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A familial disorder of altered DNA-methylation
  1. Almuth Caliebe1,
  2. Julia Richter1,
  3. Ole Ammerpohl1,
  4. Deniz Kanber2,
  5. Jasmin Beygo2,
  6. Susanne Bens1,
  7. Andrea Haake1,
  8. Eva Jüttner3,
  9. Bernhard Korn4,
  10. Deborah J G Mackay5,
  11. José I Martin-Subero1,
  12. Inga Nagel1,
  13. Neil J Sebire6,
  14. Larissa Seidmann7,
  15. Inga Vater1,
  16. Constantin Sylvius von Kaisenberg8,9,
  17. I Karen Temple5,
  18. Bernhard Horsthemke2,
  19. Karin Buiting2,
  20. Reiner Siebert1
  1. 1Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Kiel, Germany
  2. 2Institut für Humangenetik, Universitätsklinikum Essen, Essen, Germany
  3. 3Institute of Pathology, University Hospital Schleswig-Holstein Campus Kiel/Christian- Albrechts University Kiel, Kiel, Germany
  4. 4Friedrich-Miescher Institute for Biomedical Research, Basel, Switzerland
  5. 5Human Genetics and Genomic Medicine/Faculty of Medicine, University of Southampton, Southampton, UK
  6. 6Department of Histopathology, Great Ormond Street Hospital, London, UK
  7. 7Department of Pediatric Pathology, Johannes Gutenberg Universität, Mainz, Germany
  8. 8Department of Gynecology and Obstetrics, University Hospital Schleswig-Holstein Campus Kiel/Christian-Albrechts University Kiel, Kiel, Germany
  9. 9Department of Obstetrics, Gynecology and Reproductive Medicine, Hannover Medical School, Hannover, Germany
  1. Correspondence to Dr Almuth Caliebe, Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel, Schwanenweg 24, 24105 Kiel, Germany; caliebe{at}


Background In a subset of imprinting disorders caused by epimutations, multiple imprinted loci are affected. Familial occurrence of multilocus imprinting disorders is rare.

Purpose/objective We have investigated the clinical and molecular features of a familial DNA-methylation disorder.

Methods Tissues of affected individuals and blood samples of family members were investigated by conventional and molecular karyotyping. Sanger sequencing and RT-PCR of imprinting-associated genes (NLRP2, NLRP7, ZFP57, KHDC3L, DNMT1o), exome sequencing and locus-specific, array-based and genome-wide technologies to determine DNA-methylation were performed.

Results In three offspring of a healthy couple, we observed prenatal onset of severe growth retardation and dysmorphism associated with altered DNA-methylation at paternally and maternally imprinted loci. Array-based analyses in various tissues of the offspring identified the DNA-methylation of 2.1% of the genes in the genome to be recurrently altered. Despite significant enrichment of imprinted genes (OR 9.49), altered DNA-methylation predominately (90.2%) affected genes not known to be imprinted. Sequencing of genes known to cause comparable conditions and exome sequencing in affected individuals and their ancestors did not unambiguously point to a causative gene.

Conclusions The family presented herein suggests the existence of a familial disorder of DNA-methylation affecting imprinted but also not imprinted gene loci potentially caused by a maternal effect mutation in a hitherto not identified gene.

  • Clinical genetics
  • Epigenetics
  • Genetics
  • Imprinting
  • hypomethylation syndrome

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