Adverse effects of trichothiodystrophy DNA repair and transcription gene disorder on human fetal development
Version of Record online: 10 DEC 2009
© 2009 John Wiley & Sons A/S
Volume 77, Issue 4, pages 365–373, April 2010
How to Cite
Moslehi, R., Signore, C., Tamura, D., Mills, J., DiGiovanna, J., Tucker, M., Troendle, J., Ueda, T., Boyle, J., Khan, S., Oh, K.-S., Goldstein, A. and Kraemer, K. (2010), Adverse effects of trichothiodystrophy DNA repair and transcription gene disorder on human fetal development. Clinical Genetics, 77: 365–373. doi: 10.1111/j.1399-0004.2009.01336.x
- Issue online: 16 MAR 2010
- Version of Record online: 10 DEC 2009
- Received 15 June 2009, revised and accepted for publication 15 October 2009
- DNA repair;
- human fetal;
- trichothiodystrophy genes
Moslehi R, Signore C, Tamura D, Mills JL, DiGiovanna JJ, Tucker MA, Troendle J, Ueda T, Boyle J, Khan SG, Oh K-S, Goldstein AM, Kraemer KH. Adverse effects of trichothiodystrophy DNA repair and transcription gene disorder on human fetal development.
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.