TY - JOUR
T1 - Patterns of mosaicism for sequence and copy-number variants discovered through clinical deep sequencing of disease-related genes in one million individuals
AU - Truty, Rebecca
AU - Rojahn, Susan
AU - Ouyang, Karen
AU - Kautzer, Curtis
AU - Kennemer, Michael
AU - Pineda-Alvarez, Daniel
AU - Johnson, Britt
AU - Stafford, Amanda
AU - Basel-Salmon, Lina
AU - Saitta, Sulagna
AU - Slavotinek, Anne
AU - Chandrasekharappa, Settara C.
AU - Suarez, Carlos Jose
AU - Burnett, Leslie
AU - Nussbaum, Robert L.
AU - Aradhya, Swaroop
N1 - Publisher Copyright:
© 2023 American Society of Human Genetics
PY - 2023/4/6
Y1 - 2023/4/6
N2 - 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.
AB - 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.
KW - allele balance
KW - depth of coverage
KW - germline
KW - hereditary disease
KW - mosaicism
KW - next generation sequencing validation
UR - http://www.scopus.com/inward/record.url?scp=85151438854&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2023.02.013
DO - 10.1016/j.ajhg.2023.02.013
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C2 - 36933558
AN - SCOPUS:85151438854
SN - 0002-9297
VL - 110
SP - 551
EP - 564
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 4
ER -