The use of two newer genetic testing technologies (chromosomal microarray analysis and whole-exome sequencing) among children with autism spectrum disorder may help identify genetic mutations potentially linked to the disorder, according to a study in the September 1 issue of JAMA. The study also found that children with certain physical anomalies were more likely to have genetic mutations, findings that may help identify children who could benefit most from genetic testing.
Autism spectrum disorder (ASD) represents a diverse group of neurodevelopmental conditions. The clinical presentation and outcome vary substantially. The use of genome-wide tests to provide molecular diagnosis for individuals with ASD requires more study, according to background information in the article.
Stephen W. Scherer, Ph.D., of the Hospital for Sick Children, Toronto, and colleagues performed chromosomal microarray analysis (CMA) and whole-exome sequencing (WES) in a group of 258 unrelated children with ASD to determine the molecular diagnostic yield (the percentage of subjects with a genetic alteration [mutation] that may contribute to the features of autism spectrum disorder) of these tests. All children underwent CMA; a random subset of 95 also underwent WES. All children underwent detailed clinical assessments for the presence of any major congenital abnormalities and minor physical anomalies and were stratified into 3 groups of increasing morphological severity (physical aberrations): essential, equivocal, and complex.
Of the 258 children, 24 (9.3 percent) received a molecular diagnosis from CMA and 8 of 95 (8.4 percent) 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 cause was 15.8 percent. This included 2 children who received molecular diagnoses from both tests. The clinical yield for genetic testing was much higher (37.5 percent) in children with ASD who had more complex clinical presentations based on physical examination.
“In the current study, we have demonstrated differences related to morphological stratification of ASD [children] based on clinical examination. Our data suggest that medical evaluation of ASD children may help identify populations more likely to achieve a molecular diagnosis with genetic testing,” the authors write.
“It seems likely that genetic testing of children with ASD will continue to increase. In a survey of parental interest in ASD genetic testing, 80 percent of parents indicated that they would want a sibling younger than 2 years tested to identify ASD-risk mutations even if the test could not confirm or rule out the diagnosis. For some children with positive genetic test results, treatment plans targeting ASD-associated medical conditions can be offered.”
The researchers conclude that if “replicated in additional populations, these findings may inform appropriate selection of molecular diagnostic testing for children affected by ASD.”
Funding: The research was supported by the National Science Foundation through grant IIS-1111328 and by the National Institutes of Health through grants EY011747 and EY021462.
Source: JAMA Network
Image Credit: The image is in the public domain
Original Research: Full open access research for “Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder” by Kristiina Tammimies, PhD; Christian R. Marshall, PhD; Susan Walker, PhD; Gaganjot Kaur, MRes; Bhooma Thiruvahindrapuram, MSc; Anath C. Lionel, PhD; Ryan K. C. Yuen, PhD; Mohammed Uddin, PhD; Wendy Roberts, MD; Rosanna Weksberg, MD-PhD; Marc Woodbury-Smith, MD-PhD; Lonnie Zwaigenbaum, MD; Evdokia Anagnostou, MD; Zhuozhi Wang, PhD; John Wei, PhD; Jennifer L. Howe; Matthew J. Gazzellone, MSc; Lynette Lau, MSc; Wilson W. L. Sung, MSc; Kathy Whitten; Cathy Vardy, MD; Victoria Crosbie, MD; Brian Tsang, BSc; Lia D’Abate, BSc; Winnie W. L. Tong; Sandra Luscombe, MD; Tyna Doyle, MD; Melissa T. Carter, MD; Peter Szatmari, MD; Susan Stuckless, PhD; Daniele Merico, PhD; Dimitri J. Stavropoulos, PhD; Stephen W. Scherer, PhD; and Bridget A. Fernandez, MD in JAMA. Published online September 1 2015 doi:10.1001/jama.2015.10078
Abstract
Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder
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).Positive ResultsEssential GroupEquivocal GroupComplex GroupP Value for 3-Group ComparisonCMA, No./total No.7/1684/3713/53<.001 % (95% CI)4.2 (1.7-8.4)10.8 (3.0-25.4)24.5 (13.8-38.3)WES, No./total No.2/642/74/24.02 % (95% CI)3.1 (0.0-10.8)28.6 (3.7-71.0)16.7 (4.7-37.4)CMA and/or WES, No./total No.4/642/79/24.001 % (95% CI)6.3 (1.7-15.2)28.6 (3.7-71.0)37.5 (18.8-59.4)
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. For CMA, the proportion of children with a positive test result was 7 of 168 (4.2%, 95% CI, 1.7%-8.4%) in the essential group, 4 of 37 (10.8%, 95% CI, 3.0%-25.4%) in the equivocal group, and 13 of 53 (24.5%, 95% CI, 13.8%-38.3%) in the complex group (P < .001). For WES, the proportions were 2 of 64 (3.1%, 95% CI, 0.0%-10.8%), 2 of 7 (28.6%, 95% CI, 3.7%-71.0%), and 4 of 24 (16.7%, 95% CI, 4.7%-37.4%), respectively (3-group comparison, P = .02). 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 molecular diagnostic yield was 6.3% (95% CI, 1.7%-15.2%) in the essential group (4/64 children), 28.6% (95% CI, 3.7%-71.0%) in the equivocal group (2/7 children), and 37.5% (95% CI, 18.8%-59.4%) in the complex group (9/24 children; 3-group comparison, P = .001). The combined yield was significantly higher in the complex group when compared with the essential group (pairwise comparison, P = .002).
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.
“Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder” by Kristiina Tammimies, PhD; Christian R. Marshall, PhD; Susan Walker, PhD; Gaganjot Kaur, MRes; Bhooma Thiruvahindrapuram, MSc; Anath C. Lionel, PhD; Ryan K. C. Yuen, PhD; Mohammed Uddin, PhD; Wendy Roberts, MD; Rosanna Weksberg, MD-PhD; Marc Woodbury-Smith, MD-PhD; Lonnie Zwaigenbaum, MD; Evdokia Anagnostou, MD; Zhuozhi Wang, PhD; John Wei, PhD; Jennifer L. Howe; Matthew J. Gazzellone, MSc; Lynette Lau, MSc; Wilson W. L. Sung, MSc; Kathy Whitten; Cathy Vardy, MD; Victoria Crosbie, MD; Brian Tsang, BSc; Lia D’Abate, BSc; Winnie W. L. Tong; Sandra Luscombe, MD; Tyna Doyle, MD; Melissa T. Carter, MD; Peter Szatmari, MD; Susan Stuckless, PhD; Daniele Merico, PhD; Dimitri J. Stavropoulos, PhD; Stephen W. Scherer, PhD; and Bridget A. Fernandez, MD in JAMA doi:10.1001/jama.2015.10078
