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Mol. Hum. Reprod. Advance Access published online on June 3, 2009
Molecular Human Reproduction, doi:10.1093/molehr/gap038
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© The Author 2009. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Abnormal Methylation at the KvDMR1 Imprinting Control Region in Clinically Normal Children Conceived by Assisted Reproductive Technologies

M.V. Gomes1, J. Huber1, R.A. Ferriani2, A.M. Amaral Neto1 and E.S. Ramos1,2

1Department of Genetics, School of Medicine of Ribeirão Preto – University of São Paulo, Ribeirão Preto, SP, Brazil, CEP: 14049-900 2Department of Gynecology and Obstetric, School of Medicine of Ribeirão Preto – University of São Paulo, Ribeirão Preto, SP, Brazil, CEP: 14048-900

Address correspondence to: Marcus Vinicius de Matos Gomes, BSc, MSc, Ph.D, Department of Genetics, School of Medicine of Ribeirão Preto/USP. Avenida Bandeirantes, 3900, Monte Alegre. CEP: 14049-900, Ribeirão Preto, São Paulo – Brasil. Voice: 55 16 3602-3081; Fax: (+ 55 16) 3633-0069; Email: mvmgomes{at}genbov.fmrp.usp.br

Genomic imprinting alterations have been shown to be associated to assisted reproductive technologies (ART) in animals. At present, data obtained in humans are inconclusive, however, some epidemiological studies have demonstrated an increased incidence of imprinting disorders in children conceived by ART. In the present study, we focused on the effect of ART (IVF and ICSI) on the epigenetic reprogramming of the maternally methylated imprinting control region KvDMR1 in clinically normal children. Qualitative and quantitative methylation at KvDMR1 were assessed by the methylation-specific PCR approach (MS-PCR) and by the methylation-sensitive enzymatic digestion associated to real-time PCR method (MSED-qPCR), respectively. DNA was obtained from peripheral blood of 12/18 and umbilical cord blood and placenta of 6/18 children conceived by IVF or ICSI. The methylation patterns observed in this group were compared with the patterns observed in 30 clinically normal naturally conceived children (negative controls) and in three naturally conceived BWS patients (positive controls). Hypomethylation at KvDMR1 was observed in 3/18 clinically normal children conceived by ART (2 conceived by IVF and 1 by ICSI). A discordant methylation pattern was observed in the three corresponding dizygotic twins. Our findings corroborate the hypothesis of vulnerability of maternal imprinting to ART. Furthermore, the discordant methylation at KvDMR1 observed between dizygotic twins could be consequent to one of the following possibilities: (i) a differential vulnerability of maternal imprints among different embryos; or (ii) epimutations that occurred during gametogenesis resulting in the production of oocytes without the correct primary imprint at KvDMR1.

Key Words: assisted reproduction/DNA methylation/genomic imprinting/KvDMR1

Submitted on October 1, 2008; resubmitted on May 26, 2009; accepted on May 29, 2009.


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