Based on the article “Utility and Limitations of Genetic Testing in the Routine Care of Cardiovascular Disease Patients in a General Hospital” (Tomidokoro et al., Int Heart J 2025), the following key shortcomings or limitations of clinical genetic testing are identified:根据《综合医院心血管疾病常规诊疗中基因检测的效用与局限性》（Tomidokoro 等，国际心脏杂志 2025）一文，临床基因检测存在以下主要缺陷或局限性：

1. Low and Variable Diagnostic Yield1. 诊断率低且波动大

• Diagnostic yields for different cardiovascular diseases (CVDs) were modest and variable, ranging from 14% to 40%, even in clinically suspected cases:即使对临床疑似病例，不同心血管疾病（CVD）的诊断率也仅为 14%至 40%，表现平平且差异显著：

  • FH: 24% yield, improved to 70% with strict criteria.家族性高胆固醇血症（FH）：诊断率为 24%，采用严格标准后可提升至 70%。

  • HCM: 12–30% yield, dependent on selection criteria and variant interpretation.肥厚型心肌病（HCM）：检出率 12-30%，取决于选择标准和变异解读。

  • Arrhythmia: 14% yield.心律失常：检出率 14%。

  • Aortic aneurysm/dissection: 40%, but based on only 5 cases.主动脉瘤/夹层：检出率 40%，但仅基于 5 例病例。

• Implication: Many patients may not receive a definitive genetic diagnosis, limiting the utility of testing as a routine diagnostic tool.启示：许多患者可能无法获得明确的基因诊断，这限制了基因检测作为常规诊断工具的应用价值。

2. Impact of Patient Selection and Pretest Criteria2. 基因检测的局限性

• The diagnostic success is heavily influenced by pretest clinical criteria, such as:诊断成功率很大程度上取决于检测前的临床标准，例如：

  • Family history.家族病史。

  • Disease severity (e.g., untreated LDL-C >250 mg/dL for FH).疾病严重程度（例如家族性高胆固醇血症患者未经治疗的 LDL-C>250 毫克/分升）。

  • Predictive scoring (e.g., Mayo Clinic HCM genotype prediction score).预测性评分（如梅奥诊所 HCM 基因型预测评分）。

• Implication: Without careful patient selection, testing may yield low clinical utility and cost-effectiveness.影响：若未谨慎选择患者，检测可能临床效用和成本效益较低。

3. Difficulty Interpreting Variants of Uncertain Significance (VUS)3. 意义未明变异（VUS）的解读困难

• A large portion of missense variants are classified as VUS, particularly in HCM:大部分错义突变被归类为意义未明变异(VUS)，尤其在肥厚型心肌病中：

  • Reduced penetrance and genetic heterogeneity hinder pathogenicity determination.外显率降低和遗传异质性阻碍了致病性判定。

  • Many variants are “private” mutations (unique to one family), complicating assessment.许多变异属于"私有"突变（仅某个家族独有），这使得评估工作变得复杂。

  • In silico prediction tools have limited predictive power and require careful calibration (e.g., REVEL scores).计算机预测工具的预测能力有限，需要谨慎校准（如 REVEL 评分）。

• Implication: The uncertainty in variant interpretation can limit actionable outcomes from genetic testing.影响：变异解读的不确定性可能限制基因检测的可操作性结果。

4. Ethnic Disparities and Lack of Ancestry-Specific Databases4. 种族差异与缺乏特定祖先数据库

• Variant interpretation is more difficult in non-European populations (e.g., Japanese), where:对非欧洲人群（如日本人）的变异解读更为困难，原因在于：

  • Many variants are underrepresented in public databases like ClinVar.许多变异在 ClinVar 等公共数据库中代表性不足。

  • Higher rate of VUS due to limited population-specific data.特定人群数据有限导致 VUS 检出率较高。

• Implication: Current databases and knowledge bases are biased, reducing the accuracy of interpretation in underrepresented populations.影响：现有数据库和知识库存在偏差，导致在代表性不足的人群中解读准确性降低。

5. Small Sample Sizes and Limited Power5. 样本量小且统计效力不足

• The study involved a relatively small number of patients (e.g., only 43 with HCM), which:该研究涉及的病例数量相对较少（例如仅 43 例 HCM 患者），这：

