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Chitayat-Hall and Schaaf-Yang syndromes: a common aetiology: expanding the phenotype of MAGEL2-related disorders
  1. Rebekah Jobling1,2,
  2. Dimitri James Stavropoulos1,3,
  3. Christian R Marshall1,4,
  4. Cheryl Cytrynbaum2,
  5. Michelle M Axford1,
  6. Vanessa Londero1,
  7. Sharon Moalem5,
  8. Jennifer Orr1,
  9. Francis Rossignol6,7,
  10. Fatima Daniela Lopes6,8,9,
  11. Julie Gauthier6,
  12. Nathalie Alos6,7,
  13. Rosemarie Rupps10,
  14. Margaret McKinnon10,
  15. Shelin Adam10,
  16. Malgorzata J M Nowaczyk11,
  17. Susan Walker4,12,
  18. Stephen W Scherer4,12,13,
  19. Christina Nassif6,7,
  20. Fadi F Hamdan6,7,
  21. Cheri L Deal6,7,
  22. Jean-François Soucy6,7,
  23. Rosanna Weksberg2,
  24. Patrick Macleod14,
  25. Jacques L Michaud6,7,
  26. David Chitayat2,15
  1. 1Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada
  2. 2Division of Clinical Genetics and Metabolism, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada
  3. 3Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
  4. 4The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada
  5. 5Regenoron, New York City, New York, USA
  6. 6CHU Sainte-Justine, Montréal, Quebec, Canada
  7. 7Department of Pediatrics, Université de Montréal, Montréal, Quebec, Canada
  8. 8Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
  9. 9ICVS/3B’s - PT Government Associate Laboratory, Guimarães, Portugal
  10. 10Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada
  11. 11Division of Clinical Pathology, McMaster University, Hamilton, Ontario, Canada
  12. 12Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada
  13. 13Department of Molecular Genetics and McLaughlin Centre, University of Toronto, Toronto, Ontario, Canada
  14. 14The Centre for Biomedical Research, University of Victoria, Victoria, British Columbia, Canada
  15. 15The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, New York City, New York, USA
  1. Correspondence to Dr David Chitayat, Division of Clinical Genetics and Metabolism, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; David.Chitayat{at}sinaihealthsystem.ca

Abstract

Background Chitayat-Hall syndrome, initially described in 1990, is a rare condition characterised by distal arthrogryposis, intellectual disability, dysmorphic features and hypopituitarism, in particular growth hormone deficiency. The genetic aetiology has not been identified.

Methods and results We identified three unrelated families with a total of six affected patients with the clinical manifestations of Chitayat-Hall syndrome. Through whole exome or whole genome sequencing, pathogenic variants in the MAGEL2 gene were identified in all affected patients. All disease-causing sequence variants detected are predicted to result in a truncated protein, including one complex variant that comprised a deletion and inversion.

Conclusions Chitayat-Hall syndrome is caused by pathogenic variants in MAGEL2 and shares a common aetiology with the recently described Schaaf-Yang syndrome. The phenotype of MAGEL2-related disorders is expanded to include growth hormone deficiency as an important and treatable complication.

  • growth hormone deficiency
  • magel2
  • schaaf-yang syndrome
  • chitayat-hall syndrome
  • genetics

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Footnotes

  • JLM and DC contributed equally.

  • Contributors CC, SM, FR, NA, RR, MM, SA, MJMN, CLD, RW, PM and DC performed clinical assessment and provided phenotypic information regarding the patients. FR, FDL, JG, FFH, CN, J-FS, JLM, RJ, DJS, CRM, SWS, JO and SW provided sequencing, data analysis, interpretation and validation of variants. RJ, VL and MMA performed phasing experiments for the variant in family 3. The manuscript was drafted by RJ, FR, DC and JLM. All authors provided critical revision of the article.

  • Funding The McLaughlin Centre, University of Toronto, Toronto, Canada, and Fondation Jeanne et Jean- Louis Lévesque (JLM). The Centre for Genetic Medicine, The Hospital for Sick Children, Toronto, Canada. FDL has a fellowship funded by FCT - Fundação para a Ciência e a Tecnologia (SFRH/BD/84650/2010).

  • Competing interests None declared.

  • Patient consent Parental/guardian consent obtained.

  • Ethics approval The Hospital for Sick Children, Toronto, Canada, and Centre hospitalier universitaire Sainte-Justine.

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

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