Background: The cardiomyopathies are classically categorized as hypertrophic (HCM), dilated (DCM), and arrhythmogenic right ventricular (ARVC), and each have a signature genetic theme. HCM and ARVC are largely understood as genetic diseases of sarcomere or desmosome proteins, respectively. In contrast, >250 genes spanning more than 10 gene ontologies have been implicated in DCM, representing a complex and diverse genetic architecture. To clarify this, a systematic curation of evidence to establish the relationship of genes with DCM was conducted. Methods: An international Panel with clinical and scientific expertise in DCM genetics was assembled to evaluate evidence supporting monogenic relationships of genes with idiopathic DCM. The Panel utilized the ClinGen semi-quantitative gene-disease clinical validity classification framework. Results: Fifty-one genes with human genetic evidence were curated. Twelve genes (23%) from eight gene ontologies were classified as having definitive (BAG3, DES, FLNC, LMNA, MYH7, PLN, RBM20, SCN5A, TNNC1, TNNT2, TTN) or strong (DSP) evidence. Seven genes (14%) (ACTC1, ACTN2, JPH2, NEXN, TNNI3, TPM1, VCL) including two additional ontologies were classified as moderate evidence; these genes are likely to emerge as strong or definitive with additional evidence. Of the 19 genes classified as definitive, strong or moderate, six were similarly classified for HCM and three for ARVC. Of the remaining 32 genes (63%), 25 (49%) had limited evidence, 4 (8%) were disputed, 2 (4%) had no disease relationship, and 1 (2%) was supported by animal model data only. Of 16 commercially available genetic testing panels evaluated, most definitive genes were included, but panels also included numerous genes with minimal human evidence. Conclusions: In a systematic curation of published evidence for genes considered relevant for monogenic DCM, 12 were classified as definitive or strong and seven as moderate evidence spanning 10 gene ontologies. Notably, these 19 genes only explain a minority of DCM cases, leaving the remainder of DCM genetic architecture incompletely addressed. While clinical genetic testing panels include most high evidence genes, genes lacking robust evidence are also commonly included. Until the genetic architecture of DCM is more fully defined, care should be taken in the interpretation of variable evidence DCM genes in clinical practice.

中文翻译：

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扩张型心肌病基因的循证评估

背景：心肌病的经典分类为肥厚性（HCM），扩张型（DCM）和致心律失常性右心室（ARVC），并且每种都有其独特的遗传学主题。HCM和ARVC分别被广泛理解为肌节蛋白或桥粒蛋白的遗传疾病。相比之下，DCM中涉及超过250种基因，涵盖10多个基因本体，代表了复杂而多样的遗传结构。为了澄清这一点，进行了系统的证据整理，以建立基因与DCM的关系。方法：组建了具有DCM遗传学临床和科学专业知识的国际专家小组，以评估支持基因与特发性DCM的单基因关系的证据。专家组采用了ClinGen半定量基因疾病临床有效性分类框架。结果：选择了五十一种具有人类遗传学证据的基因。来自八个基因本体的十二个基因（23％）被分类为具有明确的证据（BAG3，DES，FLNC，LMNA，MYH7，PLN，RBM20，SCN5A，TNNC1，TNNT2，TTN）或有力的（DSP）证据。七个基因（14％）（ACTC1，ACTN2，JPH2，NEXN，TNNI3，TPM1，VCL），包括另外两个本体论，被分类为中等证据。这些基因可能会在没有其他证据的情况下显得强大或确定。在被分类为确定性，强或中度的19个基因中，对HCM分类了六个，对ARVC分类了三个。在其余的32个基因中（63％），有25个（49％）的证据有限，有4个（8％）的证据有争议，有2个（4％）与疾病没有关系，只有1个（2％）得到动物模型数据的支持。在评估的16个可商购的基因测试小组中，包括了大多数确定性基因，但小组成员还包括了无人类证据的众多基因。结论：在系统地整理了与单基因DCM相关的基因的公开证据中，有12种被归为确定性或强证据，有7种被归为涵盖10个基因本体的中等证据。值得注意的是，这19个基因仅能解释少数DCM病例，而其余的DCM遗传结构无法完全解决。尽管临床基因测试小组包括大多数证据最充分的基因，但缺乏可靠证据的基因也通常被包括在内。在更全面地定义DCM的遗传结构之前，在临床实践中应谨慎解释可变证据DCM基因。在对与单基因DCM相关的基因的公开证据进行系统整理的过程中，有12种被归为确定性或强证据，而有7种被归为涵盖10个基因本体的中等证据。值得注意的是，这19个基因仅能解释少数DCM病例，而其余的DCM遗传结构无法完全解决。尽管临床基因测试小组包括大多数证据最充分的基因，但缺乏可靠证据的基因也通常被包括在内。在更全面地定义DCM的遗传结构之前，在临床实践中应谨慎解释可变证据DCM基因。在对与单基因DCM相关的基因的公开证据进行系统整理的过程中，有12种被归为确定性或强证据，而有7种被归为涵盖10个基因本体的中等证据。值得注意的是，这19个基因仅能解释少数DCM病例，而其余的DCM遗传结构无法完全解决。尽管临床基因测试小组包括大多数证据最充分的基因，但缺乏可靠证据的基因也通常被包括在内。在更全面地定义DCM的遗传结构之前，在临床实践中应谨慎解释可变证据DCM基因。剩下的DCM遗传结构的其余部分未得到完全解决。尽管临床基因测试小组包括大多数证据最充分的基因，但缺乏可靠证据的基因也通常被包括在内。在更全面地定义DCM的遗传结构之前，在临床实践中应谨慎解释可变证据DCM基因。剩下的DCM遗传结构的其余部分未得到完全解决。尽管临床基因测试小组包括大多数证据最充分的基因，但缺乏可靠证据的基因也通常被包括在内。在更全面地定义DCM的遗传结构之前，在临床实践中应谨慎解释可变证据DCM基因。