  • Limits statistical power and generalizability.限制了统计功效和普适性。

  • Restricts the ability to detect significant associations, especially for polygenic risk scores (PRS).限制了检测显著关联的能力，特别是对于多基因风险评分（PRS）。

• Implication: Larger, population-level studies are needed to validate findings and build robust predictive models.启示：需要开展更大规模的群体研究来验证发现并建立稳健的预测模型。

6. Secondary Findings and Ethical Uncertainty6. 二次发现与伦理不确定性

• Secondary findings were detected in 2.8% of controls, some without corresponding phenotypes.在 2.8%的对照组中检测到次要发现，其中部分未表现出相应表型。

• Raises ethical challenges:引发伦理挑战：

  • How to handle findings not related to the primary indication?如何处理与主要适应症无关的检测结果？

  • Whether and how to disclose them to patients?是否以及如何向患者披露这些信息？

• Implication: Needs careful counseling and clear institutional guidelines.影响：需要谨慎的咨询和明确的机构指导方针。

7. Limited Functional Validation7. 功能验证有限

• The study acknowledges that functional assays for variant validation (e.g., in vivo or cell-based models) are scarce, especially for cardiomyopathy variants.该研究承认，用于变异验证的功能性检测（如体内或细胞模型）十分稀缺，尤其对于心肌病相关变异而言。

• Implication: Weakens the confidence in pathogenicity calls, particularly for novel variants.影响：削弱了对致病性判断的信心，尤其针对新型变异体。

8. Cost-Effectiveness Not Established8. 成本效益尚未明确

• The study does not evaluate cost-effectiveness, but notes it as a prerequisite before introducing broader testing.该研究未评估成本效益，但指出这是推广更广泛检测前需满足的先决条件。

• Implication: Without clear economic value, routine implementation may face barriers from payers and healthcare systems.影响：若缺乏明确的经济价值，常规实施可能面临支付方和医疗体系的阻碍。

9. Lack of Standardization for Interpretation Criteria9. 解读标准缺乏统一性

• There is no universal standard for interpreting variants across diseases or for different clinical purposes (diagnostic vs. predictive).目前尚无统一标准来解读不同疾病或不同临床目的（诊断性与预测性）的基因变异。

• Differences in criteria (e.g., ACMG/AMP 2015 vs. ClinGen 2022 updates) significantly affect yield.标准差异（如 ACMG/AMP 2015 与 ClinGen 2022 更新版）会显著影响检出率。

• Implication: Confusion and inconsistency may arise in clinical settings.临床环境中可能出现混淆与不一致的情况。

10. PRS Has Limited Current Clinical Utility10. 多基因风险评分目前临床实用性有限

• Although promising, polygenic risk scores (PRS) are not yet:尽管前景广阔，但多基因风险评分（PRS）目前仍存在不足：

  • Fully validated in non-European populations.已在非欧洲人群中得到充分验证。

  • Clinically accurate enough for decision-making.临床准确性足以支持决策。

• Implication: PRS needs refinement and validation before routine use.启示：多基因风险评分在常规应用前仍需改进和验证。

Conclusion结论

While genetic testing offers valuable diagnostic insights in cardiovascular diseases, it is currently limited by diagnostic yield, interpretive uncertainty (especially VUS), lack of ancestry-matched data, ethical complexities, and insufficient cost-effectiveness evidence. Clinicians should apply testing judiciously and in combination with rigorous clinical criteria and predictive tools.尽管基因检测为心血管疾病提供了有价值的诊断依据，但目前仍存在诸多局限：诊断检出率有限、结果解读存在不确定性（特别是意义未明的变异）、缺乏种族匹配数据、伦理问题复杂以及成本效益证据不足。临床医生应审慎应用基因检测，并需结合严格的临床标准和预测工具进行综合评估。

According to the paper “Utility and Limitations of Genetic Testing in the Routine Care of Cardiovascular Disease Patients in a General Hospital”, the diagnostic rate of genetic testing for familial hypercholesterolemia (FH) improves significantly when strict clinical criteria are applied because these criteria more accurately enrich the tested population for true monogenic FH cases. The key reasons are as follows:根据论文《综合医院心血管疾病患者常规诊疗中基因检测的效用与局限性》所述，对家族性高胆固醇血症（FH）进行基因检测时，若采用严格的临床标准，诊断率会显著提升。这是因为这些标准能更精准地筛选出真正单基因型 FH 病例的检测人群。主要原因如下：

