EMD错义变异导致伴有心肌emerin缺乏的X连锁孤立性扩张型心肌病-动脉网

EMD missense variant causes X-linked isolated dilated cardiomyopathy with myocardial emerin deficiency

Nature 等信源发布 2025-03-10 00:12

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Abstract

摘要

Pathogenic variants in the

致病性变异在

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gene cause X-linked Emery–Dreifuss muscular dystrophy type 1 (EDMD1), typically presenting with joint contractures and skeletal muscle atrophy, followed by atrial arrhythmias, cardiac conduction defects, and atrial dilatation. Although an association with isolated dilated cardiomyopathy (DCM) has been suggested, evidence is currently insufficient to verify the gene-disease association.

基因导致X连锁Emery-Dreifuss肌营养不良症1型（EDMD1），典型表现为关节挛缩和骨骼肌萎缩，随后出现心房心律失常、心脏传导缺陷和心房扩张。尽管有研究提示其与孤立性扩张型心肌病（DCM）存在关联，但目前证据尚不足以验证该基因与疾病的关系。

We investigated the causality of a missense variant, c.23C>G, p.Ser8Trp, in .

我们调查了错义变异 c.23C>G，p.Ser8Trp 在中的因果关系。

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in a large family with a history of DCM and suspected sudden cardiac death (SCD) in males. DCM was diagnosed in six hemizygous males aged 36–50 and detailed phenotyping identified end-stage heart failure, cardiac conduction defects, and ventricular arrhythmias as prominent features. Cardiac magnetic resonance imaging showed late gadolinium enhancement with mixed ischemic and non-ischemic patterns.

在一个有DCM病史且怀疑男性猝死（SCD）的大家庭中。六名36至50岁的半合子男性被诊断出患有DCM，详细的表型分析确定终末期心力衰竭、心脏传导缺陷和室性心律失常是显著特征。心脏磁共振成像显示晚期钆增强，呈现混合性缺血性和非缺血性模式。

Muscular dystrophy was absent in all six males, of whom five underwent neuromuscular examination including serum-creatine kinase measurement. Immunohistochemical analysis showed greatly reduced levels of emerin in both cardiac and skeletal muscle samples. The .

所有六名男性均未出现肌肉萎缩症，其中五人接受了包括血清肌酸激酶测量在内的神经肌肉检查。免疫组织化学分析显示，心脏和骨骼肌样本中的emerin水平显著降低。

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variant c.23C>G co-segregated with DCM, with an estimated LOD score of 3.9 and full-likelihood Bayes factor of >2500:1 in favor of causality. Among the 17 heterozygous females, ages 20–87, one developed DCM at age 72. We concluded that the

变体 c.23C>G 与 DCM 共分离，估计的 LOD 得分为 3.9，完全可能性贝叶斯因子为 >2500:1，支持因果关系。在 17 名异型合子女性中，年龄范围为 20 至 87 岁，其中一名在 72 岁时发展为 DCM。我们得出结论，

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c.23C>G missense variant is associated with DCM in the absence of muscular dystrophy, thereby providing new evidence of isolated DCM as a distinct cardiac

c.23C>G错义变异在没有肌肉营养不良的情况下与DCM相关，从而为孤立性DCM作为一种独特的心脏病提供了新的证据。

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-phenotype, separate from EDMD1. The phenotypic similarities with

-表型，与EDMD1分离。表型相似性与

LMNA

-DCM, with a high risk of cardiac conduction defects and ventricular arrhythmias, might warrant early interventions to prevent SCD.

-DCM，具有高风险的心脏传导缺陷和室性心律失常，可能需要早期干预以预防SCD。

Introduction

简介

Dilated cardiomyopathy (DCM) is defined by left or biventricular dilatation and systolic dysfunction not explained by abnormal loading conditions or coronary artery disease [

扩张型心肌病（DCM）的定义是左心室或双心室扩张且收缩功能障碍，这种状况无法用异常负荷条件或冠状动脉疾病解释。

]. In the 20–35% of idiopathic DCM cases estimated to be familial [

]. 在估计为家族性的特发性DCM病例中，占20-35% [

], identification of the underlying genetic cause is necessary to enable individualized clinical management and pre-symptomatic testing of at-risk family members. However, 60–85% of familial DCM cases remain unexplained after conventional genetic screening [

]，要实现个体化的临床管理和对有风险的家族成员进行症状前检测，确定潜在的遗传原因是必要的。然而，在常规基因筛查后，60-85%的家族性DCM病例仍然无法解释 [

]. Furthermore, among genes reported to associated with monogenic DCM, relatively few are supported by robust evidence of co-segregation or impact on protein function [

"]. 此外，在报道与单基因 DCM 相关的基因中，只有相对较少的基因有强有力的共分离或对蛋白质功能影响的证据支持 ["

The

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gene, encoding the globally expressed nuclear envelope protein emerin [

基因，编码全局表达的核膜蛋白emerin [

], has so far only been established as causative for DCM as a feature of Emery–Dreifuss muscular dystrophy type 1 (EDMD1) (MIM # 310300) [

], 到目前为止，仅被确定为与Emery-Dreifuss肌营养不良症1型（EDMD1）（MIM＃310300）相关的DCM的致病因素 [

]. EDMD1 is a rare X-linked disorder characterized by childhood onset of joint contractures and progressive muscular atrophy followed by cardiac disease from adolescence [

]. EDMD1是一种罕见的X连锁遗传病，其特征是儿童时期出现关节挛缩和进行性肌肉萎缩，青春期后出现心脏疾病 [

]. The cardiac phenotype of EDMD1 is typically dominated by atrial arrhythmias, cardiac conduction defects, and atrial dilatation [

]. EDMD1的心脏表型通常以心房心律失常、心脏传导缺陷和心房扩张为主 [

，

]. Mild left ventricular dilatation and systolic dysfunction are common [

]. 左心室轻度扩张和收缩功能障碍是常见的 [

，

] and new evidence suggests that ventricular involvement might be more severe than previously reported [

] 新证据表明心室受累可能比之前报道的更为严重 [

]. However, DCM is rarely reported in EDMD1 [

]. 然而，DCM 在 EDMD1 中很少被报道 [

The degree of neuromuscular involvement in EDMD1 shows both inter- and intrafamilial variability [

EDMD1中的神经肌肉受累程度表现出家族间和家族内的变异性[

] and there are reports of cardiac disease being the predominant manifestation in males harboring

] 有报告显示，心脏疾病是携带者的男性主要表现

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variants [

变体 [

，

]. However, studies linking isolated DCM to

]. 然而，将孤立的DCM联系起来的研究

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are scarce [

是稀缺的[

，

] and no

]并且没有

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variant has yet been shown to be causative for isolated DCM by combined evidence of co-segregation and emerin deficiency. Furthermore, there are data that contradict that

该变异尚未通过共分离和emerin缺乏的综合证据被证明是孤立型DCM的致病因素。此外，有数据对此提出了反驳。

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plays a role in isolated DCM, including a large cohort study which concluded that the prevalence of rare

在孤立性DCM中起作用，包括一项大型队列研究得出结论，罕见的患病率

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variants did not differ between DCM patients and controls [

变体在DCM患者和对照组之间没有差异 [

]. Consequently,

]. 因此，

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is not listed among the known genes associated with non-syndromic familial DCM in current guidelines on genetic screening in DCM [

在当前关于DCM基因筛查的指南中，未被列为与非综合征家族性DCM相关的已知基因 [

In this study, we applied segregation analysis and emerin immunostaining on myocardial tissue to verify the causality of a missense variant in the

在这项研究中，我们应用了分离分析和emerin免疫染色在心肌组织上，以验证错义变异的因果关系。

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gene to X-linked DCM without muscular dystrophy in a large family, thereby providing new evidence linking the

基因与一个大家族中的X连锁DCM而不伴有肌肉萎缩症相关，从而提供新的证据连接

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gene to isolated DCM.

