Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder
Abstract
IMPORTANCE: The use of genome-wide tests to provide molecular diagnosis for individuals with autism spectrum disorder (ASD) requires more study. OBJECTIVE: To perform chromosomal microarray analysis (CMA) and whole-exome sequencing (WES) in a heterogeneous group of children with ASD to determine the molecular diagnostic yield of these tests in a sample typical of a developmental pediatric clinic. DESIGN, SETTING, AND PARTICIPANTS: The sample consisted of 258 consecutively ascertained unrelated children with ASD who underwent detailed assessments to define morphology scores based on the presence of major congenital abnormalities and minor physical anomalies. The children were recruited between 2008 and 2013 in Newfoundland and Labrador, Canada. The probands were stratified into 3 groups of increasing morphological severity: essential, equivocal, and complex (scores of 0-3, 4-5, and ≥6). EXPOSURES: All probands underwent CMA, with WES performed for 95 proband-parent trios. MAIN OUTCOMES AND MEASURES: The overall molecular diagnostic yield for CMA and WES in a population-based ASD sample stratified in 3 phenotypic groups. RESULTS: Of 258 probands, 24 (9.3%, 95%CI, 6.1%-13.5%) received a molecular diagnosis from CMA and 8 of 95 (8.4%, 95%CI, 3.7%-15.9%) from WES. The yields were statistically different between the morphological groups. Among the children who underwent both CMA and WES testing, the estimated proportion with an identifiable genetic etiology was 15.8% (95%CI, 9.1%-24.7%; 15/95 children). This included 2 children who received molecular diagnoses from both tests. The combined yield was significantly higher in the complex group when compared with the essential group (pairwise comparison, P = .002). [table: see text]. CONCLUSIONS AND RELEVANCE: Among a heterogeneous sample of children with ASD, the molecular diagnostic yields of CMA and WES were comparable, and the combined molecular diagnostic yield was higher in children with more complex morphological phenotypes in comparison with the children in the essential category. If replicated in additional populations, these findings may inform appropriate selection of molecular diagnostic testing for children affected by ASD.
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Previous studies have identified molecular diagnoses in 6-37% of individuals with ASD, with higher yields in individuals with additional co-morbidities including intellectual disabilities, seizures, and other medical features.
“Previous studies have identified molecular diagnoses in 6–37% of individuals with ASD, with higher yields in individuals with additional co-morbidities that include intellectual disabilities, seizures, and other medical features.5”
From Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes (2019) · cites this paper as [5]
Known genetic factors explain only about 20% of ASD cases.
“collectively, these genetic factors are involved in the etiology of only ~20% of ASD cases17,18.”
From Genome-wide detection of tandem DNA repeats that are expanded in autism (2020) · cites this paper as [18]
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Self-citation
- Authors
- Tammimies, K., Marshall, C. R., Walker, S., Kaur, G., Thiruvahindrapuram, B., Lionel, A. C., Yuen, R. K. C., Uddin, M., Roberts, W., Weksberg, R., Woodbury-Smith, M., Zwaigenbaum, L., Anagnostou, E., Wang, Z., Wei, J., Howe, J. L., Gazzellone, M. J., Lau, L., Sung, W. W. L., Whitten, K., Vardy, C., Crosbie, V., Tsang, B., D’Abate, L., Tong, W. W. L., Luscombe, S., Doyle, T., Carter, M. T., Szatmari, P., Stuckless, S., Merico, D., Stavropoulos, D. J., Scherer, S. W., & Fernandez, B. A.
- Affiliations
- Hospital for Sick Children (CA)
- University of Toronto (CA)
- Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada
- University of Alberta (CA)
- Bloorview Research Institute (CA)
- Eastern Health (CA)
- Memorial University of Newfoundland (CA)
- Centre for Addiction and Mental Health, The Hospital for Sick Children, University of Toronto, Toronto, Canada
- ORCID
- Tammimies, Kristiina
- Marshall, Christian R.
- Walker, Susan
- Kaur, Gaganjot
- Thiruvahindrapuram, Bhooma
- Lionel, Anath C.
- Yuen, Ryan K. C.
- Uddin, Mohammed
- Weksberg, Rosanna
- Zwaigenbaum, Lonnie
- Anagnostou, Evdokia
- Wang, Zhuozhi
- Wei, John
- Lau, Lynette
- Sung, Wilson W. L.
- Tsang, Brian
- D’Abate, Lia
- Carter, Melissa T.
- Merico, Daniele
- Stavropoulos, Dimitri J.
- Scherer, Stephen W.
- Fernandez, Bridget A.
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2015-09-01
- Volume
- 314
- Issue
- 9
- Pages
- 895
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- OpenAlex
- W2128274087
- Semantic Scholar
- 30d3fc4dd10494b093f581a5f2a2573f622a9d29
- Cited by
- 419
- References
- 8
- Citations by year
- 2026: 17 · 2025: 25 · 2024: 38 · 2023: 31 · 2022: 38 · 2021: 54 · 2020: 51 · 2019: 46 · 2018: 41 · 2017: 42 · 2016: 30 · 2015: 4
- FWCI
- 23.44
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- JAMA (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- autism spectrum disorder, chromosomal microarray analysis, exome sequencing, genetic etiology, morphological phenotypes, congenital malformations, children
- MeSH terms
- Autistic Disorder, Child, Child Development Disorders, Pervasive, Child, Preschool, Female, Humans, Male, Mutation, Phenotype, Sequence Analysis, DNA, Oligonucleotide Array Sequence Analysis, Sequence Analysis, Protein, Asperger Syndrome, Molecular Diagnostic Techniques, Microarray Analysis, Exome
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