1. Higher Pretest Probability in Strictly Defined Cases1. 严格限定病例中的较高检测前概率

• When strict diagnostic criteria are applied—such as:当采用严格的诊断标准时——例如：

  • LDL-C ≥ 180 mg/dL in untreated patients with tendon xanthomas and a family history, or未经治疗患者 LDL-C≥180 mg/dL 且伴有肌腱黄色瘤及家族史，或

  • LDL-C ≥ 250 mg/dL in those without xanthomas or family history—LDL-C 水平≥250 mg/dL 且无黄瘤或家族史者——
    the likelihood of detecting a pathogenic variant increases.检测到致病性变异的可能性增加。

• In the study:研究中：

  • The baseline diagnostic yield in phenotypically diagnosed FH cases was 24%.经表型诊断为家族性高胆固醇血症病例的基线诊断率为 24%。

  • When applying the Japan Atherosclerosis Society’s 2022 strict criteria, the diagnostic yield increased to 70%.当采用日本动脉硬化学会 2022 年严格标准时，诊断率提升至 70%。

2. Greater Correlation Between Phenotype Severity and Genotype2. 表型严重程度与基因型之间的更高相关性

• Patients meeting strict criteria typically have more severe hypercholesterolemia, which correlates with a higher likelihood of monogenic FH.符合严格标准的患者通常患有更严重的高胆固醇血症，这与单基因家族性高胆固醇血症（FH）的较高可能性相关。

• The study found that LDL-C levels in GT(+) individuals (332.0 ± 32.8 mg/dL) were significantly higher than in GT(−) individuals (203.0 ± 33.6 mg/dL, P = 1.4 × 10⁻⁶), supporting the notion that genetic FH causes more extreme biochemical phenotypes.研究发现，GT(+)个体的 LDL-C 水平（332.0 ± 32.8 mg/dL）显著高于 GT(−)个体（203.0 ± 33.6 mg/dL，P = 1.4 × 10⁻⁶），这一结果支持遗传性家族性高胆固醇血症会导致更极端生化表型的观点。

3. Avoidance of Phenocopies and Polygenic Hypercholesterolemia3. 避免表型模拟与多基因性高胆固醇血症

• When looser criteria are used (e.g., relying solely on LDL-C ≥ 190 mg/dL), the tested population may include many individuals with polygenic or lifestyle-related hypercholesterolemia, not monogenic FH.当采用较宽松的标准时（例如仅依据 LDL-C≥190 mg/dL），受检人群中可能包含许多多基因性或生活方式相关的高胆固醇血症患者，而非单基因型家族性高胆固醇血症患者。

• The paper cites a study showing that only 1.7% of individuals from the general population with LDL-C ≥ 190 mg/dL had pathogenic FH variants.该论文引用的一项研究表明，在低密度脂蛋白胆固醇≥190 mg/dL 的普通人群中，仅 1.7%携带家族性高胆固醇血症致病性变异。

Conclusion结论

Applying strict clinical diagnostic criteria for FH increases the prevalence of true monogenic FH among those selected for genetic testing, thereby raising the diagnostic yield. This approach reduces false negatives, limits testing in phenocopies, and ensures efficient use of resources.对家族性高胆固醇血症（FH）采用严格的临床诊断标准，可提高基因检测人群中真正单基因 FH 的检出率，从而提升诊断效能。该方法能减少假阴性结果，避免对表型类似病例进行不必要的检测，确保资源的高效利用。

The conclusion that "without careful patient selection, testing may yield low clinical utility and cost-effectiveness" is supported throughout the paper by multiple pieces of evidence. These demonstrate that the diagnostic yield of genetic testing varies greatly depending on how carefully patients are selected based on clinical criteria. The most relevant examples and data from the paper include:论文中多处证据支持"若缺乏谨慎的患者筛选，检测可能临床效用低下且成本效益不佳"这一结论。这些证据表明，根据临床标准筛选患者的严谨程度会极大影响基因检测的诊断检出率。文中最具相关性的例证和数据包括：

1. Familial Hypercholesterolemia (FH): Detection Rate Increases with Strict Criteria1. 家族性高胆固醇血症（FH）：严格标准下检出率提升

• General FH cases (broad inclusion): Detection rate = 24%.普通家族性高胆固醇血症病例（广泛纳入标准）：检出率=24%。

