Involuntary infertility affects approximately one in ten couples, worldwide. This fraction of the population translates to a large number of individuals who are potential candidates for assisted reproductive technology (ART). In fact, more than a million children have been born as the result of in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) and children conceived by these procedures account for more than 1% of all births in several western countries. Despite the many reassuring reports on the safety of ART, there have been a small number of recent reports suggesting that ART children may be at increased risk for rare congenital malformation syndromes that are related to defects in genome imprinting. At least three children conceived by ICSI have been diagnosed with Angelman syndrome and at least 28 ART children (both IVF and ICSI cases) have been diagnosed with Beckwith-Wiedemann syndrome. The suggestion that ART children may be at modestly increased risk for rare, congenital disorders associated with defects in imprinting is troubling on two counts. The first is the obvious and direct impact of these particular syndromes on affected children and their families. The second, and more troubling, consideration is that these data may portend more widespread effects of ART on the establishment or maintenance of genome imprints, or other epigenetic marks, than can be assessed by screening for rare congenital abnormalities. For example, a strong association between sporadic colon cancer and constitutional loss of imprinting at the insulin-like growth factor 2 gene has been reported independently by two laboratories. The purpose of the proposed study is to determine whether ART increases the possibility of deregulated expression of imprinted genes and/or destabilizes epigenetic chromosomal marking. Seven measures of epigenetic chromosomal marking (DNA methylation at three differentially methylated regions, transcription of alleles at three imprinted genes, and X-chromosome inactivation ratios in females) will be analyzed on a population of 500 newborns conceived through ART and a control population of 500 newborns conceived in the traditional fashion. The incidence of abnormal epigenetic marks will be compared between the two populations to determine whether any aspect of the ART procedure results in destabilization of epigenetic structures in the genomes of early human embryos.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
Project #
Application #
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Taymans, Susan
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Temple University
Schools of Medicine
United States
Zip Code
Mainigi, Monica A; Sapienza, Carmen; Butts, Samantha et al. (2016) A Molecular Perspective on Procedures and Outcomes with Assisted Reproductive Technologies. Cold Spring Harb Perspect Med 6:a023416
Turan, Nahid; Ghalwash, Mohamed F; Katari, Sunita et al. (2012) DNA methylation differences at growth related genes correlate with birth weight: a molecular signature linked to developmental origins of adult disease? BMC Med Genomics 5:10
Kalra, Suleena Kansal; Ratcliffe, Sarah J; Barnhart, Kurt T et al. (2012) Extended embryo culture and an increased risk of preterm delivery. Obstet Gynecol 120:69-75
Kalra, Suleena Kansal; Ratcliffe, Sarah J; Coutifaris, Christos et al. (2011) Ovarian stimulation and low birth weight in newborns conceived through in vitro fertilization. Obstet Gynecol 118:863-71
Turan, Nahid; Katari, Sunita; Coutifaris, Christos et al. (2010) Explaining inter-individual variability in phenotype: is epigenetics up to the challenge? Epigenetics 5:16-9
Turan, Nahid; Katari, Sunita; Gerson, Leigh F et al. (2010) Inter- and intra-individual variation in allele-specific DNA methylation and gene expression in children conceived using assisted reproductive technology. PLoS Genet 6:e1001033
Katari, Sunita; Turan, Nahid; Bibikova, Marina et al. (2009) DNA methylation and gene expression differences in children conceived in vitro or in vivo. Hum Mol Genet 18:3769-78
Han, Zhiming; Mtango, Namdori R; Patel, Bela G et al. (2008) Hybrid vigor and transgenerational epigenetic effects on early mouse embryo phenotype. Biol Reprod 79:638-48