Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA.
Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, Milwaukee, WI, USA.
Mol Genet Genomic Med. 2020 Apr;8(4):e1152. doi: 10.1002/mgg3.1152. Epub 2020 Jan 27.
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.
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.
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.
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.
Ebstein 畸形（EA）是一种罕见的三尖瓣和右心室先天性心脏病。患有 EA 的患者常表现为左心室心肌致密化不全（LVNC），这是一种心肌病。尽管一些病例中涉及心脏肌节基因，但对于 EA/LVNC 的遗传病因知之甚少。我们的研究描述了一个有至少 17 名成员中的 10 名受 EA/LVNC 影响的多代家族。
我们对所有家族成员进行了超声心动图检查，并对 6 个人进行了外显子组测序。使用两种不同的生物信息学策略确定候选变体后，我们使用 Sanger 测序确认与表型的分离。我们使用蛋白质预测模型研究候选变体的结构影响。
对 4 名受影响和 2 名未受影响的成员的外显子组测序分析确定了位于染色体 19 上的 Kelch 样家族成员 26（KLHL26）基因中的一个新的、罕见的、有损伤的编码变体，该变体位于蛋白质的 237 位（GRCh37）。该变体区域通过 Sanger 测序在其余家族成员中得到确认。KLHL26（c.709C>T p.R237C）仅与 EA/LVNC 受影响个体（FBAT p<.05）分离。使用蛋白质预测模型研究候选变体的结构影响表明，KLHL26 变体在与泛素蛋白酶体的一部分结合时会破坏静电相互作用，特别是 Cullin3（CUL3），它是 E3 泛素连接酶的一个组成部分。
在这个 EA/LVNC 的家族病例中，我们确定了一个候选基因变体 KLHL26（p.R237C），它在心脏发育过程中的泛素介导的蛋白质降解中可能具有重要作用。
