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Increased mutation accumulation during fetal development in Down syndrome

Children with Down syndrome (DS) show a high incidence of leukemia, which is preceded by transient myeloproliferative disorder (TMD) in neonates. TMD is characterized by mutations in GATA1 that accumulate during fetal development, indicating that additional mutagenesis is required for leukemogenesis. Abnormalities in chromosome numbers can result in a mutator phenotype. However, it is unknown whether a trisomy of chromosome 21 (T21) results in enhanced mutation accumulation during human development. Here, we determined the mutational consequences of a constitutive T21 in DS fetuses compared to disomy 21 cells (D21) of D21 fetuses. We found that D21 fetal HPSCs had a higher somatic mutation rate compared to healthy adults HSPCs. Moreover, we observed an increase in somatic mutation load in T21 cells of DS fetuses, which was already apparent during the first cell divisions of embryogenesis. The mutation load could be explained by processes that are active during normal fetal development and were similar to those observed in TMD blast cells. Our study shows that T21 causes an increase in somatic load in fetal cells of DS fetuses, which may contribute to leukemia development early in life.

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Dataset ID Description Technology Samples
EGAD00001005459 HiSeq X Ten 13
EGAD00001006343 Illumina NovaSeq 6000 53
Publications Citations
Mutation accumulation and developmental lineages in normal and Down syndrome human fetal haematopoiesis.
Sci Rep 10: 2020 12991
Human induced pluripotent stem cells display a similar mutation burden as embryonic pluripotent cells <i>in vivo</i>.
iScience 25: 2022 103736
Mutation accumulation in mtDNA of cancers resembles mutagenesis in normal stem cells.
iScience 25: 2022 105610