2. Academic Validation
  3. Phenotypic spectrum associated with PTCHD1 deletions and truncating mutations includes intellectual disability and autism spectrum disorder

Phenotypic spectrum associated with PTCHD1 deletions and truncating mutations includes intellectual disability and autism spectrum disorder

  • Clin Genet. 2015 Sep;88(3):224-33. doi: 10.1111/cge.12482.
A Chaudhry 1,  A Noor 2 3,  B Degagne 3,  K Baker 4 5,  L A Bok 6,  A F Brady 7,  D Chitayat 1 8,  B H Chung 9,  C Cytrynbaum 1 10,  D Dyment 11,  I Filges 12,  B Helm 13,  H T Hutchison 14,  L J B Jeng 15,  F Laumonnier 16,  C R Marshall 17,  M Menzel 18,  S Parkash 19 20,  M J Parker 21,  DDD Study,  L F Raymond 4 5,  A L Rideout 19,  W Roberts 22,  R Rupps 23,  I Schanze 24,  C T R M Schrander-Stumpel 25,  M D Speevak 26,  D J Stavropoulos 2 17,  S J C Stevens 25,  E R A Thomas 27,  A Toutain 16 28,  S Vergano 13,  R Weksberg 1 29 30,  S W Scherer 17 29 30,  J B Vincent 3 29 31,  M T Carter 1 22
Affiliations

Affiliations

  • 1 Department of Pediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada.
  • 2 Department of Pathology and Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
  • 3 Molecular Neuropsychiatry and Development Lab, Campbell Family Mental Health Research Institute, The Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
  • 4 Department of Medical Genetics, Cambridge, UK.
  • 5 Institute for Medical Research Wellcome Trust, University of Cambridge, Cambridge, UK.
  • 6 Department of Clinical Genetics, Unit of Cytogenetics, Maastricht University Medical Center, Maastricht, The Netherlands.
  • 7 North West Thames Regional Genetics Service, Northwick Park Hospital, Harrow, UK.
  • 8 The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
  • 9 Department of Pediatrics and Adolescent Medicine, Department of Obstetrics and Gynaecology, Centre for Reproduction, Development and Growth, Centre for Genomic Sciences, The University of Hong Kong, Pok Fu Lam, Hong Kong.
  • 10 Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
  • 11 Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
  • 12 Division of Medical Genetics, Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
  • 13 Division of Medical Genetics and Metabolism, Children's Hospital of The King's Daughters/Eastern Virginia Medical School, Norfolk, VA, USA.
  • 14 Departments of Neurology and Pediatrics, UCSF Fresno Medical Education Program, San Francisco, CA, USA.
  • 15 Department of Laboratory Medicine, University of California, San Francisco, CA, USA.
  • 16 UMR_INSERM U930 Faculté de Médecine, Université François Rabelais, Tours, France.
  • 17 The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
  • 18 CeGaT GmbH, Tuebingen, Germany.
  • 19 Maritime Medical Genetics Service, IWK Health Centre, Halifax, Nova Scotia, Canada.
  • 20 Dalhousie University Halifax, Nova Scotia, Canada.
  • 21 Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Western Bank, Sheffield, UK.
  • 22 Autism Research Unit, The Hospital for Sick Children, Toronto, Ontario, Canada.
  • 23 Department of Medical Genetics, Children's and Women's Health Centre, University of British Columbia, Vancouver, BC, Canada.
  • 24 Institute of Human Genetics, University Hospital Magedeburg, Magedeburg, Germany.
  • 25 Department of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht UMC+, Maastricht, The Netherlands.
  • 26 Credit Valley Site, Trillium Health Partners, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Onatario, Canada.
  • 27 Clinical Genetics Department, Guy's and St Thomas' NHS Foundation Trust, London, UK.
  • 28 Service de Génétique, Centre Hospitalo-Universitaire, Tours, France.
  • 29 Institute of Medical Science, Toronto, Ontario, Canada.
  • 30 McLaughlin Centre and Department of Molecular Genetics, Toronto, Ontario, Canada.
  • 31 Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
PMID: 25131214 DOI: 10.1111/cge.12482
Abstract

Studies of genomic copy number variants (CNVs) have identified genes associated with autism spectrum disorder (ASD) and intellectual disability (ID) such as NRXN1, SHANK2, SHANK3 and PTCHD1. Deletions have been reported in PTCHD1 however there has been little information available regarding the clinical presentation of these individuals. Herein we present 23 individuals with PTCHD1 deletions or truncating mutations with detailed phenotypic descriptions. The results suggest that individuals with disruption of the PTCHD1 coding region may have subtle dysmorphic features including a long face, prominent forehead, puffy eyelids and a thin upper lip. They do not have a consistent pattern of associated congenital anomalies or growth abnormalities. They have mild to moderate global developmental delay, variable degrees of ID, and many have prominent behavioral issues. Over 40% of subjects have ASD or ASD-like behaviors. The only consistent neurological findings in our cohort are orofacial hypotonia and mild motor incoordination. Our findings suggest that hemizygous PTCHD1 loss of function causes an X-linked neurodevelopmental disorder with a strong propensity to autistic behaviors. Detailed neuropsychological studies are required to better define the cognitive and behavioral phenotype.

Keywords

PTCHD1; X-linked; autism spectrum disorder; intellectual disability; phenotype.

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