基因导致孤立性DCM。

Methods

方法

Study participants

研究参与者

The Swedish family was investigated at the Cardiogenetic clinic at Sahlgrenska University Hospital between 2015 and 2024, and the study included adult family members. Written informed consent was obtained from all participants prior to inclusion in the study. Medical records from deceased family members were evaluated after obtaining consent from close relatives..

2015年至2024年期间，该瑞典家庭在萨尔格伦斯卡大学医院的心脏遗传诊所接受了调查，研究包括成年家庭成员。所有参与者在纳入研究之前均签署了书面知情同意书。已故家庭成员的医疗记录在获得近亲同意后进行了评估。

Phenotype characterization

表型特征

Results of the clinical investigations were obtained from medical records. Cardiac magnetic resonance imaging (CMRI) exams were reanalyzed based on current recommendations using IntelliSpace (Philips Healthcare, Best, The Netherlands). DCM was diagnosed by the presence of left ventricular dilatation and systolic dysfunction in the absence of hypertension, valvular disease, or coronary artery disease sufficient to cause global systolic impairment, or congenital heart disease [.

临床调查结果从医疗记录中获得。心脏磁共振成像（CMRI）检查根据当前的建议使用IntelliSpace（飞利浦医疗，荷兰Best）重新分析。扩张型心肌病（DCM）的诊断依据是存在左心室扩张和收缩功能障碍，且没有足以导致全心收缩功能受损的高血压、瓣膜病或冠状动脉疾病，或先天性心脏病。

]. When available, left ventricular dilatation was diagnosed according to indexed left ventricular end-diastolic volume by CMRI. For cardiac ultrasound, a left ventricular end-diastolic diameter above 58 mm for males and above 52 mm for females was considered diagnostic. Systolic dysfunction was diagnosed as ejection fraction below 50%.

]. 左心室扩张根据心脏磁共振成像（CMRI）测得的左心室舒张末期容积指数来诊断（如可用）。对于心脏超声检查，男性左心室舒张末期内径超过58毫米，女性超过52毫米被认为具有诊断意义。收缩功能障碍被定义为射血分数低于50%。

Other causes of DCM were excluded according to clinical routine, as presented in Supplementary Table .

根据临床常规排除了DCM的其他原因，如补充表中所示。

。

All males with DCM, except the deceased, were examined by a specialist in neurology at the Centre for Neuromuscular Disorders at Sahlgrenska University Hospital. Evaluations included physical examination (including assessment of joint contractures and skeletal muscle atrophy), neurological status, and serum-creatine kinase measurement.

所有患有DCM的男性，除了已故者外，都在萨尔格伦斯卡大学医院的神经肌肉疾病中心接受了神经科专家的检查。评估内容包括身体检查（包括关节挛缩和骨骼肌萎缩的评估）、神经功能状态以及血清肌酸激酶测量。

Histopathological examination following deltoid muscle biopsy was performed on two males..

对两名男性进行了三角肌活检后的组织病理学检查。

Genetic analyses

遗传分析

Genetic screening was performed by targeted sequencing of exon and exon-intron boundaries using a commercial gene panel for DCM (Blueprint Genetics, Helsinki, Finland). Gene lists are available in Supplementary Table

使用针对DCM（Blueprint Genetics，赫尔辛基，芬兰）的商业基因面板对基因和基因内含子边界进行靶向测序，以进行基因筛查。基因列表见补充表格。

. Cascade screening by targeted testing for the detected

通过针对检测到的变异进行靶向检测的级联筛查

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variant c. 23C>G, p.Ser8Trp (NM_000117.3) was conducted for relatives at risk of inheriting the variant, either via NGS (Blueprint Genetics) or Sanger sequencing. Sanger sequencing was performed using BigDye Terminator v3.1 cycle sequencing kit (ThermoFisher Scientific, Waltham, MA, USA) on an ABI 3500xl Genetic Analyzer (ThermoFisher Scientific).

对有遗传该变异风险的亲属进行了变异 c. 23C>G, p.Ser8Trp (NM_000117.3) 的检测，检测方法要么是通过NGS（Blueprint Genetics），要么是Sanger测序。Sanger测序使用BigDye Terminator v3.1循环测序试剂盒（ThermoFisher Scientific，美国马萨诸塞州沃尔瑟姆）在ABI 3500xl基因分析仪（ThermoFisher Scientific）上进行。

In male participants unavailable for testing, the presence of the .

在无法进行测试的男性参与者中，存在 .

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variant was determined indirectly by testing their daughters, if possible.

通过检测他们的女儿来间接确定变异，如果可能的话。

Whole genome sequencing was performed to investigate the occurrence of other rare variants linked to the

进行了全基因组测序以调查与其他罕见变异的关联情况

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locus. DNA extracted from blood was prepped using TruSeq DNA PCR-free (Illumina, San Diego, CA, USA) and sequenced using NovaSeq 6000 (Illumina) to a genome-wide average coverage of 44×. Bioinformatic analysis was performed at SciLife Clinical Genomics (Gothenburg, Sweden) with variant calling for SNPs and indels performed using DNA-scope (Sentieon, San Jose, CA, USA) and copy number analysis using CANVAS (Illumina).

位点。从血液中提取的DNA使用TruSeq DNA PCR-free（Illumina，美国加利福尼亚州圣地亚哥）进行制备，并使用NovaSeq 6000（Illumina）进行测序，全基因组平均覆盖率为44×。生物信息学分析在SciLife临床基因组学中心（瑞典哥德堡）完成，SNP和indel的变异检测使用DNA-scope（Sentieon，美国加利福尼亚州圣何塞）进行，拷贝数分析使用CANVAS（Illumina）完成。

All genes within 1 Mb upstream and downstream of .

范围内所有基因，包括 1 Mb 上游和下游。

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were manually curated and six were identified as potentially related to DCM (

被手动整理，并确定了六个可能与DCM相关(

FLNA, TAFAXZZIN, CLIC2, BGN, SLC6A8

FLNA、TAFAXZZIN、CLIC2、BGN、SLC6A8

, and

，以及

MECP2

). All variants in

). 所有变体在

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and the listed genes ±1 Kb were extracted (84 variants total). Variants with an allele frequency above 1% in GnomAD v2.1.1 [

并提取了列出的基因±1Kb（总共84个变异）。在GnomAD v2.1.1中等位基因频率高于1%的变异[

] were filtered out leaving only two variants: the

] 被过滤掉，只剩下两个变体：the

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variant c.23C>G and an intronic 1 bp deletion in the

变体 c.23C>G 和内含子 1 bp 缺失在

FLNA

gene, with no predicted effect on splicing (SpliceAI) [

基因，对剪接没有预测影响（SpliceAI）[

Segregation analysis

分离分析

The association between the

之间的关联

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c.23C>G variant and DCM was investigated by segregation analysis in male family members with known genotype and phenotype. Their phenotypes were denoted as affected, unaffected, or unknown based on the phenotype characterization. Those fulfilling the diagnostic criteria for DCM were classified as affected regardless of age.

通过对已知基因型和表型的男性家族成员进行分离分析，研究了c.23C>G变异与DCM的关系。根据表型特征，他们的表型被定义为受影响、不受影响或未知。符合DCM诊断标准的个体无论年龄如何均被归类为受影响。

For those not diagnosed with DCM, the phenotype was denoted as unaffected only if they were 60 years or older. This age threshold was based on family history and previous reports on the age of onset of cardiac disease in EDMD1 [.

对于那些未被诊断为DCM的个体，只有当他们年满60岁或以上时，其表型才被记为未受影响。这一年龄阈值基于家族史以及先前关于EDMD1中心脏病发病年龄的报告。

，

]. Younger males (<60 years) without DCM were denoted as unknown phenotypes due to the uncertainty regarding DCM development later in life. Pedigrees used for the segregation analyses are shown in Supplementary Figs.

