Disruption at the PTCHD1 locus on Xp22.11 in autism spectrum disorder and intellectual disability

Abdul Noor, Annabel Whibley, Christian R. Marshall, Peter J. Gianakopoulos, Amelie Piton, Andrew R. Carson, Marija Orlic-Milacic, Anath C. Lionel, Daisuke Sato, Dalila Pinto, Irene Drmic, Carolyn Noakes, Lili Senman, Xiaoyun Zhang, Rong Mo, Julie Gauthier, Jennifer Crosbie, Alistair T. Pagnamenta, Jeffrey Munson, Annette M. EstesAndreas Fiebig, Andre Franke, Stefan Schreiber, Alexandre F R Stewart, Robert Roberts, Ruth McPherson, Stephen J. Guter, Edwin H. Cook, Geraldine Dawson, Gerard D. Schellenberg, Agatino Battaglia, Elena Maestrini, Linda Jeng, Terry Hutchison, Evica Rajcan-Separovic, Albert E. Chudley, Suzanne M E Lewis, Xudong Liu, Jeanette J. Holden, Bridget Fernandez, Lonnie Zwaigenbaum, Susan E. Bryson, Wendy Roberts, Peter Szatmari, Louise Gallagher, Michael R. Stratton, Jozef Gecz, Angela F. Brady, Charles E. Schwartz, Russell J. Schachar, Anthony P. Monaco, Guy A. Rouleau, Chi Chung Hui, F. Lucy Raymond, Stephen W. Scherer, John B. Vincent

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number49ra68
JournalScience Translational Medicine
Volume2
Issue number49
DOIs
Publication statusPublished - Sep 15 2010

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Intellectual Disability
5' Flanking Region
Untranslated RNA
Autism Spectrum Disorder
Learning Disorders
X Chromosome
Autistic Disorder
Genes
Exons
Mutation

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Noor, A., Whibley, A., Marshall, C. R., Gianakopoulos, P. J., Piton, A., Carson, A. R., ... Vincent, J. B. (2010). Disruption at the PTCHD1 locus on Xp22.11 in autism spectrum disorder and intellectual disability. Science Translational Medicine, 2(49), [49ra68]. https://doi.org/10.1126/scitranslmed.3001267

Disruption at the PTCHD1 locus on Xp22.11 in autism spectrum disorder and intellectual disability. / Noor, Abdul; Whibley, Annabel; Marshall, Christian R.; Gianakopoulos, Peter J.; Piton, Amelie; Carson, Andrew R.; Orlic-Milacic, Marija; Lionel, Anath C.; Sato, Daisuke; Pinto, Dalila; Drmic, Irene; Noakes, Carolyn; Senman, Lili; Zhang, Xiaoyun; Mo, Rong; Gauthier, Julie; Crosbie, Jennifer; Pagnamenta, Alistair T.; Munson, Jeffrey; Estes, Annette M.; Fiebig, Andreas; Franke, Andre; Schreiber, Stefan; Stewart, Alexandre F R; Roberts, Robert; McPherson, Ruth; Guter, Stephen J.; Cook, Edwin H.; Dawson, Geraldine; Schellenberg, Gerard D.; Battaglia, Agatino; Maestrini, Elena; Jeng, Linda; Hutchison, Terry; Rajcan-Separovic, Evica; Chudley, Albert E.; Lewis, Suzanne M E; Liu, Xudong; Holden, Jeanette J.; Fernandez, Bridget; Zwaigenbaum, Lonnie; Bryson, Susan E.; Roberts, Wendy; Szatmari, Peter; Gallagher, Louise; Stratton, Michael R.; Gecz, Jozef; Brady, Angela F.; Schwartz, Charles E.; Schachar, Russell J.; Monaco, Anthony P.; Rouleau, Guy A.; Hui, Chi Chung; Raymond, F. Lucy; Scherer, Stephen W.; Vincent, John B.

In: Science Translational Medicine, Vol. 2, No. 49, 49ra68, 15.09.2010.

