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

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/ 2 of 9 | SAMUDRALA et AL.

The Role of Cullin-RING Ligases in Striated Muscle Development, Function, and Disease

“…Mutations in Klhl26 (Kelch-like family member protein 26) have been associated with Ebstein’s anomaly. Patients manifest with left ventricular non-compaction [ 240 ]. In silico analysis suggests that this variant may disrupt the interaction with cullin-3, but functional analysis will be required to confirm its pathogenicity [ 240 ].…”

“…Patients manifest with left ventricular non-compaction [ 240 ]. In silico analysis suggests that this variant may disrupt the interaction with cullin-3, but functional analysis will be required to confirm its pathogenicity [ 240 ]. Substrates of Klhl26 in cardiac cells are still unknown and muscle-specific functions for this cullin-3 substrate adapter protein await further characterization.…”

KLHL38 facilitates staurosporine‐induced apoptosis in HL‐1 cells via myocardin degradation

“…Increasing evidence has demonstrated that KLHL family members play a vital role in mammalian cardiac development and occurrence of myocardial disease. Mutations in KLHL26 cause malformations of cardiac development and function 15 . Inactivation of KLHL24 leads to the accumulation of desmin intermediate filaments, which causes the occurrence of hypertrophic cardiomyopathy (HCM) 16 .…”

“…All KLHL family members contain a highly conserved BTB/POZ domain, back domain, and six repeating Kelch motifs, in which BTB domain can bind with cullin3 (CUL3) to form an E3 ligase, recruit substrates for ubiquitination and degradation and play an essential role in post‐translational gene expression regulation via mediating many important physiological and pathological processes, including mitosis, embryonic development, inflammatory response, cell cycle regulation, and cell apoptosis 11–14 . In particular, resent studies found that aberrant expression of KLHL genes is highly associated with the occurrence and development of cardiovascular disease and has attracted wide attention 15–17 . Using database mining (https://www.ncbi.nlm.nih.gov/geo/) and analysis, KLHL38 may be a new potential target in the therapeutic of HF.…”

“…[11][12][13][14] In particular, resent studies found that aberrant expression of KLHL genes is highly associated with the occurrence and development of cardiovascular disease and has attracted wide attention. [15][16][17] Using database mining (https://www.ncbi.nlm.nih.gov/geo/) and analysis, KLHL38 may be a new potential target in the therapeutic of HF. However, as a member of the same family, the role and mechanism of KLHL38 remains unclear in HF.…”