title: Adverse effects of trichothiodystrophy DNA repair and transcription gene disorder on human fetal development.
abstract: 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.
authors.affiliation: Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA. rmoslehi@albany.edu
authors.forename: R
authors.initials: R
authors.lastname: Moslehi
authors.forename: C
authors.initials: C
authors.lastname: Signore
authors.forename: D
authors.initials: D
authors.lastname: Tamura
authors.forename: J L
authors.initials: JL
authors.lastname: Mills
authors.forename: J J
authors.initials: JJ
authors.lastname: Digiovanna
authors.forename: M A
authors.initials: MA
authors.lastname: Tucker
authors.forename: J
authors.initials: J
authors.lastname: Troendle
authors.forename: T
authors.initials: T
authors.lastname: Ueda
authors.forename: J
authors.initials: J
authors.lastname: Boyle
authors.forename: S G
authors.initials: SG
authors.lastname: Khan
authors.forename: K-S
authors.initials: KS
authors.lastname: Oh
authors.forename: A M
authors.initials: AM
authors.lastname: Goldstein
authors.forename: K H
authors.initials: KH
authors.lastname: Kraemer
mesh_terms: D000328:Adult; D004260:DNA Repair / Q000235:genetics*; D003710:Demography; D005190:Family; D005260:Female; D047109:Fetal Development / Q000235:genetics*; D006801:Humans; D050498:Live Birth; D008875:Middle Aged; D011247:Pregnancy; D011256:Pregnancy Outcome; D012016:Reference Values; D014158:Transcription, Genetic; D054463:Trichothiodystrophy Syndromes / Q000196:embryology* / Q000235:genetics*; D055815:Young Adult