]. 未知表型的年轻男性（<60岁）由于不确定生命后期是否会发展为DCM，因此未标记为DCM。用于分离分析的家系图见补充图。

and

和

。

The estimated LOD score was calculated using the following formula, with

使用以下公式计算估计的LOD评分，

北

denoting the number of informative meioses/segregations in the pedigree:

表示谱系中有信息的减数分裂/分离次数：

$${{{\rm{Z}}}}({{{\rm{LOD\; score}}}})=\log 10\frac{1}{{0,5}^{N}}$$

$$Z(\text{LOD\; score}) = \log_{10} \frac{1}{0.5^N}$$

values > 3.0 were considered evidence of linkage between the

值 > 3.0 被认为是两者之间存在联系的证据

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locus and DCM, and values ≤ 2.0 were considered evidence against linkage.

位点和DCM，且值≤2.0被视为反对连锁的证据。

Full-likelihood Bayes factor (FLB) was calculated according to the method presented by Thompson et al. [

全似然贝叶斯因子 (FLB) 根据 Thompson 等人提出的方法进行计算 [

] using the segregatr package in R [

] 使用 R 中的 segregatr 包 [

]. Calculations were performed for the whole pedigree using penetrance 100%, phenocopy rate 1/250 [

]. 使用100%的外显率和1/250的表现复制率对整个家系进行了计算 [

], and allele frequency 0.000001. Recognizing the uncertainty of the chosen parameters, the analysis was recalculated systematically using values ranging from 90 to 100% for penetrance, 1/100 to 1/2000 for phenocopy rate, and 0.0000005 to 0.00001 for allele frequency.

]，等位基因频率为0.000001。考虑到所选参数的不确定性，分析通过系统性地重新计算，其中外显率取值范围为90%到100%，表型模拟率取值范围为1/100到1/2000，等位基因频率取值范围为0.0000005到0.00001。

Immunohistochemical analyses on cardiac and skeletal muscle specimens

免疫组织化学分析心脏和骨骼肌标本

Cardiac and skeletal muscle specimens were collected in a clinical setting. The explanted hearts were fixed in 4% paraformaldehyde and selected parts were embedded in paraffin. The muscle biopsies were snap-frozen in liquid propane chilled with liquid nitrogen. Sections were cut in a cryostat for histological and histochemical analyses applying standard techniques [.

在临床环境中收集了心脏和骨骼肌标本。摘除的心脏被固定在4%的多聚甲醛中，并选择部分嵌入石蜡。肌肉活检样本则用液氮冷却的液态丙烷快速冷冻。使用标准技术，在恒冷切片机上切片以进行组织学和组织化学分析。

]. Emerin immunohistochemistry was conducted using the NCL-Emerin mouse monoclonal antibody (Leica Biosystems, Newcastle, UK) at 1:500 dilution. The immunostaining was performed using a Dako Autostainer with EnVision FLEX (Agilent, Santa Clara, CA, USA) visualization.

使用NCL-Emerin小鼠单克隆抗体（Leica Biosystems，纽卡斯尔，英国）以1:500稀释度进行了Emerin免疫组织化学染色。免疫染色使用Dako Autostainer以及EnVision FLEX（安捷伦，圣克拉拉，加利福尼亚州，美国）可视化系统进行。

Western blot analysis on skeletal muscle specimen

骨骼肌样本的蛋白质印迹分析

Western blot analysis of emerin was performed on protein extracted from sections of fresh-frozen skeletal muscle specimens. Cleared lysates were loaded and separated on a 4–12% Bis-Tris-Protein gel (Novex NP0321BOX; ThermoFisher Scientific), followed by electroblotting. The membrane was incubated with a monoclonal antibody against human emerin as primary antibody (NCL-Emerin; Leica, used at 1:500 dilution).

对从新鲜冷冻的骨骼肌样本切片中提取的蛋白质进行了emerin的Western blot分析。将澄清的裂解液加载并分离在4-12% Bis-Tris蛋白凝胶（Novex NP0321BOX；ThermoFisher Scientific）上，随后进行电转印。膜与针对人类emerin的单克隆抗体作为一抗孵育（NCL-Emerin；Leica，稀释比例为1:500）。

The SuperSignal West Femto Maximum Sensitivity Substrate (ThermoFisher Scientific) was used for antibody detection. The band corresponding to myosin heavy chain in the Coomassie-stained gel was used as loading control..

使用SuperSignal West Femto最高灵敏度底物（ThermoFisher Scientific）进行抗体检测。Coomassie染色凝胶中与肌球蛋白重链对应的条带被用作上样对照。

cDNA analysis on skeletal muscle specimen

骨骼肌标本的cDNA分析

Total RNA was isolated from fresh-frozen skeletal muscle specimens using the RNeasy Fibrous Tissue Mini Kit (Qiagen, Venlo, Netherlands). RNA was reverse transcribed with the QuantiTect reverse transcription kit (Qiagen), and cDNA was analyzed by PCR and Sanger sequencing. The forward and reverse primers were designed to hybridize to different exons that were separated by large introns to generate a specific PCR product (forward primer located in exon 1 and reverse primer located in exon 3, .

使用RNeasy Fibrous Tissue Mini Kit（Qiagen，荷兰芬洛）从新鲜冷冻的骨骼肌样本中提取总RNA。使用QuantiTect逆转录试剂盒（Qiagen）将RNA逆转录为cDNA，并通过PCR和Sanger测序进行分析。设计的正向和反向引物分别与被大内含子分隔的不同外显子结合，以生成特异性的PCR产物（正向引物位于外显子1，反向引物位于外显子3）。

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NM_000117.3). The β-actin gene (NM_001101.3) was used as an internal control. Primer sequences and PCR conditions are available upon request.

NM_000117.3）。β-肌动蛋白基因（NM_001101.3）被用作内参。引物序列和PCR条件可应要求提供。

Results

结果

Pedigree consistent with X-linked inheritance of DCM

与DCM的X连锁遗传一致的家系

The study included 25 living members (six male and 19 female) of a Swedish family with a history of suspected X-linked DCM (Fig.

该研究包括瑞典一个有疑似X连锁扩张型心肌病（DCM）家族史的25名在世成员（6名男性和19名女性）（图。

). Additionally, the medical records of five deceased male family members were evaluated. In total, six male family members (five living, one deceased) met the diagnostic criteria for DCM. Their clinical phenotypes are described in Table

此外，还评估了五名已故男性家族成员的医疗记录。总计六名男性家族成员（五名在世，一名已故）符合扩张型心肌病（DCM）的诊断标准。他们的临床表型描述见表。

and Supplementary Table

和补充表格

。

Fig. 1: Pedigree showing the

图1：显示

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variant c.23C>G co-segregating with DCM in an X-linked manner, and suspected sudden cardiac death in male family members.

变体 c.23C>G 以 X 连锁方式与 DCM 共分离，并怀疑导致男性家族成员猝死。

The proband is designated with an arrow. Individuals diagnosed with DCM are denoted by black-filled symbols and males deceased due to suspected sudden cardiac death are denoted by gray-filled symbols. Genetic test results are shown by “+”, indicating hemizygosity or heterozygosity for the

先证者用箭头表示。确诊为DCM的个体用黑色填充符号表示，因疑似猝死而去世的男性用灰色填充符号表示。基因测试结果用“+”表示，表明半合子或杂合子状态。

EMD

经验模态分解

variant, or “−”, indicating that the

变体，或“-”，表示

EMD

经验模式分解

variant was not detected. In addition to “+” indicating a positive carrier test, female carriers are designated with a bull’s eye to show obligate carriers who did not undergo genetic testing.

变异未被检测到。除了“+”表示阳性携带者测试外，女性携带者用靶心标记，以显示那些未进行基因测试的必然携带者。

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Table 1 Clinical features of affected males hemizygous for the

表1 男性半合子患者的临床特征

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经验模态分解

variant c.23C>G.

变体 c.23C>G。

Full size table

全尺寸表格

The six-generation pedigree was consistent with the X-linked inheritance of DCM (Fig.

六代系谱与DCM的X连锁遗传一致（图。

), with the six affected males being related through non-symptomatic females and one male who died of suspected SCD at the age of 58. Family history revealed an additional five males who died unexpectedly between the ages 39 and 50.

