Novel KLHL26 variant associated with a familial case of Ebstein's anomaly and left ventricular noncompaction. Mol Genet Genomic Med 2020 Apr;8(4):e1152
Date
01/28/2020Pubmed ID
31985165Pubmed Central ID
PMC7196453DOI
10.1002/mgg3.1152Scopus ID
2-s2.0-85078673520 (requires institutional sign-in at Scopus site) 10 CitationsAbstract
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.
Author List
Samudrala SSK, North LM, Stamm KD, Earing MG, Frommelt MA, Willes R, Tripathi S, Dsouza NR, Zimmermann MT, Mahnke DK, Liang HL, Lund M, Lin CW, Geddes GC, Mitchell ME, Tomita-Mitchell AAuthors
Chien-Wei Lin PhD Associate Professor in the Data Science Institute department at Medical College of WisconsinDonna K. Mahnke Research Scientist I in the Pediatrics department at Medical College of Wisconsin
Michael Edward Mitchell MD Chief, Professor in the Surgery department at Medical College of Wisconsin
Aoy Tomita Mitchell PhD Professor in the Surgery department at Medical College of Wisconsin
Lauren North MD Assistant Professor in the Otolaryngology department at Medical College of Wisconsin
Michael T. Zimmermann PhD Director, Assistant Professor in the Clinical and Translational Science Institute department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AdultBinding Sites
Child
Child, Preschool
Cullin Proteins
Ebstein Anomaly
Female
Genetic Testing
Heart Defects, Congenital
Humans
Infant, Newborn
Loss of Function Mutation
Male
Middle Aged
Pedigree
Protein Binding