Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 2, Issue 49, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.3001267
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Categories
Funding
- Autism Speaks
- Wellcome Trust
- Action Medical Research
- National Institute for Health Research
- CIHR
- German National Genome Research Network
- Simons Foundation
- Nancy Lurie Marks (NLM) Family Foundation
- Autistica
- Medical Research Council (MRC)
- The Health Research Board, Ireland
- Canada Graduate Scholarship
- National Alliance for Research on Schizophrenia and Depression (NARSAD)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development [P50 HD055751]
- Michael Smith Foundation for Health Research
- National Institute of Child Health and Human Development [CPEA HD35465]
- Ontario Mental Health Foundation
- Canada Foundation for Innovation
- Ontario Ministry of Research and Innovation
- MRC
- Simon's Foundation
- NLM Family Foundation
- European Union
- TCAG
- Genome Canada/Ontario Genomics Institute
- Canadian Institute for Advanced Research
- McLaughlin Centre
- Hospital for Sick Children Foundation
- Board of Trustees of Genome Canada
- Scientific Advisory Committee of Autism Speaks
- MRC [G0601030] Funding Source: UKRI
- Medical Research Council [G0601030] Funding Source: researchfish
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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 non-coding 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 similar to 1% of individuals with ASD and intellectual disability.
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