Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
Clin Genet. 2010 Apr;77(4):365-73. doi: 10.1111/j.1399-0004.2009.01336.x. Epub 2009 Dec 10.
The effects of DNA repair and transcription gene abnormalities in human pre-natal life have never been studied. Trichothiodystrophy (TTD) is a rare (affected frequency of 10(-6)) recessive disorder caused by mutations in genes involved in nucleotide excision repair (NER) pathway and in transcription. Based on our novel clinical observations, we conducted a genetic epidemiologic study to investigate gestational outcomes associated with TTD. We compared pregnancies resulting in TTD-affected offspring (n = 24) with respect to abnormalities during their antenatal and neonatal periods to pregnancies resulting in their unaffected siblings (n = 18), accounting for correlation, and to population reference values. Significantly higher incidence of several severe gestational complications was noted in TTD-affected pregnancies. Small for gestational age (SGA) <10th percentile [Relative risk (RR ) = 9.3, 95% CI = 1.4-60.5, p = 0.02], SGA <3rd percentile (RR = 7.2, 95% CI = 1.1-48.1, p = 0.04), and neonatal intensive care unit (NICU) hospitalization (RR = 6.4, 95% CI = 1.4-29.5, p = 0.02) occurred more frequently among TTD-affected neonates compared with their unaffected siblings. Compared with reference values from general obstetrical population, pregnancies that resulted in TTD-affected infants were significantly more likely to be complicated by hemolysis, elevated liver enzymes and low platelets (HELLP) syndrome (RR = 35.7, 95% CI = 7.6-92.5, p = 0.0002), elevated mid-trimester maternal serum human chorionic gonadotropin (hCG) levels (RR = 14.3, 95% CI = 7.0-16.6, p < 0.0001), SGA <3rd percentile (RR = 13.9, 95% CI = 7.4-21.1, p < 0.0001), pre-term delivery (<32 weeks) (RR = 12.0, 95% CI = 4.9-21.6, p < 0.0001), pre-eclampsia (RR = 4.0, 95% CI = 1.6-7.4, p = 0.006), and decreased fetal movement (RR = 3.3, 95% CI = 1.6-5.2, p = 0.0018). Abnormal placental development is an underlying mechanism that may explain the constellation of observed complications in our study. Thus, we hypothesize that TTD DNA repair and transcription genes play an important role in normal human placental development.
人类产前生活中 DNA 修复和转录基因异常的影响从未被研究过。先天性毛发硫营养不良症（TTD）是一种罕见的（发病率为 10（-6））隐性疾病，由核苷酸切除修复（NER）途径和转录中涉及的基因突变引起。基于我们新的临床观察，我们进行了一项遗传流行病学研究，以调查与 TTD 相关的妊娠结局。我们将导致 TTD 受累后代的妊娠（n = 24）与他们未受影响的兄弟姐妹（n = 18）的产前和新生儿期的异常进行了比较，并考虑了相关性和人群参考值。在 TTD 受累的妊娠中，明显更高的严重妊娠并发症发生率。小于胎龄儿（SGA）<第 10 百分位（RR = 9.3，95%CI = 1.4-60.5，p = 0.02），SGA <第 3 百分位（RR = 7.2，95%CI = 1.1-48.1，p = 0.04）和新生儿重症监护病房（NICU）住院（RR = 6.4，95%CI = 1.4-29.5，p = 0.02）在 TTD 受累的新生儿中比他们未受影响的兄弟姐妹更频繁发生。与一般产科人群的参考值相比，导致 TTD 受累婴儿的妊娠更有可能出现溶血性贫血、肝酶升高和血小板减少症（HELLP）综合征（RR = 35.7，95%CI = 7.6-92.5，p = 0.0002）、中期母体血清人绒毛膜促性腺激素（hCG）水平升高（RR = 14.3，95%CI = 7.0-16.6，p < 0.0001）、SGA <第 3 百分位（RR = 13.9，95%CI = 7.4-21.1，p < 0.0001）、早产（<32 周）（RR = 12.0，95%CI = 4.9-21.6，p < 0.0001）、子痫前期（RR = 4.0，95%CI = 1.6-7.4，p = 0.006）和胎动减少（RR = 3.3，95%CI = 1.6-5.2，p = 0.0018）。胎盘发育异常是一种潜在的机制，可能解释了我们研究中观察到的并发症的组合。因此，我们假设 TTD DNA 修复和转录基因在正常人类胎盘发育中起着重要作用。
