Abstract：
BACKGROUND: A high frequency of single nucleotide somatic mutations in the placenta has been recently described, but its relationship to placental dysfunction is unknown.
METHODS: We performed a pilot case-control study using paired fetal, maternal, and placental samples collected from healthy live birth controls (n = 10), live births with fetal growth restriction (FGR) due to placental insufficiency (n = 7), and stillbirths with FGR and placental insufficiency (n = 11). We quantified single nucleotide and structural somatic variants using bulk whole genome sequencing (30-60X coverage) in four biopsies from each placenta. We also assessed their association with clinical and histological evidence of placental dysfunction.
RESULTS: Seventeen pregnancies had sufficiently high-quality placental, fetal, and maternal DNA for analysis. Each placenta had a median of 473 variants (range 111-870), with 95 % arising in just one biopsy within each placenta. In controls, live births with FGR, and stillbirths, the median variant counts per placenta were 514 (IQR 381-779), 582 (450-735), and 338 (245-441), respectively. After adjusting for depth of sequencing coverage and gestational age at birth, the somatic mutation burden was similar between groups (FGR live births vs. controls, adjusted diff. 59, 95 % CI -218 to +336; stillbirths vs controls, adjusted diff. -34, -351 to +419), and with no association with placental dysfunction (p = 0.7).
CONCLUSIONS: We confirmed the high prevalence of somatic mutation in the human placenta and conclude that the placenta is highly clonal. We were not able to identify any relationship between somatic mutation burden and clinical or histologic placental insufficiency.
METHODS: We performed a pilot case-control study using paired fetal, maternal, and placental samples collected from healthy live birth controls (n = 10), live births with fetal growth restriction (FGR) due to placental insufficiency (n = 7), and stillbirths with FGR and placental insufficiency (n = 11). We quantified single nucleotide and structural somatic variants using bulk whole genome sequencing (30-60X coverage) in four biopsies from each placenta. We also assessed their association with clinical and histological evidence of placental dysfunction.
RESULTS: Seventeen pregnancies had sufficiently high-quality placental, fetal, and maternal DNA for analysis. Each placenta had a median of 473 variants (range 111-870), with 95 % arising in just one biopsy within each placenta. In controls, live births with FGR, and stillbirths, the median variant counts per placenta were 514 (IQR 381-779), 582 (450-735), and 338 (245-441), respectively. After adjusting for depth of sequencing coverage and gestational age at birth, the somatic mutation burden was similar between groups (FGR live births vs. controls, adjusted diff. 59, 95 % CI -218 to +336; stillbirths vs controls, adjusted diff. -34, -351 to +419), and with no association with placental dysfunction (p = 0.7).
CONCLUSIONS: We confirmed the high prevalence of somatic mutation in the human placenta and conclude that the placenta is highly clonal. We were not able to identify any relationship between somatic mutation burden and clinical or histologic placental insufficiency.
摘要：
背景：最近已经描述了胎盘中高频率的单核苷酸体细胞突变，但其与胎盘功能障碍的关系尚不清楚。
方法：我们使用配对胎儿进行了一项先导病例对照研究，母性,和从健康活产对照组收集的胎盘样本（n=10），胎盘功能不全导致胎儿生长受限（FGR）的活产（n=7），FGR和胎盘功能不全的死胎（n=11）。我们在来自每个胎盘的四个活检中使用批量全基因组测序(30-60X覆盖)定量单核苷酸和结构体细胞变体。我们还评估了它们与胎盘功能障碍的临床和组织学证据的关联。
结果：17次妊娠有足够高质量的胎盘，胎儿,和母体DNA进行分析。每个胎盘的中位数为473个变异体（范围为111-870），每个胎盘中只有95%的活检。在控件中，FGR的活产，和死产，每个胎盘的变异计数中位数为514（IQR381-779），582(450-735),和338（245-441），分别。在调整测序覆盖深度和出生时的胎龄后，各组之间的体细胞突变负担相似(FGR活产与controls,调整后的差异。59，95%CI-218至+336；死胎与对照组，调整后的差异。-34，-351至+419），与胎盘功能障碍无关（p=0.7）。
结论：我们证实了人类胎盘中体细胞突变的高患病率，并得出结论，胎盘是高度克隆的。我们无法确定体细胞突变负荷与临床或组织学胎盘功能不全之间的任何关系。
方法：我们使用配对胎儿进行了一项先导病例对照研究，母性,和从健康活产对照组收集的胎盘样本（n=10），胎盘功能不全导致胎儿生长受限（FGR）的活产（n=7），FGR和胎盘功能不全的死胎（n=11）。我们在来自每个胎盘的四个活检中使用批量全基因组测序(30-60X覆盖)定量单核苷酸和结构体细胞变体。我们还评估了它们与胎盘功能障碍的临床和组织学证据的关联。
结果：17次妊娠有足够高质量的胎盘，胎儿,和母体DNA进行分析。每个胎盘的中位数为473个变异体（范围为111-870），每个胎盘中只有95%的活检。在控件中，FGR的活产，和死产，每个胎盘的变异计数中位数为514（IQR381-779），582(450-735),和338（245-441），分别。在调整测序覆盖深度和出生时的胎龄后，各组之间的体细胞突变负担相似(FGR活产与controls,调整后的差异。59，95%CI-218至+336；死胎与对照组，调整后的差异。-34，-351至+419），与胎盘功能障碍无关（p=0.7）。
结论：我们证实了人类胎盘中体细胞突变的高患病率，并得出结论，胎盘是高度克隆的。我们无法确定体细胞突变负荷与临床或组织学胎盘功能不全之间的任何关系。