），六个受影响的男性通过无症状的女性和一名58岁死于疑似SCD的男性相关联。家族史揭示了另外五名在39至50岁之间意外死亡的男性。

Missense variant in the

错义变异在

EMD

gene identified by genetic screening

通过基因筛选鉴定的基因

Genetic screening of two affected males, V:17 and V:29, using broad exome-based gene panels for DCM identified a missense variant in the

使用针对DCM的广泛外显子基因面板对两名受影响的男性（V:17 和 V:29）进行基因筛查，发现了一个错义变异。

EMD

经验模态分解

gene located on the X-chromosome, c. 23C>G, p.Ser8Trp (NM_000117.3). The

位于X染色体上的基因，c. 23C>G，p.Ser8Trp (NM_000117.3)。

EMD

经验模态分解

c.23C>G variant is predicted to result in substitution of serine for tryptophan in position 8 in the LEM domain of the emerin protein (Fig.

c.23C>G 变异预计会导致 emerin 蛋白的 LEM 结构域中第 8 位的丝氨酸被色氨酸取代（图。

2A, B

2A，B

). The position is conserved in mammals (Fig.

）。该位置在哺乳动物中是保守的（图。

) and there is a large physiochemical difference between serine and tryptophan (Grantham distance 177). Computational prediction tools provide conflicting interpretations of pathogenicity. It was absent in the Genome Aggregation Database version 4.1.0 as of 2023. At the time of genetic screening, the .

）丝氨酸和色氨酸之间存在较大的理化差异（Grantham 距离 177）。计算预测工具对致病性的解释存在冲突。截至 2023 年，在基因组聚合数据库版本 4.1.0 中未发现该变异。在进行基因筛查时，。

EMD

c.23C>G variant had not been previously reported but has since been submitted to ClinVar on one other occasion (ClinVar accession number VCV000222597.2).

c.23C>G 变异此前未被报道过，但后来已被提交至 ClinVar 一次（ClinVar 登录号 VCV000222597.2）。

Fig. 2: Characteristics of the

图 2：特性

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经验模态分解

variant c.23C>G, p.Ser8Trp and effect on

变体 c.23C>G，p.Ser8Trp 及其影响

EMD

经验模态分解

expression.

表达式。

Schematic diagram of emerin (P50402) showing the location of the N-terminal LEM domain and the C-terminal transmembrane (TM) domain. The location of the missense variant identified in the family, c.23C>G, p.Ser8Trp, is marked in red.

显示N端LEM结构域和C端跨膜（TM）结构域位置的emerin（P50402）示意图。家族中鉴定出的错义变异c.23C>G，p.Ser8Trp的位置用红色标记。

Illustration of the stereo view of the emerin LEM domain. The exchange from serine (Ser), marked in green in the wild type, to tryptophan (Trp), marked in red in the mutant, is shown.

Emerin LEM结构域的立体视图示意图。丝氨酸（Ser）在野生型中用绿色标记，色氨酸（Trp）在突变体中用红色标记，展示了从丝氨酸到色氨酸的替换。

C语言

Illustration showing the evolutionary conservation of the amino acid sequence in emerin. The position of the exchange, 8, is highlighted in yellow and the exchange from serine (S) to tryptophan (W) in the patient is marked in red.

显示emerin中氨基酸序列进化保守性的插图。交换位置8以黄色突出显示，患者中从丝氨酸（S）到色氨酸（W）的交换以红色标记。

Western blot analysis on skeletal muscle lysates from individual V:15 (patient) and two age-matched controls showing that emerin is almost completely absent and that no aberrantly spliced protein was detected in the patient compared to the control samples. The band corresponding to myosin heavy chain in the Coomassie-stained gel was used as loading control.

对来自个体V:15（患者）和两个年龄匹配对照的骨骼肌裂解物进行Western blot分析，结果显示emerin几乎完全缺失，并且与对照样本相比，在患者中未检测到异常剪接的蛋白。Coomassie染色凝胶中对应于肌球蛋白重链的条带被用作上样对照。

。

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经验模态分解

expression was investigated via reverse transcriptase polymerase chain reaction followed by PCR and Sanger on RNA extracted from skeletal muscle tissue from individual V:15 (patient), showing transcripts at near normal levels compared to two age-matched controls samples and no aberrant spliced transcripts were detected.

通过逆转录酶聚合酶链反应（RT-PCR）后接PCR和Sanger测序，对从个体V:15（患者）骨骼肌组织中提取的RNA进行了表达研究，结果显示转录水平接近正常，与两个年龄匹配的对照样本相比无异常剪接转录本检测到。

The β-actin gene was used as a loading control..

β-肌动蛋白基因被用作加载对照。

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Co-segregation of the

共分离

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经验模态分解

variant with DCM

带有DCM的变体

Targeted testing of the remaining four affected males, V:15, V:24, IV:4, and V:31, confirmed that all six were hemizygous for the

对其余四位受影响的男性，V:15、V:24、IV:4 和 V:31 进行了针对性检测，确认这六人均为半合子。

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经验模态分解

variant c.23C>G. Additionally, two male family members not harboring the

变体 c.23C>G。此外，两名未携带该变异的男性家族成员

EMD

经验模态分解

variant, V:2 and V:4, were confirmed to be unaffected by the age of 63 and 66 years, respectively. A segregation analysis was conducted for these male family members. Those deceased due to suspected SCD were not included since a diagnosis of underlying DCM could not be confirmed by a review of their medical records..

变异体V:2和V:4分别在63岁和66岁时被确认未受影响。对这些男性家族成员进行了分离分析。那些因疑似SCD去世的个体未被包括在内，因为通过审查他们的医疗记录无法确认潜在的DCM诊断。

The LOD score was estimated at 3.9, with values above 3.0 considered evidence of linkage between the

LOD 得分估计为 3.9，高于 3.0 的值被认为是两者之间存在连锁的证据。

EMD

locus and DCM. Calculations of the FLB yielded odds of 4617:1 in favor of causality. Since the exact penetrance, phenocopy rate and allele frequency were unknown, the analysis was repeated systematically with a range of more conservative values and constantly yielded odds above 2500:1 in favor of causality.

基因座与DCM。FLB的计算得出因果关系的支持几率为4617:1。由于确切的外显率、表型模拟率和等位基因频率未知，分析通过一系列更保守的值系统地重复进行，并持续得出高于2500:1的支持因果关系的几率。

The occurrence of other potential disease-causing variants in the .

其他潜在致病性变异在中的发生。

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经验模态分解

gene or linkage interval was excluded by manual examination of whole genome sequencing data in V:29.

通过手动检查V:29中的全基因组测序数据，排除了基因或连锁区间。

Emerin deficiency in cardiac and skeletal muscle

心脏和骨骼肌中的Emerin缺乏症

Myocardial samples were available from three affected males (two explanted hearts and one endomyocardial biopsy), and deltoid muscle samples from two affected males. Histopathological examination of the myocardial specimens showed cardiomyocyte hypertrophy and interstitial fibrosis (Table

心肌样本来自三名受影响的男性（两个移植的心脏和一个心内膜心肌活检），三角肌样本来自两名受影响的男性。心肌标本的组织病理学检查显示心肌细胞肥大和间质纤维化（表）。

; Fig.

图。

) consistent with DCM. Immunohistochemical staining for emerin was conducted on the myocardial specimens from the two explanted hearts, showing greatly reduced levels of emerin in nuclear envelopes of cardiomyocytes from the affected males, although not complete absence (Table

）与DCM一致。对两颗移植心脏的心肌标本进行了emerin的免疫组织化学染色，结果显示受影响男性心肌细胞核膜中的emerin水平显著降低，但并未完全缺失（表

; Fig.

图。

), when compared with a control sample (Fig.

)，与对照样本相比（图。

). In the specimen from the endomyocardial biopsy, immunostaining showed complete absence of emerin.

）。在心内膜心肌活检标本中，免疫染色显示emerin完全缺失。

Fig. 3: Histopathology and emerin immunostaining in samples collected from individual V:15 showing myopathy in cardiac muscle but not skeletal muscle while emerin immunostaining is markedly reduced in both tissues.

图3：从个体V:15收集的样本中显示心肌病在心肌中而不在骨骼肌中，而emerin免疫染色在这两种组织中均显著减少。

Bars correspond to 50 µm.

