Patterns of mosaicism for sequence and copy-number variants discovered through clinical deep sequencing of disease-related genes in one million individuals

Rebecca Truty, Susan Rojahn, Karen Ouyang, Curtis Kautzer, Michael Kennemer, Daniel Pineda-Alvarez, Britt Johnson, Amanda Stafford, Lina Basel-Salmon, Sulagna Saitta, Anne Slavotinek, Settara C. Chandrasekharappa, Carlos Jose Suarez, Leslie Burnett, Robert L. Nussbaum, Swaroop Aradhya*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)551-564
Number of pages14
JournalAmerican Journal of Human Genetics
Issue number4
StatePublished - 6 Apr 2023


  • allele balance
  • depth of coverage
  • germline
  • hereditary disease
  • mosaicism
  • next generation sequencing validation


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