title: Phenotypic spectrum associated with PTCHD1 deletions and truncating mutations includes intellectual disability and autism spectrum disorder.
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.
authors.affiliation: Department of Pediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Chaudhry
authors.affiliation: Department of Pathology and Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.|Molecular Neuropsychiatry and Development Lab, Campbell Family Mental Health Research Institute, The Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Noor
authors.affiliation: Molecular Neuropsychiatry and Development Lab, Campbell Family Mental Health Research Institute, The Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
authors.forename: B
authors.initials: B
authors.lastname: Degagne
authors.affiliation: Department of Medical Genetics, Cambridge, UK.|Institute for Medical Research Wellcome Trust, University of Cambridge, Cambridge, UK.
authors.forename: K
authors.initials: K
authors.lastname: Baker
authors.affiliation: Department of Clinical Genetics, Unit of Cytogenetics, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: L A
authors.initials: LA
authors.lastname: Bok
authors.affiliation: North West Thames Regional Genetics Service, Northwick Park Hospital, Harrow, UK.
authors.forename: A F
authors.initials: AF
authors.lastname: Brady
authors.affiliation: Department of Pediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada.|The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Chitayat
authors.affiliation: 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.
authors.forename: B H
authors.initials: BH
authors.lastname: Chung
authors.affiliation: Department of Pediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada.|Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Cytrynbaum
authors.affiliation: Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Dyment
authors.affiliation: Division of Medical Genetics, Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
authors.forename: I
authors.initials: I
authors.lastname: Filges
authors.affiliation: Division of Medical Genetics and Metabolism, Children's Hospital of The King's Daughters/Eastern Virginia Medical School, Norfolk, VA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Helm
authors.affiliation: Departments of Neurology and Pediatrics, UCSF Fresno Medical Education Program, San Francisco, CA, USA.
authors.forename: H T
authors.initials: HT
authors.lastname: Hutchison
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, CA, USA.
authors.forename: L J B
authors.initials: LJ
authors.lastname: Jeng
authors.affiliation: UMR_INSERM U930 Faculté de Médecine, Université François Rabelais, Tours, France.
authors.forename: F
authors.initials: F
authors.lastname: Laumonnier
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: C R
authors.initials: CR
authors.lastname: Marshall
authors.affiliation: CeGaT GmbH, Tuebingen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Menzel
authors.affiliation: Maritime Medical Genetics Service, IWK Health Centre, Halifax, Nova Scotia, Canada.|Dalhousie University Halifax, Nova Scotia, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Parkash
authors.affiliation: Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Western Bank, Sheffield, UK.
authors.forename: M J
authors.initials: MJ
authors.lastname: Parker
authors.affiliation: Department of Medical Genetics, Cambridge, UK.|Institute for Medical Research Wellcome Trust, University of Cambridge, Cambridge, UK.
authors.forename: L F
authors.initials: LF
authors.lastname: Raymond
authors.affiliation: Maritime Medical Genetics Service, IWK Health Centre, Halifax, Nova Scotia, Canada.
authors.forename: A L
authors.initials: AL
authors.lastname: Rideout
authors.affiliation: Autism Research Unit, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: W
authors.initials: W
authors.lastname: Roberts
authors.affiliation: Department of Medical Genetics, Children's and Women's Health Centre, University of British Columbia, Vancouver, BC, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Rupps
authors.affiliation: Institute of Human Genetics, University Hospital Magedeburg, Magedeburg, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Schanze
authors.affiliation: Department of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht UMC+, Maastricht, The Netherlands.
authors.forename: C T R M
authors.initials: CT
authors.lastname: Schrander-Stumpel
authors.affiliation: Credit Valley Site, Trillium Health Partners, Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Onatario, Canada.
authors.forename: M D
authors.initials: MD
authors.lastname: Speevak
authors.affiliation: Department of Pathology and Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.|The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: D J
authors.initials: DJ
authors.lastname: Stavropoulos
authors.affiliation: Department of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht UMC+, Maastricht, The Netherlands.
authors.forename: S J C
authors.initials: SJ
authors.lastname: Stevens
authors.affiliation: Clinical Genetics Department, Guy's and St Thomas' NHS Foundation Trust, London, UK.
authors.forename: E R A
authors.initials: ER
authors.lastname: Thomas
authors.affiliation: UMR_INSERM U930 Faculté de Médecine, Université François Rabelais, Tours, France.|Service de Génétique, Centre Hospitalo-Universitaire, Tours, France.
authors.forename: A
authors.initials: A
authors.lastname: Toutain
authors.affiliation: Division of Medical Genetics and Metabolism, Children's Hospital of The King's Daughters/Eastern Virginia Medical School, Norfolk, VA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Vergano
authors.affiliation: Department of Pediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada.|Institute of Medical Science, Toronto, Ontario, Canada.|McLaughlin Centre and Department of Molecular Genetics, Toronto, Ontario, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Weksberg
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.|Institute of Medical Science, Toronto, Ontario, Canada.|McLaughlin Centre and Department of Molecular Genetics, Toronto, Ontario, Canada.
authors.forename: S W
authors.initials: SW
authors.lastname: Scherer
authors.affiliation: Molecular Neuropsychiatry and Development Lab, Campbell Family Mental Health Research Institute, The Centre for Addiction and Mental Health, Toronto, Ontario, Canada.|Institute of Medical Science, Toronto, Ontario, Canada.|Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: J B
authors.initials: JB
authors.lastname: Vincent
authors.affiliation: Department of Pediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada.|Autism Research Unit, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: M T
authors.initials: MT
authors.lastname: Carter
mesh_terms: D000293:Adolescent; D000328:Adult; D000067877:Autism Spectrum Disorder / Q000175:diagnosis* / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005091:Exons; D019066:Facies; D005260:Female; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D017384:Sequence Deletion; D055815:Young Adult
chemical_list: D008565:Membrane Proteins; C000607409:PTCHD1 protein, human
keywords: PTCHD1; X-linked; autism spectrum disorder; intellectual disability; phenotype