条形对应于50微米。

The myocardium of the explanted heart shows marked cardiomyocyte hypertrophy and increased interstitial connective tissue (hematoxylin and eosin staining).

移植心脏的心肌层显示出显著的心肌细胞肥大和间质结缔组织增加（苏木精和伊红染色）。

The skeletal muscle specimen collected at age 61 shows no signs of myopathy (hematoxylin and eosin staining).

在61岁时采集的骨骼肌标本显示无肌病迹象（苏木精和伊红染色）。

Heart explant showing markedly reduced emerin immunostaining of nuclear membranes.

心脏移植显示核膜的emerin免疫染色显著减少。

Heart specimen from control with normal immunostaining of nuclei.

正常免疫染色的对照组心脏标本。

Skeletal muscle specimen showing markedly reduced emerin immunostaining of nuclear membranes.

骨骼肌标本显示核膜的emerin免疫染色显著减少。

Skeletal muscle specimen from control with normal immunostaining of nuclei.

正常细胞核免疫染色的对照组骨骼肌样本。

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Greatly reduced emerin levels in the nuclear envelope of myocytes were also seen in the two available deltoid muscle samples (Table

在两个可用的三角肌样本中，也观察到肌细胞核膜中emerin水平大幅降低（表

; Fig.

图。

), when compared with a control (Fig.

），与对照组相比（图。

). To quantify the level of residual emerin, Western blot on skeletal muscle tissue from one affected male was conducted, resulting in levels of full-length emerin too low to quantify and only just visible by overexposure (Fig.

）。为了量化残留emerin的水平，对一名受影响男性骨骼肌组织进行了Western blot分析，结果发现全长emerin的水平太低而无法量化，仅在过度曝光下勉强可见（图。

二维

). cDNA analysis performed on the same sample confirmed that the

）。对同一样本进行的cDNA分析证实了

EMD

gene was transcribed and that mRNA isolated from skeletal muscle included the missense variant and showed no signs of aberrant splicing (Fig.

基因被转录，并且从骨骼肌中分离的mRNA包含错义变异，没有显示出异常剪接的迹象（图。

）。

Muscular dystrophy absent in all affected males

所有受影响的男性均未出现肌肉萎缩症。

There was no history of neuromuscular symptoms in any of the six affected males. The five living affected males underwent neuromuscular examination without findings of joint or skeletal muscle symptoms associated with EDMD1, at ages 61, 47, 37, 47, and 37. Serum-creatine kinase levels were normal. Deltoid muscle samples from the two affected males biopsied at ages 61 and 37 showed no evidence of myopathy on histopathological examination (Table .

六名受影响的男性均无神经肌肉症状的病史。五名在世的受影响男性分别在61岁、47岁、37岁、47岁和37岁时接受了神经肌肉检查，未发现与EDMD1相关的关节或骨骼肌症状。血清肌酸激酶水平正常。从两名分别在61岁和37岁时接受活检的受影响男性身上取得的三角肌样本，在组织病理学检查中未显示肌病的证据（见表）。

; Fig.

图。

). None of them reported limitations regarding strength or flexibility despite active lifestyles.

). 尽管生活方式活跃，但 none of them 报告了关于力量或灵活性的限制。

Cardiac phenotypes in affected males

受影响男性的心脏表型

The six affected males were diagnosed with DCM between ages 36 and 50, and three of them had progressed to end-stage heart failure and undergone heart transplantation. Cardiac conduction defects and ventricular arrhythmias were frequent, requiring implantable cardioverter defibrillator (ICD) in all five living affected males.

六名受影响的男性在36至50岁之间被诊断为DCM，其中三人已进展为终末期心力衰竭并接受了心脏移植。心脏传导缺陷和室性心律失常频发，所有五名在世的受影响男性均需植入心脏复律除颤器（ICD）。

In three, premature ventricular contractions (PVCs), non-sustained ventricular tachycardia (nsVT), or complete atrioventricular block were documented while ventricular dimensions were still normal, 2 to 9 years before they met the criteria for DCM. One of the affected males experienced malignant ventricular arrhythmia including several episodes of sustained ventricular tachycardia and one episode of ventricular fibrillation aborted by ICD shock.

在三例中，记录到室性早搏（PVCs）、非持续性室性心动过速（nsVT）或完全性房室传导阻滞，而此时心室尺寸仍然正常，发生在他们符合扩张型心肌病（DCM）诊断标准的2至9年前。其中一名受影响的男性经历了恶性室性心律失常，包括多次持续性室性心动过速发作和一次由ICD电击终止的室颤发作。

Left ventricular fibrosis was detected in the five living affected males examined, either by histopathological examination or visualized as late gadolinium enhancement (LGE) by CMRI. CMRI revealed both ischemic and non-ischemic distribution of LGE. Detailed information concerning CMRI findings in affected males is presented in Fig. .

通过对五名在世的受影响男性进行检查，发现左心室纤维化，要么通过组织病理学检查发现，要么通过心脏磁共振成像（CMRI）显示为晚期钆增强（LGE）。CMRI揭示了LGE的缺血性和非缺血性分布。有关受影响男性CMRI结果的详细信息见图。

4A–C, E–G

4A–C，E–G

, and Supplementary Table

，以及补充表格

。

Fig. 4: CMRI showing both ischemic and non-ischemic LGE patterns.

图4：CMRI显示缺血性和非缺血性LGE模式。

CMRI revealed partly similar delayed enhancement patterns in the short- (

CMRI 显示在短轴上部分相似的延迟增强模式 (

–

) and long-axis projections (

`) 和长轴投影 (`

–

) of individuals V:24 (

个体 V:24 (

，

), V:29 (

)，V:29（

，

), V:31 (

C语言

，

), and IV:11 (

），以及IV:11（

，

). A detailed description of all LGE findings (indicated by white and black arrows) can be found in Supplementary Table

). 所有LGE结果的详细描述（由黑白箭头指示）见补充表格。

. The left ventricle is denoted by LV and the right ventricle by RV.

左心室用LV表示，右心室用RV表示。

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Early-stage disease progression documented in one affected male

一名受影响男性记录了早期疾病进展

For one of the affected males, V:24, cardiac investigations were initiated due to the detection of ECG abnormalities at a routine medical check-up, which permitted monitoring of the early stages of disease progression for 9 years. The first 24-h ECG recording, at 29 years of age, showed up to 6880 (5.5%) PVCs as well as several short episodes of nsVT.

对于其中一名受影响的男性，V:24，由于在常规体检中检测到心电图异常，心脏检查得以启动，这使得疾病进展的早期阶段能够被监测长达9年。他在29岁时的首次24小时心电图记录显示有多达6880次（5.5%）室性早搏（PVCs），以及数次短暂的非持续性室性心动过速（nsVT）。

At the time, left ventricular dimensions were normal and systolic function only slightly decreased. However, subendocardial LGE was already present in the basal inferior and inferolateral segments, as well as subendocardial to transmural LGE in all apical segments including the apex. Thus, a purely ischemic LGE pattern was initially present.

当时，左心室尺寸正常，收缩功能仅略有下降。然而，基底段下侧壁和下外侧壁已经存在心内膜下LGE，所有心尖段包括心尖部也出现了从心内膜下到透壁的LGE。因此，最初呈现的是一种纯粹的缺血性LGE模式。

It was not until the age of 37 that he fulfilled the diagnostic criteria for DCM. His most recent CMRI, at age 38, showed severe left ventricular dilatation and systolic dysfunction with decreased ventricular motility. Furthermore, widespread LGE, including a non-ischemic LGE pattern was now visible (Fig. .

直到37岁，他才符合DCM的诊断标准。他在38岁时最近的一次心脏磁共振成像（CMRI）显示严重的左心室扩张和收缩功能障碍，心室运动能力下降。此外，现在可以看到广泛的晚期钆增强（LGE），包括非缺血性LGE模式（图）。

4A, E

4A，E

; Supplementary Table

；补充表格

）。

Cardiac phenotypes in female

女性心脏表型

EMD

variant carriers

变体携带者

Initially, there were no reported cases of DCM in female family members. Subsequent carrier testing in the family identified 17 females heterozygous for the

最初，女性家族成员中没有报告DCM病例。随后的家族携带者检测发现了17名女性为异型合子。

EMD

variant c.23C>G (four obligate carriers were not confirmed by genetic analysis) (Fig.

