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Maternal variants in NLRP and other maternal effect proteins are associated with multilocus imprinting disturbance in offspring
  1. Matthias Begemann1,
  2. Faisal I Rezwan2,
  3. Jasmin Beygo3,
  4. Louise E Docherty4,
  5. Julia Kolarova5,
  6. Christopher Schroeder3,
  7. Karin Buiting3,
  8. Kamal Chokkalingam6,
  9. Franziska Degenhardt7,
  10. Emma L Wakeling8,
  11. Stephanie Kleinle9,
  12. Daniela González Fassrainer9,
  13. Barbara Oehl-Jaschkowitz10,
  14. Claire L S Turner11,
  15. Michal Patalan12,
  16. Maria Gizewska12,
  17. Gerhard Binder13,
  18. Can Thi Bich Ngoc14,
  19. Vu Chi Dung14,
  20. Sarju G Mehta15,
  21. Gareth Baynam16,17,
  22. Julian P Hamilton-Shield18,
  23. Sara Aljareh2,
  24. Oluwakemi Lokulo-Sodipe2,19,
  25. Rachel Horton2,19,
  26. Reiner Siebert5,
  27. Miriam Elbracht1,
  28. Isabel Karen Temple2,19,
  29. Thomas Eggermann1,
  30. Deborah J G Mackay2
  1. 1 Institute of Human Genetics, RWTH Aachen University, Aachen, Germany
  2. 2 Faculty of Medicine, University of Southampton, Southampton, UK
  3. 3 Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany
  4. 4 MRC Human Genetics Unit, The Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
  5. 5 Institute of Human Genetics, University of Ulm, Ulm, Germany
  6. 6 Department of Diabetic Medicine, Nottingham University Hospital NHS Trust, Nottingham, UK
  7. 7 Institute of Human Genetics, Bonn, Germany
  8. 8 North West Thames Regional Genetics Service, London North West Healthcare NHS Trust, London, UK
  9. 9 Medical Genetics Center München, München, Germany
  10. 10 Praxis für Humangenetik Homburg, Homburg, Germany
  11. 11 Peninsula Genetics Service, Royal Devon and Exeter Hospital, Exeter, UK
  12. 12 Department of Pediatrics, Endocrinology, Diabetology, Metabolic Diseases and Cardiology, Pomeranian Medical University, Szczecin, Poland
  13. 13 Pediatric Endocrinology, University Children’s Hospital, Tübingen, Germany
  14. 14 Department of Medical Genetics, Metabolism and Endocrinology, The National Children’s Hospital, Hanoi, Vietnam
  15. 15 Department of Clinical Genetics, Cambridge University Hospitals Trust, Cambridge, UK
  16. 16 School of Paediatrics and Child Health, The University of Western Australia, Perth, Western Australia, Australia
  17. 17 Genetic Services of Western Australian and Western Australian Register of Developmental Anomalies, Perth, Western Australia, Australia
  18. 18 School of Clinical Sciences, University of Bristol, Bristol, UK
  19. 19 Wessex Clinical Genetics Service, University Hospital, Southampton, UK
  1. Correspondence to Dr Deborah J G Mackay, Faculty of Medicine, University of Southampton, Southampton SP2 8BJ, UK; djgm{at}


Background Genomic imprinting results from the resistance of germline epigenetic marks to reprogramming in the early embryo for a small number of mammalian genes. Genetic, epigenetic or environmental insults that prevent imprints from evading reprogramming may result in imprinting disorders, which impact growth, development, behaviour and metabolism. We aimed to identify genetic defects causing imprinting disorders by whole-exome sequencing in families with one or more members affected by multilocus imprinting disturbance.

Methods Whole-exome sequencing was performed in 38 pedigrees where probands had multilocus imprinting disturbance, in five of whom maternal variants in NLRP5 have previously been found.

Results We now report 15 further pedigrees in which offspring had disturbance of imprinting, while their mothers had rare, predicted-deleterious variants in maternal effect genes, including NLRP2, NLRP7 and PADI6. As well as clinical features of well-recognised imprinting disorders, some offspring had additional features including developmental delay, behavioural problems and discordant monozygotic twinning, while some mothers had reproductive problems including pregnancy loss.

Conclusion The identification of 20 putative maternal effect variants in 38 families affected by multilocus imprinting disorders adds to the evidence that maternal genetic factors affect oocyte fitness and thus offspring development. Testing for maternal-effect genetic variants should be considered in families affected by atypical imprinting disorders.

  • genomic imprinting
  • multi-locus imprinting disorder
  • Beckwith-Wiedemann syndrome
  • Silver-Russell syndrome
  • NLRP5
  • NLRP7
  • NLRP2
  • PADI6

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  • Contributors MB and LED coordinated and interpreted exome sequencing and epigenetic analysis of the German and UK cohorts. FIR, JB, CS and KB performed bioinformatic analysis. JK and RS performed epigenomic studies. Families were referred, consented and phenotyped by KC, FD, ELW, SK, DGF, BO-J, CLST, MP, MG, GB, CTBN, VCD, SGM, GB, JPH-S, SA, OL-S and RH. Patient studies were planned and co-ordinated by ME and IKT. TE and DJGM planned, wrote and submitted the study.

  • Funding MB and TE were funded by the German national BMBF (Ministry of Education and Science, Grant 01GM1513B) and the Deutsche Forschungsgemeinschaft (DFG; Grants EG115/10-1 and INST 948/32-1FUGG). LED and FIR were funded by Medical Research Council (MR/J000329/1). KB and JB were funded by the Bundesministerium für Bildung und Forschung (BMBF; Imprinting diseases, grant no. 01GM1513A). RS was funded by the German national BMBF (grant no: 01GM1513F). OL-S was funded by the National Institute for Health Research (NIHR) under its Research for Patient Benefit (RfPB) Programme (STAARS UK: Grant Reference Number PB-PG-1111-26003); IKT is supported by the NIHR Biomedical Research Centre (BRC), Southampton.

  • Competing interests None declared.

  • Patient consent Detail has been removed from this case description/these case descriptions to ensure anonymity. The editors and reviewers have seen the detailed information available and are satisfied that the information backs up the case the authors are making.

  • Ethics approval Ethical committee at the University Hospital Aachen, Southampton and South West Hampshire Research Ethics Committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement No additional unpublished data are available from the families involved in this study.

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