在受孕后出现的DNA变异可以呈现出色斑现象，在组织中的存在和程度也会有所差异。色斑的变异在孟德尔遗传病中有所表现，但需要进一步研究以广泛了解它们的发生率、传播和临床影响。疾病相关基因中的色斑致病变异可能会导致相对于严重程度、临床特征或疾病发病时间而言的非典型表型。我们使用高深度测序，研究了近1900个疾病相关基因的遗传测试结果，包括100万个无关个体。我们发现在近5700个个体中分布了5939个色斑序列或基因内拷贝数异质，分布在509个基因中，约占队列中分子诊断的2%。与癌症相关的基因具有最多的色斑变异，并显示出年龄特异性富集，部分反映出年长个体中克隆性造血作用。我们还在与早发性疾病相关的基因中观察到许多色斑变异。在对克隆性造血参与的潜在影响进行控制后，大多数色斑变异在年轻人中富集，并且比年长人存在更高的水平。此外，患有色斑的个体表现出的疾病发生时间较晚或表型较轻，与同一基因的非色斑变异个体相比。总之，这项研究中涉及的大量变异、疾病相关性和年龄特异性结果扩展了我们对色斑DNA变异对诊断和遗传咨询的影响的理解。版权所有© 2023美国人类遗传学会。保留所有权利。

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 to 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.Copyright © 2023 American Society of Human Genetics. All rights reserved.