变体 c.23C>G（四个必有携带者未通过基因分析确认）（图。

). All female carriers were referred for cardiac monitoring. Thirteen females underwent combined cardiac ultrasonography and ECG, three only cardiac ultrasonography, and one only ECG. Ages ranged from 20 to 87 (median age 42).

）。所有女性携带者均被转诊进行心脏监测。十三名女性接受了心脏超声和心电图联合检查，三名仅接受心脏超声检查，一名仅接受心电图检查。年龄范围为20至87岁（中位年龄42岁）。

Cardiac monitoring yielded normal results for all female carriers, except one who at age 71 presented with frequent PVCs on ECG, while left ventricular end-diastolic diameter (42 mm) and ejection fraction (60%) were still normal. Three years later, at 74 years of age, she was diagnosed with heart failure due to DCM.

心脏监测对所有女性携带者的结果均正常，除了一名71岁时心电图显示频发室性早搏（PVCs）的女性，而她的左心室舒张末期内径（42毫米）和射血分数（60%）仍然正常。三年后，她在74岁时被诊断为因扩张型心肌病（DCM）导致的心力衰竭。

CMRI showed a dilated left ventricle with severely reduced systolic function, as well as widespread LGE (Fig. .

心脏磁共振成像显示左心室扩张，收缩功能严重减退，同时存在广泛的心肌延迟强化（图.

4D, H

4D，H

; Supplementary Table

；补充表格

). ECG showed frequent PVCs and nsVT and she received an ICD. She had no ischemic heart disease at coronary angiography and no neuromuscular symptoms.

心电图显示频发室性早搏和非持续性室性心动过速，她接受了ICD植入。冠状动脉造影显示她没有缺血性心脏病，也没有神经肌肉症状。

Discussion

讨论

This study provides new support for an association between the

本研究为以下关联提供了新的支持：

EMD

gene and DCM without muscular dystrophy, by presenting evidence of co-segregation in a large family, emerin deficiency in the myocardium and skeletal muscle, and normal neuromuscular examinations.

通过在一个大家庭中提供共分离证据、心肌和骨骼肌中的emerin缺乏以及正常的神经肌肉检查，研究了没有肌肉营养不良的基因和DCM。

Currently, the

当前，

EMD

经验模态分解

gene is only established as causative for DCM as a feature of EDMD1 [

基因仅被确定为DCM的致病因素，这是EDMD1的一个特征 [

，

]. However, DCM is rarely seen in EDMD1 [

]. 然而，DCM 在 EDMD1 中很少见 [

，

] and the cardiac phenotype is generally dominated by atrial pathology due to fibroadipose tissue remodeling of the atria. This results in atrial enlargement, predominantly of the right atrium, as well as atrial arrhythmias and cardiac conduction defects in the second and third decade [

] 心脏表型通常以心房病变为主，这是由于心房的纤维脂肪组织重构所致。这会导致心房扩大，主要在右心房，以及在第二和第三十年出现心房心律失常和心脏传导缺陷。[

，

], which progress to atrial stand-still in the fourth [

], 进展为第四度心房静止 [

]. In general, ventricular dilatation is less severe and precedes ventricular arrhythmias which develop in the sixth decade [

]. 一般来说，心室扩张较轻，并且先于心室心律失常，而心室心律失常则在第六个十年发展出来 [

，

]. Importantly, even in EDMD1 cases with mild or no neuromuscular symptoms, the cardiac phenotype is usually consistent, with predominantly atrial pathology [

]. 重要的是，即使在轻度或无神经肌肉症状的EDMD1病例中，心脏表型通常是一致的，主要表现为心房病理变化 [

，

Our results indicate that isolated DCM might be a separate

我们的结果表明，孤立的DCM可能是独立的

EMD

phenotype, as opposed to an instance of phenotypical variability. Firstly, neuromuscular symptoms were completely absent in all six males harboring the

表型，而不是表型变异性的实例。首先，所有六个携带该基因的男性完全没有神经肌肉症状。

EMD

地球移动距离

variant c.23C>G. Detailed neuromuscular examination in adulthood excluded even subtle signs of muscular dystrophy, which was emphasized by normal skeletal muscle morphology on histopathological examination. Secondly, the progression of cardiac symptoms in the six affected males differed from that of EDMD1.

变异c.23C>G。成年期详细的神经肌肉检查排除了即使是最细微的肌营养不良迹象，这在组织病理学检查中通过正常的骨骼肌形态得到了强调。其次，六名受影响男性的心脏症状进展与EDMD1不同。

The atrial pathology in the transplanted males, with predominantly left-sided dilatation and atrial fibrillation and flutter, was considered secondary to ventricular dilatation, and no early atrial manifestations were present in the three males who had not reached end-stage DCM..

移植男性患者的心房病理变化，主要表现为左侧扩张、心房颤动和扑动，被认为是继发于心室扩张，而尚未发展到终末期DCM的三位男性患者中未发现早期心房表现。

Instead, the cardiac phenotype was characterized by severe arrhythmogenic DCM with onset in the fourth or fifth decade in males. In one affected male, V:24, disease progression was documented 8 years before DCM diagnosis. He initially showed an ischemic LGE pattern on CMRI and a high frequency of PVCs and nsVT on ECG, several years before dilatation of the left ventricle, corresponding to non-dilated left ventricular cardiomyopathy preceding DCM development [.

相反，心脏表型的特征是严重的致心律失常性扩张型心肌病（DCM），男性通常在四五十岁发病。在一名受影响的男性（V:24）中，疾病进展在DCM诊断前8年已有记录。他最初在心脏磁共振成像（CMRI）上显示出缺血性晚期钆增强（LGE）模式，并在心电图（ECG）上出现高频室性早搏（PVCs）和非持续性室性心动过速（nsVT），这比左心室扩张早了数年，对应于在DCM发展之前的非扩张型左心室心肌病。

]. Given the ischemic pattern of LGE, early stages of disease progression could easily be misdiagnosed as ischemic cardiomyopathy, emphasizing the need for coronary angiography and for the clinician to be alert to differential diagnoses. Myocardial fibrosis was also seen in the two other affected males examined with CMRI, including septal intramural LGE which has been associated with greater arrhythmic risk than other patterns [.

]. 鉴于LGE的缺血模式，疾病进展的早期阶段很容易被误诊为缺血性心肌病，这强调了进行冠状动脉造影的必要性，并且临床医生需要警惕鉴别诊断。在另外两名接受CMRI检查的受影响男性中也观察到心肌纤维化，包括与其它模式相比具有更高心律失常风险的间隔壁内LGE [。

]. Furthermore, malignant ventricular arrhythmias were prominent in one male and the family history revealed several cases of suspected SCD.

]. 此外，一位男性患者中显著出现了恶性室性心律失常，且家族史显示有多例疑似SCD（猝死）病例。

Taken together, the cardiac phenotype in the family differed from that of classical EDMD1 and shared common features with

综合来看，该家族的心脏表型与典型的EDMD1有所不同，并且与以下特征有共同之处：

LMNA

-related DCM, such as cardiac conduction defects and ventricular arrhythmias preceding DCM development, which warrant consideration of early ICD implantation due to the risk of cardiac arrest. This notion is supported by results from a cohort study by Cannie et al., indicating that male

与DCM相关的情况，例如心脏传导缺陷和室性心律失常在DCM发展之前出现，这些情况由于存在心脏骤停的风险，值得考虑早期植入ICD。这一观点得到了Cannie等人的一项队列研究结果的支持，该研究表明男性

EMD

经验模态分解

variant carriers had a risk of malignant ventricular arrhythmias and heart failure similar to that of

变异携带者发生恶性室性心律失常和心力衰竭的风险与

LMNA

-variant carriers [

-变异携带者 [

]. The similarities with

]. 与以下内容的相似之处

LMNA

-related DCM are highlighted by the shared LGE pattern, with both ischemic [

-相关的DCM通过共享的LGE模式突出显示，包括缺血性[

] and non-ischemic distribution [

] 和非缺血性分布 [

], which can be helpful in recognizing this phenotype. These similarities might be explained by shared functions between emerin and lamin A/C, encoded by the

]，这有助于识别该表型。这些相似性可能由emerin和lamin A/C之间的共同功能解释，它们由以下基因编码：

LMNA

gene, which are binding partners in the nuclear envelope [

基因，它们是核膜中的结合伙伴 [

]. In addition, the cardiac features described here also overlap with other genetic arrhythmogenic cardiomyopathies with predominant left ventricular involvement, such as

]. 此外，这里描述的心脏特征也与其他以左心室受累为主的遗传性心律失常性心肌病重叠，例如

FLNC

-related cases.