Research output: Contribution to journalArticle

Noor, A, Whibley, A, Marshall, CR, Gianakopoulos, PJ, Piton, A, Carson, AR, Orlic-Milacic, M, Lionel, AC, Sato, D, Pinto, D, Drmic, I, Noakes, C, Senman, L, Zhang, X, Mo, R, Gauthier, J, Crosbie, J, Pagnamenta, AT, Munson, J, Estes, AM, Fiebig, A, Franke, A, Schreiber, S, Stewart, AFR, Roberts, R, McPherson, R, Guter, SJ, Cook, EH, Dawson, G, Schellenberg, GD, Battaglia, A, Maestrini, E, Jeng, L, Hutchison, T, Rajcan-Separovic, E, Chudley, AE, Lewis, SME, Liu, X, Holden, JJ, Fernandez, B, Zwaigenbaum, L, Bryson, SE, Roberts, W, Szatmari, P, Gallagher, L, Stratton, MR, Gecz, J, Brady, AF, Schwartz, CE, Schachar, RJ, Monaco, AP, Rouleau, GA, Hui, CC, Raymond, FL, Scherer, SW & Vincent, JB 2010, 'Disruption at the PTCHD1 locus on Xp22.11 in autism spectrum disorder and intellectual disability', Science Translational Medicine, vol. 2, no. 49, 49ra68. https://doi.org/10.1126/scitranslmed.3001267
Noor, Abdul ; Whibley, Annabel ; Marshall, Christian R. ; Gianakopoulos, Peter J. ; Piton, Amelie ; Carson, Andrew R. ; Orlic-Milacic, Marija ; Lionel, Anath C. ; Sato, Daisuke ; Pinto, Dalila ; Drmic, Irene ; Noakes, Carolyn ; Senman, Lili ; Zhang, Xiaoyun ; Mo, Rong ; Gauthier, Julie ; Crosbie, Jennifer ; Pagnamenta, Alistair T. ; Munson, Jeffrey ; Estes, Annette M. ; Fiebig, Andreas ; Franke, Andre ; Schreiber, Stefan ; Stewart, Alexandre F R ; Roberts, Robert ; McPherson, Ruth ; Guter, Stephen J. ; Cook, Edwin H. ; Dawson, Geraldine ; Schellenberg, Gerard D. ; Battaglia, Agatino ; Maestrini, Elena ; Jeng, Linda ; Hutchison, Terry ; Rajcan-Separovic, Evica ; Chudley, Albert E. ; Lewis, Suzanne M E ; Liu, Xudong ; Holden, Jeanette J. ; Fernandez, Bridget ; Zwaigenbaum, Lonnie ; Bryson, Susan E. ; Roberts, Wendy ; Szatmari, Peter ; Gallagher, Louise ; Stratton, Michael R. ; Gecz, Jozef ; Brady, Angela F. ; Schwartz, Charles E. ; Schachar, Russell J. ; Monaco, Anthony P. ; Rouleau, Guy A. ; Hui, Chi Chung ; Raymond, F. Lucy ; Scherer, Stephen W. ; Vincent, John B. / Disruption at the PTCHD1 locus on Xp22.11 in autism spectrum disorder and intellectual disability. In: Science Translational Medicine. 2010 ; Vol. 2, No. 49.
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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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AU - Whibley, Annabel

AU - Marshall, Christian R.

AU - Gianakopoulos, Peter J.

AU - Piton, Amelie

AU - Carson, Andrew R.

AU - Orlic-Milacic, Marija

AU - Lionel, Anath C.

AU - Sato, Daisuke

AU - Pinto, Dalila

AU - Drmic, Irene

AU - Noakes, Carolyn

AU - Senman, Lili

AU - Zhang, Xiaoyun

AU - Mo, Rong

AU - Gauthier, Julie

AU - Crosbie, Jennifer

AU - Pagnamenta, Alistair T.

AU - Munson, Jeffrey

AU - Estes, Annette M.

AU - Fiebig, Andreas

AU - Franke, Andre

AU - Schreiber, Stefan

AU - Stewart, Alexandre F R

AU - Roberts, Robert

AU - McPherson, Ruth

AU - Guter, Stephen J.

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AU - Hutchison, Terry

AU - Rajcan-Separovic, Evica

AU - Chudley, Albert E.

AU - Lewis, Suzanne M E

AU - Liu, Xudong

AU - Holden, Jeanette J.

AU - Fernandez, Bridget

AU - Zwaigenbaum, Lonnie

AU - Bryson, Susan E.

AU - Roberts, Wendy

AU - Szatmari, Peter

AU - Gallagher, Louise

AU - Stratton, Michael R.

AU - Gecz, Jozef

AU - Brady, Angela F.

AU - Schwartz, Charles E.

AU - Schachar, Russell J.

AU - Monaco, Anthony P.

AU - Rouleau, Guy A.

AU - Hui, Chi Chung

AU - Raymond, F. Lucy

AU - Scherer, Stephen W.

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