• With strict criteria (e.g., untreated LDL-C ≥ 250 mg/dL without xanthoma, or ≥180 mg/dL with xanthoma and family history): Detection rate = 70%.采用严格标准时（如未经治疗的 LDL-C≥250mg/dL 且无黄色瘤，或≥180mg/dL 伴有黄色瘤及家族史）：检出率=70%。

• The paper states:该论文指出：

  “The diagnostic yield ... could have increased to 70% if strict diagnostic criteria for FH ... were adopted”."如果采用严格的家族性高胆固醇血症（FH）诊断标准...诊断率本可提升至 70%。"

• Interpretation: Testing broadly defined FH cases yields many false negatives (low utility), while strict pre-selection enriches for monogenic cases, improving yield and value.解读：对广泛定义的家族性高胆固醇血症病例进行检测会产生许多假阴性（实用性低），而严格的预筛选可富集单基因病例，从而提高检出率和价值。

2. Hypertrophic Cardiomyopathy (HCM): Pretest Probability Affects Yield2. 肥厚型心肌病（HCM）：检测前概率影响检出率

• HCM detection rate varied from 12% to 30% depending on:HCM 检出率介于 12%至 30%之间，具体取决于：

  • Family history.家族病史。

  • LV wall thickness (≥15 mm vs. borderline).左心室壁厚度（≥15 毫米 vs. 临界值）

  • Use of prediction tools (e.g., Mayo Clinic genotype score).使用预测工具（如梅奥诊所基因型评分）。

• The study found that 86% of their HCM patients fell into low-scoring groups (−1 to 1) in the Mayo Clinic pretest prediction score, explaining the lower overall yield.研究发现，86%的肥厚型心肌病患者在梅奥诊所预测评分系统中属于低分组（-1 至 1 分），这解释了整体检出率较低的原因。

• The authors note:作者指出：

  “The application of more stringent criteria ... may have slightly increased the diagnosis rate of HCM”."采用更严格的标准...可能略微提高了 HCM 的诊断率"

• Interpretation: Without selecting patients based on phenotype severity or prediction scores, genetic testing is less effective and potentially wasteful.解读：若不根据表型严重程度或预测评分筛选患者，基因检测的效果会降低，并可能造成资源浪费。

3. Atrial Fibrillation (AF): Low Yield Without Selection3. 房颤（AF）：未经筛选检测价值低

• In early-onset AF cases, no pathogenic variants were found except for a few rare variants of uncertain significance.在早发性房颤病例中，除少数意义未明的罕见变异外，未发现致病性变异。

• However, applying polygenic risk scores (PRS) helped identify a subset with increased risk, especially those with onset before age 50.然而，应用多基因风险评分（PRS）有助于识别出风险较高的亚群，尤其是 50 岁前发病的患者。

• The authors conclude:作者总结道：

  “Validation of the findings in the age-group analysis is needed to draw meaningful conclusions” and stress careful subgroup selection for PRS to be useful."需对年龄组分析结果进行验证才能得出有意义的结论"，并强调必须谨慎选择亚组才能使多基因风险评分发挥效用。

• Interpretation: Genetic testing for AF without age- or risk-based stratification has low yield and questionable cost-effectiveness.解读：在不考虑年龄或风险分层的情况下，对房颤进行基因检测的检出率较低，且成本效益存疑。

4. General Statement in Discussion4. 讨论部分的一般性陈述

• The authors explicitly warn:作者明确警告：

  “When considering the cost-effectiveness of a genetic test, the ordering clinicians ... must be aware of relevant technical limitations, factors affecting the diagnostic capability ..., and challenges in data interpretation”."在评估基因检测的成本效益时，开具检测的临床医生...必须了解相关技术局限性、影响诊断能力的因素...以及数据解读中的挑战。"

Summary Table of Supporting Evidence支持性证据汇总表

Conclusion结论

The paper provides compelling empirical evidence that careful patient selection based on strict clinical criteria or predictive scores substantially improves the diagnostic yield of genetic testing for cardiovascular diseases. Without this stratification, the testing process may return low diagnostic value, resulting in poor clinical utility and reduced cost-effectiveness.该研究提供了有力实证，表明基于严格临床标准或预测评分的谨慎患者筛选能显著提高心血管疾病基因检测的诊断率。若缺乏这种分层策略，检测过程可能诊断价值低下，导致临床效用不佳且成本效益降低。