Protonotarios Alexandros, Brodehl Andreas, Asimaki Angeliki, Jager Joanna, Quinn Ellie, Stanasiuk Caroline, Ratnavadivel Sandra, Futema Marta, Akhtar Mohammed M, Gossios Thomas D, Ashworth Michael, Savvatis Konstantinos, Walhorn Volker, Anselmetti Dario, Elliott Perry M, Syrris Petros, Milting Hendrik, Lopes Luis R
Institute of Cardiovascular Science, University College London, London, United Kingdom; Inherited Cardiovascular Disease Unit, St Bartholomew's Hospital, London, United Kingdom; William Harvey Research Institute, Queen Mary University of London, London, United Kingdom.
Erich and Hanna Klessmann Institute for Cardiovascular Research & Development (EHKI), Heart and Diabetes Center NRW, University Hospital of the Ruhr-University Bochum, Germany.
Can J Cardiol. 2021 Jun;37(6):857-866. doi: 10.1016/j.cjca.2020.11.017. Epub 2020 Dec 5.
Arrhythmogenic cardiomyopathy (AC) is a heritable myocardial disorder and a major cause of sudden cardiac death. It is typically caused by mutations in desmosomal genes. Desmin gene (DES) variants have been previously reported in AC but with insufficient evidence to support their pathogenicity.
We aimed to assess a large AC patient cohort for DES mutations and describe a unique phenotype associated with a recurring variant in three families. A cohort of 138 probands with a diagnosis of AC and no identifiable desmosomal gene mutations were prospectively screened by whole-exome sequencing.
A single DES variant (p.Leu115Ile, c.343C>A) was identified in 3 index patients (2%). We assessed the clinical phenotypes within their families and confirmed cosegregation. One carrier required heart transplantation, 2 died suddenly, and 1 died of noncardiac causes. All cases had right- and left-ventricular (LV) involvement. LV late gadolinium enhancement was present in all, and circumferential subepicardial distribution was confirmed on histology. A significant burden of ventricular arrhythmias was noted. Desmin aggregates were not observed macroscopically, but analysis of the desmin filament formation in transfected cardiomyocytes derived from induced pluripotent stem cells, and SW13 cells revealed cytoplasmic aggregation of mutant desmin. Atomic force microscopy revealed that the mutant form accumulates into short protofilaments and small fibrous aggregates.
DES p.Leu115Ile leads to disruption of the desmin filament network and causes a malignant biventricular form of AC, characterized by LV dysfunction and a circumferential subepicardial distribution of myocardial fibrosis.
致心律失常性心肌病（AC）是一种遗传性心肌疾病，是心源性猝死的主要原因。它通常由桥粒基因突变引起。此前已有报道在AC患者中发现结蛋白基因（DES）变异，但支持其致病性的证据不足。
我们旨在评估一大群AC患者的DES突变情况，并描述与三个家族中一个反复出现的变异相关的独特表型。对138例诊断为AC且未发现桥粒基因突变的先证者队列进行全外显子组测序的前瞻性筛查。
在3例索引患者（2%）中鉴定出一个单一的DES变异（p.Leu115Ile，c.343C>A）。我们评估了其家族中的临床表型并确认了共分离现象。一名携带者需要进行心脏移植，2例猝死，1例死于非心脏原因。所有病例均有右心室和左心室（LV）受累。所有患者均有左心室晚期钆增强，组织学证实为环形心外膜下分布。观察到大量室性心律失常。肉眼未观察到结蛋白聚集体，但对源自诱导多能干细胞的转染心肌细胞和SW13细胞中的结蛋白丝形成进行分析，发现突变型结蛋白在细胞质中聚集。原子力显微镜显示突变形式聚集成短原纤维和小纤维聚集体。
DES p.Leu115Ile导致结蛋白丝网络破坏，引起一种恶性双心室型AC，其特征为左心室功能障碍和心肌纤维化的心外膜下环形分布。
