Deep genome sequencing reveals 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 have mapped the mutational landscape across multiple sites and stages of placental development. We have revealed wide-spread mutations, with distinct clusters of postzygotic non-fetal small sequence variants, indicating extensive clonal evolution in all early placental biopsies, including first-trimester chorionic villus samples. Our study illuminates spatial and temporal genetic heterogeneity of the developing placenta. While most clonal sequence variants in placental biopsies exhibit low variant allele frequency, their presence underscores the need for caution when using placental tissue as a fetal proxy for diagnostics. These findings highlight the importance of confirmatory testing using AF in cases where placental mosaicism is suspected to avoid misinterpretation and unnecessary interventions.