相关案例。

EMD

经验模态分解

may therefore be considered along with

因此可以一并考虑

LMNA

，

FLNC

, and other similar genes for genetic screening in men presenting with the described pattern.

，并对呈现所述模式的男性进行其他类似基因的基因筛查。

In our study, the

在我们的研究中，

EMD

c.23C>G variant was shown to co-segregate with X-linked DCM based on an estimated LOD score above 3.0. To account for the risk of phenocopies, the calculation of FLB [

c.23C>G 变异被证明与 X 连锁 DCM 共分离，基于估计的 LOD 值大于 3.0。为了考虑表型模拟的风险，计算了 FLB [

] was also performed, yielding odds above 2500:1 in favor of causality. There are no generally accepted thresholds for FLB, although for single families 32:1 has been suggested as strong evidence for co-segregation [

] 也进行了分析，得出的因果关系支持率超过2500:1。对于FLB，目前没有普遍接受的阈值，尽管对于单个家族，32:1已被认为是共分离的强有力证据 [

] and previously applied to this method [

] 并且之前已应用于此方法 [

], which illustrates the strength of our evidence of co-segregation. Additionally, the

]，这说明了我们共分离证据的强度。此外，

EMD

经验模态分解

c.23C>T variant has been reported in three males from a cohort of EDMD1 with cardiac disease, further supporting causality although detailed phenotype information was not provided [

c.23C>T 变异已在一组伴有心脏疾病的 EDMD1 男性患者中的三人被报道，尽管没有提供详细的表型信息，但进一步支持了其因果关系 [

]. To our knowledge, the only previous evidence on co-segregation between

]. 据我们所知，之前关于共分离的唯一证据是

EMD

经验模态分解

and isolated DCM was of a founder-variant (c.77T > C) on Tenerife Island, where hemizygous males from 20 separate families displayed the same cardiac-specific phenotype of severe arrhythmogenic DCM as in our study [

而孤立的DCM是由特内里费岛上的一个创始人变异（c.77T > C）引起的，该岛20个不同家族中的半合子男性表现出与我们研究中相同的严重心律失常型DCM的心脏特异性表型。

，

By immunohistochemical staining for emerin, we demonstrated greatly reduced emerin levels in both myocardium and skeletal muscle, strongly indicating a defect in the

通过emerin的免疫组织化学染色，我们发现心肌和骨骼肌中的emerin水平显著降低，强烈表明存在缺陷。

EMD

经验模态分解

gene with an effect on the encoded protein in both tissues. Immunohistochemical detection of emerin deficiency in skeletal muscle is considered diagnostic for EDMD1 [

在两种组织中对编码蛋白均有影响的基因。骨骼肌中emerin缺乏的免疫组化检测被认为是EDMD1的诊断依据[

，

] and presents a clinically available method of investigating the functional effect of new

】并提出了一种临床上可用的研究新功能效应的方法

EMD

经验模式分解

variants.

变体。

While our study links

虽然我们的研究链接

EMD

经验模式分解

to isolated DCM, we expect

转换为孤立的DCM，我们预计

EMD

经验模态分解

variants to have a limited contribution to the overall disease burden. This was demonstrated in a recent large case-control study showing no difference in the distribution of

变异对整体疾病负担的贡献有限。这一点在最近的一项大型病例对照研究中得到了证明，该研究显示

EMD

经验模态分解

variants in DCM patients and controls [

DCM患者和对照组的变异 [

], which might be due to the rarity of

], 可能是由于

EMD

经验模式分解

variants [

变体 [

], and possibly accentuated by the autosomal dominant model of the study. Hence, further strong case-level data are necessary to determine the role of

]，并且可能被该研究的常染色体显性模型所加剧。因此，需要进一步的强有力病例数据来确定

EMD

in DCM.

在 DCM 中。

Of the 17 female carriers included in our study, one developed DCM after 70 years of age, with a similar presentation as her affected male relatives. Literature data on the penetrance of cardiac disease in females in the context of EDMD1 are limited. In one study of 30

在我们研究中包含的17名女性携带者中，其中一名在70岁以后发展为DCM，表现与其受影响的男性亲属相似。关于EDMD1背景下女性心脏疾病外显率的文献数据有限。在一项针对30例的研究中

EMD

经验模式分解

variant carriers, five had cardiac symptoms including atrioventricular block or atrial fibrillation [

变异携带者中有五人出现心脏症状，包括房室传导阻滞或心房颤动 [

]. In another study, nine of 21 female

]. 在另一项研究中，21名女性中有九名

EMD

经验模式分解

variant carriers developed cardiac disease at a median age of 58.6 [

变异携带者在中位年龄58.6岁时发展为心脏疾病 [

]. Taken together, the data suggest an increased risk of cardiac disease in female carriers, and cardiac monitoring may therefore be indicated.

]. 综合来看，数据表明女性携带者患心脏病的风险增加，因此可能需要进行心脏监测。

A limitation of this study was that the participants were characterized in the context of clinical care, and clinical examination, imaging, and immunohistochemical data were not consistently obtained across all patients. There are also limitations adhered to studying a single family, and to validate our findings they need to be confirmed in additional families..

本研究的一个局限性在于，参与者是在临床护理的背景下进行描述的，且并非所有患者都一致获取了临床检查、影像学和免疫组化数据。此外，研究单一家庭也存在局限性，为了验证我们的发现，还需要在其他家庭中进一步确认。

A further limitation is that our study does not provide an explanation for why the

另一个限制是我们的研究没有解释为什么

EMD

variant c.23C>G results in a cardiac-specific phenotype, despite equal emerin deficiency in cardiac and skeletal muscle. Given the greatly reduced, although not completely absent, levels of emerin in both tissues, small amounts of residual full-length emerin in the inner nuclear membrane of myocytes might be sufficient to rescue skeletal but not cardiac muscle function.

变异 c.23C>G 导致心脏特异性表型，尽管心肌和骨骼肌中emerin缺乏程度相同。鉴于两种组织中emerin的水平均显著降低，虽然并非完全缺失，肌细胞内核膜中少量残留的全长emerin可能足以恢复骨骼肌而非心肌功能。

However, studies of phenotype correlations with partial emerin deficiency are scarce and do not lend clear support for a cardiac-specific phenotype [.

然而，关于表型与部分emerin缺乏相关性的研究很少，并且不支持心脏特异性表型。

四十三

EMD

null variants, resulting in complete emerin deficiency, are the predominant cause of EDMD1 [

空变异导致完全的emerin缺乏，是EDMD1的主要原因 [

，

]. Further research is needed to understand by which mechanism the c.23C>G missense variant in

]. 需要进一步研究来理解c.23C>G错义变异通过何种机制在

EMD

经验模态分解

results in emerin deficiency, considering that the variant was not shown to alter gene transcription or splicing. To investigate if there are specific locations and sequence impacts in the

导致emerin缺乏，考虑到该变异未被证明会改变基因转录或剪接。为了研究是否存在特定的位置和序列影响在

EMD

经验模态分解

gene that may lead to isolated DCM, we performed a literature search with the aim to identify all

可能导致孤立性DCM的基因，我们进行了文献检索，旨在识别所有相关基因。

EMD

variants reported in association with predominant cardiac phenotypes (Supplementary Fig.

