Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder | Autism Spectrum Disorders | JAMA | JAMA Network
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Original Investigation
September 1, 2015

Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder

Author Affiliations
  • 1The Centre for Applied Genomics, Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada
  • 2Center of Neurodevelopmental Disorders (KIND), Pediatric Neuropsychiatry Unit, Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
  • 3Genome Diagnostics, Department of Pediatrics Laboratory Medicine, The Hospital for Sick Children, Toronto, Canada
  • 4Autism Research Unit, The Hospital for Sick Children, Toronto, Ontario, Canada
  • 5Department of Pediatrics and Genome Biology Program, The Hospital for Sick Children and Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
  • 6Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada
  • 7Department of Pediatrics, University of Alberta, Edmonton, Canada
  • 8Bloorview Research Institute, Toronto, Ontario, Canada
  • 9Provincial Medical Genetics Program, Eastern Health, St John’s, Newfoundland and Labrador, Canada
  • 10Child Health Program, Eastern Health, St John’s, Newfoundland and Labrador, Canada
  • 11Department of Pediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada
  • 12Centre for Addiction and Mental Health, The Hospital for Sick Children, University of Toronto, Toronto, Canada
  • 13Discipline of Pediatrics, Memorial University of Newfoundland, St John’s, Newfoundland and Labrador, Canada
  • 14Disciplines of Genetics and Medicine, Memorial University of Newfoundland, St John’s, Newfoundland and Labrador, Canada
  • 15Cytogenetics Laboratory, Department of Pediatrics Laboratory Medicine, The Hospital for Sick Children, Toronto, Canada
  • 16Department of Molecular Genetics and the McLaughlin Centre, University of Toronto, Toronto, Canada
JAMA. 2015;314(9):895-903. doi:10.1001/jama.2015.10078

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. 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.