1. ¹Institut für Humangenetik, Universitätsklinikum Essen, Essen, Germany
2. ²Endokrinologikum Hamburg, Hamburg, Germany

Correspondence: Professor B Horsthemke, Institut für Humangenetik, Universitätsklinkum Essen, Hufelandstrasse 55, 45122 Essen, Germany. Tel: +49 201 723 4560; Fax: +49 201 723 5900; E-mail: bernhard.horsthemke@uni-due.de

Received 12 June 2008; Revised 19 August 2008; Accepted 3 September 2008; Published online 22 October 2008.

Abstract

Although there is an increased frequency of low birth weight after assisted reproduction, the mechanisms underlying this association are unclear. We have proposed that some of the children conceived by intracytoplasmic sperm injection (ICSI) with low birth weight might have an epimutation (faulty methylation pattern) in one of the imprinted genes involved in fetal growth control, eg, KCNQ1OT1, PEG1, PEG3, GTL2, IGF2/H19 and PLAGL1. Using bisulfite DNA sequencing and sequence-based quantitative methylation analysis (SeQMA), we determined the methylation pattern of these genes in buccal smears from 19 ICSI children born small for gestational age (SGA, birth weight <3rd percentile) and from 29 term-born normal weight children after spontaneous conception. We detected clear hypermethylation of KCNQ1OT1 and borderline hypermethylation of PEG1 in one and the same ICSI child. The other children and the parents of the affected child have normal methylation patterns. Imprinting defects appear to be a rare finding in ICSI children born SGA. Methylation of the paternal KCNQ1OT1 and PEG1 alleles may be a previously unrecognized cause of SGA. The epimutations found in the SGA child, whose father had oligozoospermia, probably result from an imprint erasure defect in the paternal germ line and therefore appear to be linked to the fertility problem of the father and not to in vitro fertilization/ICSI.