconsin Research Institute. S.S. is a member of the Medical Scientist Training Program at MCW, which is partially supported by a training grant from National Institute of General Medical Sciences T32‐GM080202. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 ObjectType-Case Study-2 ObjectType-Feature-4 content type line 23 ObjectType-Report-1 ObjectType-Article-3
ISSN:	2324-9269 2324-9269
DOI:	10.1002/mgg3.1152