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Further molecular and clinical delineation of co-locating 17p13.3 microdeletions and microduplications that show distinctive phenotypes
  1. Damien L Bruno1,2,
  2. Britt-Marie Anderlid3,
  3. Anna Lindstrand3,
  4. Conny van Ravenswaaij-Arts4,
  5. Devika Ganesamoorthy1,2,
  6. Johanna Lundin3,
  7. Christa Lese Martin5,
  8. Jessica Douglas6,
  9. Catherine Nowak6,
  10. Margaret P Adam5,
  11. R Frank Kooy7,
  12. Nathalie Van der Aa7,
  13. Edwin Reyniers7,
  14. Geert Vandeweyer7,
  15. Irene Stolte-Dijkstra4,
  16. Trijnie Dijkhuizen4,
  17. Alison Yeung1,
  18. Martin Delatycki1,
  19. Birgit Borgström8,
  20. Lena Thelin9,
  21. Carlos Cardoso10,
  22. Bregje van Bon11,
  23. Rolph Pfundt11,
  24. Bert B A de Vries11,
  25. Anders Wallin12,
  26. David J Amor1,
  27. Paul A James1,
  28. Howard R Slater1,2,
  29. Jacqueline Schoumans3
  1. 1Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Australia
  2. 2Department of Pediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Australia
  3. 3Clinical Genetics Unit, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
  4. 4Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
  5. 5Department of Human Genetics, Emory University, Atlanta, Georgia, USA
  6. 6The National Birth Defects Center, Waltham, Massachusetts, USA
  7. 7University and University Hospital Antwerp, Antwerp, Belgium
  8. 8Department of Endocrinology, Clinic of Pediatrics, Karolinska University Hospital, Huddinge, Sweden
  9. 9Sachs' Children's Hospital, Södersjukhuset, Stockholm, Sweden
  10. 10INMED, INSERM U901, Université de la Méditerranee, Campus de Luminy, Marseille, France
  11. 11Department of Human Genetics, Radboud University, Nijmegen Medical Centre, Nijmegen, The Netherlands
  12. 12Mälar Hospital, Eskilstuna, Sweden
  1. Correspondence to Dr Howard R Slater, Cytogenetics Department, VCGS Pathology, MCRI, Royal Children's Hospital, Parkville, Victoria 3052, Australia; howard.slater{at}


Background Chromosome 17p13.3 contains extensive repetitive sequences and is a recognised region of genomic instability. Haploinsufficiency of PAFAH1B1 (encoding LIS1) causes either isolated lissencephaly sequence or Miller–Dieker syndrome, depending on the size of the deletion. More recently, both microdeletions and microduplications mapping to the Miller–Dieker syndrome telomeric critical region have been identified and associated with distinct but overlapping phenotypes.

Methods Genome-wide microarray screening was performed on 7678 patients referred with unexplained learning difficulties and/or autism, with or without other congenital abnormalities. Eight and five unrelated individuals, respectively, were identified with microdeletions and microduplications in 17p13.3.

Results Comparisons with six previously reported microdeletion cases identified a 258 kb critical region, encompassing six genes including CRK (encoding Crk) and YWHAE (encoding 14-3-3ε). Clinical features included growth retardation, facial dysmorphism and developmental delay. Notably, one individual with only subtle facial features and an interstitial deletion involving CRK but not YWHAE suggested that a genomic region spanning 109 kb, encompassing two genes (TUSC5 and YWHAE), is responsible for the main facial dysmorphism phenotype. Only the microduplication phenotype included autism. The microduplication minimal region of overlap for the new and previously reported cases spans 72 kb encompassing a single gene, YWHAE. These genomic rearrangements were not associated with low-copy repeats and are probably due to diverse molecular mechanisms.

Conclusions The authors further characterise the 17p13.3 microdeletion and microduplication phenotypic spectrum and describe a smaller critical genomic region allowing identification of candidate genes for the distinctive facial dysmorphism (microdeletions) and autism (microduplications) manifestations.

  • 17p13.3
  • microdeletion
  • microduplication
  • CRK
  • clinical genetics
  • molecular genetics

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  • DLB and B-MA contributed equally to this work.

  • Funding Swedish Research Council, Karolinska Institute Foundation, Stockholm County Council, Perpetual Trustees Australia, EU-funded AnEUploidy Project, The Netherlands Organisation for Health Research and Development.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of the Karolinska Institute, Stockholm, Sweden.

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