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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, 10 Alexandre Stewart 11 Robert Roberts 11 Ruth Mcpherson 11 Stephen Guter 12 Edwin Cook 12 Geraldine Dawson 13, 7, 14 Gerard Schellenberg 15 Agatino Battaglia 16 Elena Maestrini 17 Catalina Betancur 18 Linda Jeng 19 Terry Hutchison 19 Evica Rajcan-Separovic 20 Albert Chudley 21 Suzanne Lewis 22 Xudong Liu 23 Jeanette Holden 23 Bridget Fernandez 24 Lonnie Zwaigenbaum 25 Susan Bryson 26 Wendy Roberts 3 Peter Szatmari 27 Louise Gallagher 28 Michael Stratton 29 Jozef Gecz 30, 31 Angela Brady 32 Charles Schwartz 33 Russell Schachar 3 Anthony Monaco 6 Guy Rouleau 4, 5 Chi-Chung Hui 3, 34 F. Lucy Raymond 35 Stephen Scherer 3, 34 John Vincent 1, 34
Abstract : 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.
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Submitted on : Monday, February 8, 2021 - 7:39:58 PM
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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, American Association for the Advancement of Science, 2010, 2 (49), pp.49ra68-49ra68. ⟨10.1126/scitranslmed.3001267⟩. ⟨inserm-03135307⟩

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