Format

Send to

Choose Destination
JAMA. 2015 Sep 1;314(9):895-903. doi: 10.1001/jama.2015.10078.

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

Author information

1
The Centre for Applied Genomics, Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada2Center of Neurodevelopmental Disorders (KIND), Pediatric Neuropsychiatry Unit, Department of Women's and Children's Health, K.
2
The Centre for Applied Genomics, Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada3Genome Diagnostics, Department of Pediatrics Laboratory Medicine, The Hospital for Sick Children, Toronto, Canada.
3
The Centre for Applied Genomics, Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
4
Autism Research Unit, The Hospital for Sick Children, Toronto, Ontario, Canada.
5
Department of Pediatrics and Genome Biology Program, The Hospital for Sick Children and Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
6
Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada.
7
Department of Pediatrics, University of Alberta, Edmonton, Canada.
8
Bloorview Research Institute, Toronto, Ontario, Canada.
9
Provincial Medical Genetics Program, Eastern Health, St John's, Newfoundland and Labrador, Canada.
10
Child Health Program, Eastern Health, St John's, Newfoundland and Labrador, Canada13Discipline of Pediatrics, Memorial University of Newfoundland, St John's, Newfoundland and Labrador, Canada.
11
Child Health Program, Eastern Health, St John's, Newfoundland and Labrador, Canada.
12
Department of Pediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada.
13
Centre for Addiction and Mental Health, The Hospital for Sick Children, University of Toronto, Toronto, Canada.
14
Disciplines of Genetics and Medicine, Memorial University of Newfoundland, St John's, Newfoundland and Labrador, Canada.
15
Genome Diagnostics, Department of Pediatrics Laboratory Medicine, The Hospital for Sick Children, Toronto, Canada15Cytogenetics Laboratory, Department of Pediatrics Laboratory Medicine, The Hospital for Sick Children, Toronto, Canada.
16
The Centre for Applied Genomics, Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada16Department of Molecular Genetics and the McLaughlin Centre, University of Toronto, Toronto, Canada.
17
Provincial Medical Genetics Program, Eastern Health, St John's, Newfoundland and Labrador, Canada14Disciplines of Genetics and Medicine, Memorial University of Newfoundland, St John's, Newfoundland and Labrador, Canada.

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.

PMID:
26325558
DOI:
10.1001/jama.2015.10078
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Silverchair Information Systems
Loading ...
Support Center