Patterns of mosaicism for sequence and copy-number variants discovered through clinical deep sequencing of disease-related genes in one million individuals.
Patterns of mosaicism for sequence and copy-number variants discovered through clinical deep sequencing of disease-related genes in one million individuals.
复制标题
通过对一百万人的疾病相关基因进行临床深度测序发现序列和拷贝数变异的嵌合模式。
DOI：
10.1016/j.ajhg.2023.02.013
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发表时间：
2023
影响因子：
9.8
通讯作者：
Burnett,
中科院分区：
文献类型：
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作者：
Truty,Rebecca;Rojahn,Susan;Ouyang,Karen;Kautzer,Curtis;Kennemer,Michael;Pineda-Alvarez,Daniel;Johnson,Britt;Stafford,Amanda;Basel-Salmon,Lina;Saitta,Sulagna;Slavotinek,Anne;Chandrasekharappa,SettaraC;Suarez,CarlosJose;Burnett,
受孕后出现的DNA变异可以显示出镶嵌性，在组织中的存在和程度不同。嵌合体变异已报告在孟德尔疾病，但进一步的调查是必要的，以广泛了解其发病率，传播和临床影响。疾病相关基因中的嵌合致病性变体可能导致在严重程度、临床特征或疾病发作时间方面的非典型表型。使用高深度测序，我们研究了100万无关个体的结果，这些个体被转介进行近1,900个疾病相关基因的基因检测。我们在近5，700名个体中观察到5，939个镶嵌序列或基因内拷贝数变异，分布在509个基因中，约占队列中分子诊断的2%。癌症相关基因具有最多的嵌合变体，并显示出年龄特异性富集，部分反映了老年人的克隆造血。我们还观察到许多与早发性疾病相关的基因中的嵌合变体。在用于生殖载体筛查的基因分析中观察到额外的嵌合体变体，或与低突变率的显性疾病相关，这对解释其临床意义提出了挑战。当我们控制克隆造血的潜在参与时，大多数嵌合体变体在年轻个体中富集，并且比老年个体中存在更高的水平。此外，与嵌合体的个人表现出较晚的疾病发作或较轻的表型比个人与非嵌合体变异在相同的基因。总的来说，本研究中确定的大量变异、疾病相关性和年龄特异性结果的概要扩大了我们对嵌合DNA变异对诊断和遗传咨询的影响的理解。
DNA variants that arise after conception can show mosaicism, varying in presence and extent among tissues. Mosaic variants have been reported in Mendelian diseases, but further investigation is necessary to broadly understand their incidence, transmission, and clinical impact. A mosaic pathogenic variant in a disease-related gene may cause an atypical phenotype in terms of severity, clinical features, or timing of disease onset. Using high-depth sequencing, we studied results from one million unrelated individuals referred for genetic testing for almost 1,900 disease-related genes. We observed 5,939 mosaic sequence or intragenic copy number variants distributed across 509 genes in nearly 5,700 individuals, constituting approximately 2% of molecular diagnoses in the cohort. Cancer-related genes had the most mosaic variants and showed age-specific enrichment, in part reflecting clonal hematopoiesis in older individuals. We also observed many mosaic variants in genes related to early-onset conditions. Additional mosaic variants were observed in genes analyzed for reproductive carrier screening or associated with dominant disorders with low penetrance, posing challenges for interpreting their clinical significance. When we controlled for the potential involvement of clonal hematopoiesis, most mosaic variants were enriched in younger individuals and were present at higher levels than in older individuals. Furthermore, individuals with mosaicism showed later disease onset or milder phenotypes than individuals with non-mosaic variants in the same genes. Collectively, the large compendium of variants, disease correlations, and age-specific results identified in this study expand our understanding of the implications of mosaic DNA variation for diagnosis and genetic counseling.