Deep Genome Sequencing Uncovers Extensive Genetic Heterogeneity in Early Human Placentas

Placental biopsy in early pregnancy is widely used in prenatal genetic diagnostics as a surrogate for fetal tissue. Confined placental chromosomal mosaicism is a well-documented phenomenon causing genetic discrepancies between the fetus and placenta. Although comprehensive sequencing methods are becoming popular for prenatal screening of monogenic disorders, knowledge of concordance between the fetus and early placenta at the sequence level remains limited. By deep genome sequencing, we mapped the mutational landscape across multiple sites and stages of placental development. We revealed profound mutations, with distinct clusters of postzygotic non-fetal small sequence variants, indicating extensive clonal evolution in all early placenta samples, including first-trimester CVS. Our study illuminates spatial and temporal genetic heterogeneity of the developing placenta. These findings underscore the need for awareness and caution when using placental biopsies as fetal proxy for diagnostics and emphasize the importance of confirmatory testing using amniotic fluid when placenta mosaicism is suspected.