ID
45460
Description
Principal Investigator: Evan E. Eichler, PhD, Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA; Howard Hughes Medical Institute, Seattle, WA, USA MeSH: Autistic Disorder,Child Development Disorders, Pervasive https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000482 It is well established that autism spectrum disorders (ASD) have a strong genetic component; however, for at least 70% of cases, the underlying genetic cause is unknown. Under the hypothesis that de novo mutations underlie a substantial fraction of the risk for developing ASD in families with no previous history of ASD or related phenotypes-so-called sporadic or simplex families-we sequenced all coding regions of the genome (the exome) for parent-child trios exhibiting sporadic ASD, including 189 new trios and 20 that were previously reported. Additionally, we also sequenced the exomes of 50 unaffected siblings corresponding to these new (n = 31) and previously reported trios (n = 19), for a total of 617 individual exomes from 209 families deposited in dbGaP. Here we show that de novo point mutations are overwhelmingly paternal in origin (4:1 bias) and positively correlated with paternal age, consistent with the modest increased risk for children of older fathers to develop ASD. Moreover, 39% (49 of 126) of the most severe or disruptive de novo mutations map to a highly interconnected beta-catenin/chromatin remodelling protein network ranked significantly for autism candidate genes. In proband exomes, recurrent protein-altering mutations were observed in two genes: CHD8 and NTNG1. Mutation screening of six candidate genes in 1,703 ASD probands identified additional de novo, protein-altering mutations in GRIN2B, LAMC3 and SCN1A. Combined with copy number variant (CNV) data, these results indicate extreme locus heterogeneity but also provide a target for future discovery, diagnostics and therapeutics.
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Keywords
Versions (2)
- 10/20/22 10/20/22 - Simon Heim
- 12/12/22 12/12/22 - Kristina Keller
Copyright Holder
Evan E. Eichler, PhD, Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA; Howard Hughes Medical Institute, Seattle, WA, USA
Uploaded on
December 12, 2022
DOI
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License
Creative Commons BY 4.0
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dbGaP phs000482 Sporadic Autism Exomes Reveal a Highly Interconnected Protein Network of De Novo Mutations
Eligibility Criteria
- StudyEvent: SEV1
- Eligibility Criteria
- This data table contains subject IDs, consent group information, subject aliases, and affection status for sporadic autism spectrum disorder (ASD).
- The pedigree table includes parent-child trios exhibiting sporadic autism spectrum disorder (ASD), including 189 new trios and 20 that were previously reported. Additionally, there are 50 unaffected siblings corresponding to these new (n = 31) and previously reported trios (n = 19) for a total of 617 subjects listed in this file.
- The data table contains mapping of study subject IDs to sample IDs and sample source. Samples are the final preps submitted for genotyping, sequencing, and/or expression data. For example, if one patient (subject ID) gave one sample, and that sample was processed differently to generate 2 sequencing runs, there would be two rows, both using the same subject ID, but having 2 unique sample IDs. Sample use is also included.
- The sample attributes data table includes sample analyte type (DNA or RNA), body site where samples were collected, is tumor status, and histological type.
Similar models
Eligibility Criteria
- StudyEvent: SEV1
- Eligibility Criteria
- This data table contains subject IDs, consent group information, subject aliases, and affection status for sporadic autism spectrum disorder (ASD).
- The pedigree table includes parent-child trios exhibiting sporadic autism spectrum disorder (ASD), including 189 new trios and 20 that were previously reported. Additionally, there are 50 unaffected siblings corresponding to these new (n = 31) and previously reported trios (n = 19) for a total of 617 subjects listed in this file.
- The data table contains mapping of study subject IDs to sample IDs and sample source. Samples are the final preps submitted for genotyping, sequencing, and/or expression data. For example, if one patient (subject ID) gave one sample, and that sample was processed differently to generate 2 sequencing runs, there would be two rows, both using the same subject ID, but having 2 unique sample IDs. Sample use is also included.
- The sample attributes data table includes sample analyte type (DNA or RNA), body site where samples were collected, is tumor status, and histological type.
C0015671 (UMLS CUI [1,2])
C1948021 (UMLS CUI [1,3])
C1511518 (UMLS CUI [1,2])
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C0086582 (UMLS CUI [1,2])
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C0086287 (UMLS CUI [1,2])
C1510586 (UMLS CUI [1,3])
C1298908 (UMLS CUI [1,4])
C3714756 (UMLS CUI [1,5])
C0086287 (UMLS CUI [1,2])
C1510586 (UMLS CUI [1,3])
C3714756 (UMLS CUI [1,4])
C2986417 (UMLS CUI [1,2])
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C0150103 (UMLS CUI [1,3])
C1948021 (UMLS CUI [1,4])
C0037047 (UMLS CUI [1,2])
C0150103 (UMLS CUI [1,3])
C1948021 (UMLS CUI [1,4])