Disruption at the PTCHD1 Locus on Xp22.11 in Autism Spectrum Disorder and Intellectual Disability

Abdul Noor (1) , Annabel Whibley (2) , Christian Marshall (3) , Peter Gianakopoulos (1) , Amelie Piton (4, 5) , Andrew Carson (3) , Marija Orlic-Milacic (1) , Anath Lionel (3) , Daisuke Sato (3) , Dalila Pinto (3) , Irene Drmic (3) , Carolyn Noakes (3) , Lili Senman (3) , Xiaoyun Zhang (3) , Rong Mo (3) , Julie Gauthier (4, 5) , Jennifer Crosbie (3) , Alistair Pagnamenta (6) , Jeffrey Munson (7) , Annette Estes (7) , Andreas Fiebig (8, 9) , Andre Franke (8, 9) , Stefan Schreiber (8, 9, 8) , Alexandre Stewart (10) , Robert Roberts (10) , Ruth Mcpherson (10) , Stephen Guter (11) , Edwin Cook (11) , Geraldine Dawson (12, 7, 13) , Gerard Schellenberg (14) , Agatino Battaglia (15) , Elena Maestrini (16) , Catalina Betancur (17) , Linda Jeng (18) , Terry Hutchison (18) , Evica Rajcan-Separovic (19) , Albert Chudley (20) , Suzanne Lewis (21) , Xudong Liu (22) , Jeanette Holden (22) , Bridget Fernandez (23) , Lonnie Zwaigenbaum (24) , Susan Bryson (25) , Wendy Roberts (3) , Peter Szatmari (26) , Louise Gallagher (27) , Michael Stratton (28) , Jozef Gecz (29, 30) , Angela Brady (31) , Charles Schwartz (32) , Russell Schachar (3) , Anthony Monaco (6) , Guy Rouleau (4, 5) , Chi-Chung Hui (3, 33) , F. Lucy Raymond (34) , Stephen Scherer (3, 33) , John Vincent (1, 33)

1 CAMH - Centre for Addiction and Mental Health [Toronto]
2 CIMR - Cambridge Institute for Medical Research
3 SickKids - The Hospital for sick children [Toronto]
4 CR CHUM - Centre de Recherche du Centre Hospitalier de l’Université de Montréal
5 UQAM - Université du Québec à Montréal = University of Québec in Montréal
6 The Wellcome Trust Centre for Human Genetics [Oxford]
7 University of Washington [Seattle]
8 CAU - Christian-Albrechts-Universität zu Kiel = Christian-Albrechts University of Kiel = Université Christian-Albrechts de Kiel
9 Biobank PopGen [Kiel, Germany]
10 uOttawa - Université d'Ottawa [Ontario]
11 UIC - University of Illinois [Chicago]
12 Autism Speaks [New York, NY, USA]
13 UNC - University of North Carolina [Chapel Hill]
14 University of Pennsylvania
15 Stella Maris Institute for Child and Adolescent Neuropsychiatry [Pisa, Italy]
16 UNIBO - Alma Mater Studiorum Università di Bologna = University of Bologna
17 NPS-01 - Génétique de l'autisme = Genetics of Autism
18 UC San Francisco - University of California [San Francisco]
19 British Columbia
20 The Children's Hospital of Winnipeg [Winnipeg, Canada]
21 UBC - University of British Columbia
22 Queen's University [Kingston, Canada]
23 MUN - Memorial University of Newfoundland = Université Memorial de Terre-Neuve [St. John's, Canada]
24 University of Alberta
25 Dalhousie University [Halifax]
26 McMaster University [Hamilton, Ontario]
27 Trinity College Dublin
28 The Wellcome Trust Sanger Institute [Cambridge]
29 Women’s and Children’s Hospital [Adelaide]
30 University of South Australia [Adelaide]
31 NPH - Northwick Park Hospital [Harrow, UK]
32 The Greenwood Genetic Center
33 University of Toronto
34 CAM - University of Cambridge [UK]

Autism is a common neurodevelopmental disorder with a complex mode of inheritance. It is one of the most highly heritable of the complex disorders, although the underlying genetic factors remain largely unknown. Here, we report mutations in the X-chromosome PTCHD1 (patched-related) gene in seven families with autism spectrum disorder (ASD) and in three families with intellectual disability. A 167-kilobase microdeletion spanning exon 1 was found in two brothers, one with ASD and the other with a learning disability and ASD features; a 90-kilobase microdeletion spanning the entire gene was found in three males with intellectual disability in a second family. In 900 probands with ASD and 208 male probands with intellectual disability, we identified seven different missense changes (in eight male probands) that were inherited from unaffected mothers and not found in controls. Two of the ASD individuals with missense changes also carried a de novo deletion at another ASD susceptibility locus (DPYD and DPP6), suggesting complex genetic contributions. In additional males with ASD, we identified deletions in the 5' flanking region of PTCHD1 that disrupted a complex noncoding RNA and potential regulatory elements; equivalent changes were not found in male control individuals. Thus, our systematic screen of PTCHD1 and its 5' flanking regions suggests that this locus is involved in ~1% of individuals with ASD and intellectual disability.

Domaines: Génétique

Abdul Noor, Annabel Whibley, Christian Marshall, Peter Gianakopoulos, Amelie Piton, et al.. Disruption at the PTCHD1 Locus on Xp22.11 in Autism Spectrum Disorder and Intellectual Disability. Science Translational Medicine, 2010, 2 (49), pp.49ra68-49ra68. ⟨10.1126/scitranslmed.3001267⟩. ⟨inserm-03135307⟩