与主要心脏表型相关的变异（补充图）。

; Supplementary Table

；补充表格

). This literature review could only identify two

）。这篇文献综述仅能识别出两个

EMD

经验模态分解

variants associated with isolated DCM: the previously mentioned variant c.77T > C described in multiple families by Cuenca et al. [

与孤立性DCM相关的变异：Cuenca 等人描述的前述变异 c.77T > C 在多个家族中被提及。[

], and c.23C>T described in an individual case by Ishikawa et al. [

], 以及 Ishikawa 等人描述的个别案例中的 c.23C>T [

]. In addition, we are aware of one abstract describing a family with isolated DCM due to the variant c.65C > T [

]. 此外，我们了解到有一篇摘要描述了一个因变异 c.65C > T 而导致孤立性 DCM 的家族 [

]. These three variants and the c.23C>G variant in our study have all in common that they are located in the LEM domain of emerin, a conserved region between LEM-domain proteins with functions of importance for chromatin organization, regulation of gene expression, and nuclear assembly at mitosis [

]. 这三种变异和我们研究中的 c.23C>G 变异的共同点在于，它们都位于 emerin 的 LEM 结构域中，这是 LEM 结构域蛋白之间的一个保守区域，对染色质组织、基因表达调控以及有丝分裂时的核组装具有重要作用 [

，

]. Additionally, LEM-domain alterations in proteins encoded by

此外，由以下编码的蛋白质中的LEM结构域改变

LEMD2

and

和

TMPO

临时的

have recently been associated with arrhythmogenic cardiomyopathy with DCM combined with juvenile cataract [

最近与扩张型心肌病（DCM）合并青少年白内障相关联的病例已被报道。

], and isolated DCM [

], 和孤立的 DCM [

], respectively. Taken together, the limited evidence thus far suggests that the LEM domain might be of interest for further studies to elucidate the molecular basis for the suggested association between the

】，分别。综上所述，目前有限的证据表明，LEM 结构域可能为进一步研究阐明所建议的关联的分子基础提供兴趣点。

EMD

经验模式分解

gene and isolated DCM.

基因和孤立的DCM。

Conclusion

结论

The c.23C>G missense variant in

c.23C>G错义变异

EMD

经验模态分解

is associated with severe arrhythmogenic DCM without muscular dystrophy, thereby providing new evidence that

与无肌肉营养不良的严重心律失常性DCM相关，从而提供了新的证据表明

EMD

经验模态分解

is a causative gene for isolated DCM, as a separate phenotype from EDMD1. Hence,

是孤立性DCM的致病基因，与EDMD1作为不同的表型。因此，

EMD

经验模态分解

may be relevant to include in genetic screening for non-syndromic DCM or arrhythmogenic cardiomyopathy. Furthermore, the phenotypic similarities with

可能与非综合征型DCM或致心律失常性心肌病的基因筛查相关。此外，与表型相似的

LMNA

-related DCM might warrant early interventions to prevent SCD due to malignant ventricular arrhythmias.

相关的DCM可能需要早期干预，以预防恶性室性心律失常导致的SCD。

Data availability

数据可用性

The data supporting the findings of this study are available from the corresponding author upon reasonable request.

本研究结果的数据可在合理要求下由通讯作者提供。

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Acknowledgements

致谢

We would like to thank the staff at the Cardiogenetics Center and the Center for Neuromuscular Disorders at the Sahlgrenska University Hospital, Gothenburg, as well as colleagues at several cardiology departments in Region Västra Götaland, for managing the patients and providing important contributions to the clinical phenotyping.

我们谨感谢哥德堡萨尔格伦斯卡大学医院心脏遗传中心和神经肌肉疾病中心的工作人员，以及西约特兰地区多家心脏病科的同事，感谢他们管理患者并为临床表型分析提供了重要贡献。

We would also like to thank the family members for their participation in this study..

我们还要感谢家人参与这项研究。

Funding

资金筹集

This study was supported by grants from the Swedish Research Council (No 2021-02109 to AO), the Swedish Heart-Lung Foundation (No 20180236 to AO), the Swedish state under the agreement between the Swedish government and the county councils, the ALF agreement (ALFGBG-978196 to AO, ALFGBG-965898 to CHO, and ALFGBG-991828 to AG), and the Western Sweden Muscle Foundation (to AO and CHO).

本研究得到了瑞典研究委员会（2021-02109号资助给AO）、瑞典心肺基金会（20180236号资助给AO）、瑞典政府与郡议会之间的协议下瑞典国家的资助、ALF协议（ALFGBG-978196号资助给AO，ALFGBG-965898号资助给CHO，ALFGBG-991828号资助给AG）以及西瑞典肌肉基金会（资助给AO和CHO）的支持。

Open access funding provided by University of Gothenburg..

由哥德堡大学提供开放获取资助。

Author information

作者信息

Authors and Affiliations

作者与所属机构

Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden

瑞典哥德堡萨尔格伦斯卡大学医院临床遗传学与基因组学系

Linda Bulmer, Johan Hallin & Anders Gummesson

琳达·布尔默、约翰·哈林和安德斯·古梅松

Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

瑞典哥德堡大学萨尔格伦斯卡学院医学研究所分子与临床医学系

Linda Bulmer, Charlotta Ljungman, Pia Dahlberg, Christian L. Polte & Anders Gummesson

琳达·布尔默、夏洛塔·容格曼、皮娅·达尔伯格、克里斯蒂安·L·波尔特、安德斯·古梅松

Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden

瑞典哥德堡萨尔格伦斯卡大学医院心脏病科

Charlotta Ljungman & Pia Dahlberg

夏洛塔·容曼和皮娅·达尔伯格

Departments of Clinical Physiology and Radiology, Sahlgrenska University Hospital, Gothenburg, Sweden

瑞典哥德堡萨尔格伦斯卡大学医院临床生理学与放射科部门

Christian L. Polte

克里斯蒂安·L·波尔特

Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

瑞典哥德堡大学萨尔格伦斯卡学院生物医学研究所临床检验医学系

Carola Hedberg-Oldfors & Anders Oldfors

卡罗拉·赫德伯格-奥尔福斯和安德斯·奥尔福斯

Authors

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Linda Bulmer

琳达·布尔默

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Charlotta Ljungman

夏洛塔·容曼

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Johan Hallin

约翰·哈林

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Pia Dahlberg

皮娅·达尔伯格

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Christian L. Polte

克里斯蒂安·L·波尔特

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Carola Hedberg-Oldfors

卡罗拉·赫德伯格-奥尔福尔斯

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Anders Oldfors

安德斯·奥尔德福什

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Anders Gummesson

安德斯·古姆森

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Contributions

贡献

LB: manuscript drafting, data collection, segregation analysis. CL and PD: cardiological data interpretation. CLP: interpretation of CMRI examinations, figure preparation. JH: interpretation of whole genome sequencing data, segregation analysis. CHO: cDNA analysis, figure preparation. AO: histopathological examination, immunohistochemical analysis, Western blot analysis, figure preparation.

LB：手稿起草、数据收集、分离分析。CL和PD：心脏数据解读。CLP：CMRI检查的解读、图表准备。JH：全基因组测序数据的解读、分离分析。CHO：cDNA分析、图表准备。AO：组织病理学检查、免疫组化分析、蛋白质印迹分析、图表准备。

AG: conceiving of study, supervision. All authors: manuscript editing and approval..

AG：构思研究、监督。所有作者：稿件编辑和批准。

Corresponding author

通讯作者

Correspondence to

致信给

Anders Gummesson

安德斯·古姆森

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Ethics declarations

伦理声明

Competing interests

利益冲突

The authors declare no competing interests.

作者声明不存在竞争性利益。

Ethical approval

伦理批准

The study conforms to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the Swedish Ethical Review Agency (Dnr 2022-02542-01).

本研究符合1975年《赫尔辛基宣言》的伦理准则，并获得了瑞典伦理审查局的批准（批准号：2022-02542-01）。

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Bulmer, L., Ljungman, C., Hallin, J.