结构性拷贝数增加的解读标准:来自美国医学遗传学与基因组学学会(ACMG)和临床基因组资源中心(ClinGen)的建议

基因组拷贝数变异(copy number variants,CNVs)是人类遗传病的重要致病原因,也是儿科神经发育障碍和多种先天性畸形、产前胎儿超声异常等疾病的必检项目。尽管CNVs的检测技术日趋成熟,但其临床意义的解读却仍不够规范。2020年,美国医学遗传学与基因组学学会(American College of Medical Genetics and Genomics,ACMG)和临床基因组资源中心(Clinical Genome Resource,ClinGen)基于循证原则,采用定量计分,就结构性(constitutional)基因组CNVs的致病性评估和临床报告制定了推荐指南。本文对该指南中涉及拷贝数增加的分析要点进行了详细的解读,并利用6个不同类型的案例来展示如何正确使用打分系统,以鼓励临床诊断实验室根据这一专业标准对检测出的基因组变异开展解读、报告,以期提升遗传诊断报告中拷贝数增加临床评估的正确性和一致性。

Standards for the interpretation of constitutional copy number gain:Recommendation from the American College of Medical Genetics and Genomics(ACMG)and Clinical Genome Resource(ClinGen)

Copy number variants(CNVs)are common causes of human genetic diseases.CNVs detection has become a routine component of genetic testing,especially for pediatric neurodevelopmental disorders,multiple congenital abnormalities,prenatal evaluation of fetuses with structural anomalies detected by ultrasound.Although the technologies for CNVs detection are continuously improving,the interpretation is still challenging,with significant discordance across different laboratories.In 2020,the American College of Medical Genetics and Genomics(ACMG)and the Clinical Genome Resource(ClinGen)developed a guideline for the interpreting and reporting of constitutional copy number variants,which introduced a quantitative,evidence-based scoring framework.Here,we detailed the key points of interpreting the copy number gain based on the guideline,used six examples of different categories to illuminate the scoring process and principles.We encourage a professional understanding and application of this guideline for the detected copy number gains in China in order to further improve the clinical evaluation accuracy and consistency across different laboratories.