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Paternal uniparental disomy of chromosome 19 in a pair of monochorionic diamniotic twins with dysmorphic features and developmental delay
  1. Kit San Yeung1,
  2. Matthew Sai Pong Ho1,
  3. So Lun Lee1,2,
  4. Anita Sik Yau Kan3,4,
  5. Kelvin Yuen Kwong Chan3,4,
  6. Mary Hoi Yin Tang5,
  7. Christopher Chun Yu Mak1,
  8. Gordon Ka Chun Leung1,
  9. Po Lam So6,
  10. Rolph Pfundt7,
  11. Christian R Marshall8,9,
  12. Stephen W Scherer10,11,12,
  13. Sanaa Choufani12,
  14. Rosanna Weksberg12,13,14,
  15. Brian Hon-Yin Chung1,2,5
  1. 1 Department of Paediatrics and Adolescent Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
  2. 2 Department of Paediatrics and Adolescent Medicine, The Duchess of Kent Children’s Hospital, Hong Kong
  3. 3 Department of Obstetrics and Gynaecology, Queen Mary Hospital, Hong Kong
  4. 4 Prenatal Diagnostic Laboratory, Tsan Yuk Hospital, Hong Kong
  5. 5 Department of Obstetrics and Gynaecology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
  6. 6 Department of Obstetrics and Gynecology, Tuen Mun Hospital, Hong Kong
  7. 7 Department of Human Genetics, Donders Institute, Radboud University Medical Center, Nijmegen, The Netherlands
  8. 8 Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada
  9. 9 Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
  10. 10 The Centre for Applied Genomics and Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada
  11. 11 McLaughlin Centre and Department of Molecular Genetics, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
  12. 12 Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
  13. 13 Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada
  14. 14 Institute of Medical Science and Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada
  1. Correspondence to Dr Rosanna Weksberg, Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada; rweksb{at}sickkids.ca and Dr Brian Hon-Yin Chung, Department of Paediatrics and Adolescent Medicine, The University of Hong Kong, Hong Kong; bhychung{at}hku.hk

Abstract

Background We report here clinical, cytogenetic and molecular data for a pair of monochorionic diamniotic twins with paternal isodisomy for chromosome 19. Both twins presented with dysmorphic features and global developmental delay. This represents, to our knowledge, the first individual human case of paternal uniparental disomy for chromosome 19 (UPD19).

Methods Whole-exome sequencing, together with conventional karyotype and SNP array analysis were performed along with genome-wide DNA methylation array for delineation of the underlying molecular defects.

Results Conventional karyotyping on amniocytes and lymphocytes showed normal karyotypes for both twins. Whole-exome sequencing did not identify any pathogenic sequence variants but >5000 homozygous exonic variants on chromosome 19, suggestive of UPD19. SNP arrays on blood and buccal DNA both showed paternal isodisomy for chromosome 19. Losses of imprinting for known imprinted genes on chromosome 19 were identified, including ZNF331, PEG3, ZIM2 and MIMT1. In addition, imprinting defects were also identified in genes located on other chromosomes, including GPR1-AS, JAKMP1 and NHP2L1.

Conclusion Imprinting defects are the most likely cause for the dysmorphism and developmental delay in this first report of monozygotic twins with UPD19. However, epigenotype-phenotype correlation will require identification of additional individuals with UPD19 and further molecular analysis.

  • uniparental sisomy
  • upd19
  • imprinting
  • paternal upd
  • dna methylation

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Footnotes

  • Contributors RAW and BHYC conceived and supervised the study. KSY and MSPH drafted the manuscript. SLL, ASYK, MHYT, PLS and BHYC recruited and managed the patients. KSY, MSPH, SLL, ASYK, MHYT, KYKC, CCYM, PLS, GKCL, RP, CRM, SWS and SC analysed and interpreted the data. SLL, ASYK, SWS, RAW and BHYC provided facilities and resources for the study. All authors read the manuscript, revised it critically for important intellectual content and approved the final manuscript.

  • Funding BHYC is funded by the Society for the Relief of Disabled Children and Medix. SWS is funded by the GlaxoSmithKline/ Canadian Institute of Health Research Chair in the Genome Sciences at the University of Toronto and The Hospital for Sick Children.

  • Competing interests None declared.

  • Patient consent Parental/guardian consent obtained.

  • Ethics approval This study was approved by the Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster (UW 12–211).

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

  • Data sharing statement Not applicable.

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