J Med Genet 42:289-291 doi:10.1136/jmg.2004.026930
  • Hypothesis

Increased prevalence of imprinting defects in patients with Angelman syndrome born to subfertile couples

  1. M Ludwig1,
  2. A Katalinic2,
  3. S Groß3,
  4. A Sutcliffe4,
  5. R Varon5,
  6. B Horsthemke3
  1. 1Endokrinologikum Hamburg, Germany
  2. 2Institut für Krebsepidemiologie, Medizinische Universität Lübeck, Germany
  3. 3Institut für Humangenetik, Universitätsklinikum Essen, Germany
  4. 4Department of Paediatrics, University College London, UK
  5. 5Institut für Humangenetik, Charité, Humboldt Universität Berlin, Germany
  1. Correspondence to:
 Dr M Ludwig
 Endokrinologikum Hamburg, Zentrum für Hormon und Stoffwechselerkrankungen, Gynäkologische Endokrinologie und Reproduktionsmedizin, Lornsenstrasse 6, 22767 Hamburg, Germany;
  • Received 6 September 2004
  • Accepted 29 October 2004
  • Revised 25 October 2004


Recent case reports have suggested that infertility treatment with intracytoplasmic sperm injection (ICSI) may increase the risk of imprinting defects leading to Angelman syndrome (AS). Although imprinting defects account for only 4% of patients with AS, we have found four cases among 16 AS patients born to subfertile couples, who conceived with or without infertility treatment (25%; relative risk (RR) 6.25; 95% confidence interval (CI) 1.68 to 16.00). The risk in untreated couples with time to pregnancy (TTP) exceeding 2 years was identical to that of those treated by ICSI or by hormonal stimulation alone (RR 6.25; 95% CI 0.70 to 22.57). It was twice as high in couples who had received treatment and also had TTP >2 years (RR 12.5; 95% CI 1.40 to 45.13). Our findings suggest that imprinting defects and subfertility may have a common cause, and that superovulation rather than ICSI may further increase the risk of conceiving a child with an imprinting defect.


  • M Ludwig and A Sutcliffe designed the study. M Ludwig recruited the patients. A Katalinic gave advice on the study design, performed the statistical analysis. S Groß and R Varon performed the DNA studies. B Horsthemke collected the samples and evaluated the molecular data. M Ludwig and B Horsthemke interpreted the results and wrote the manuscript.

  • Competing interests: none declared