Journal
GENETICS IN MEDICINE
Volume 21, Issue 7, Pages 1611-1620Publisher
ELSEVIER SCIENCE INC
DOI: 10.1038/s41436-018-0380-2
Keywords
autism spectrum disorders; genome sequencing; exome sequencing; multiple-hit events; diagnostic utility
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Funding
- Simons Foundation Autism Research Initiative [SFARI 303241]
- National Institutes of Health (NIH) [R01MH101221]
- NIH [1K99MH117165, R01MH100047]
- NYGC CCDG [UM1HG008901]
- Genome Sequencing Program (GSP) Coordinating Center [U24HG008956]
- National Human Genome Research Institute
- National Heart, Lung, and Blood Institute
- NHGRI
- NHLBI [UM1 HG006493, U24 HG008956]
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Purpose: To maximize the discovery of potentially pathogenic variants to better understand the diagnostic utility of genome sequencing (GS) and to assess how the presence of multiple risk events might affect the phenotypic severity in autism spectrum disorders (ASD). Methods: GS was applied to 180 simplex and multiplex ASD families (578 individuals, 213 patients) with exome sequencing and array comparative genomic hybridization further applied to a subset for validation and cross-platform comparisons. Results: We found that 40.8% of patients carried variants with evidence of disease risk, including a de novo frameshift variant in NR4A2 and two de novo missense variants in SYNCRIP, while 21.1% carried clinically relevant pathogenic or likely pathogenic variants. Patients with more than one risk variant (9.9%) were more severely affected with respect to cognitive ability compared with patients with a single or no-risk variant. We observed no instance among the 27 multiplex families where a pathogenic or likely pathogenic variant was transmitted to all affected members in the family. Conclusion: The study demonstrates the diagnostic utility of GS, especially for multiple risk variants that contribute to the phenotypic severity, shows the genetic heterogeneity in multiplex families, and provides evidence for new genes for follow up.
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