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


METHODS
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).


METHODS
All probands underwent CMA, with WES performed for 95 proband-parent trios.


METHODS
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
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.
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.
Kristiina
K
Tammimies
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.
Christian R
CR
Marshall
The Centre for Applied Genomics, Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Susan
S
Walker
The Centre for Applied Genomics, Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Gaganjot
G
Kaur
The Centre for Applied Genomics, Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Bhooma
B
Thiruvahindrapuram
The Centre for Applied Genomics, Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Anath C
AC
Lionel
The Centre for Applied Genomics, Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Ryan K C
RK
Yuen
The Centre for Applied Genomics, Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Mohammed
M
Uddin
Autism Research Unit, The Hospital for Sick Children, Toronto, Ontario, Canada.
Wendy
W
Roberts
Department of Pediatrics and Genome Biology Program, The Hospital for Sick Children and Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
Rosanna
R
Weksberg
Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada.
Marc
M
Woodbury-Smith
Department of Pediatrics, University of Alberta, Edmonton, Canada.
Lonnie
L
Zwaigenbaum
Bloorview Research Institute, Toronto, Ontario, Canada.
Evdokia
E
Anagnostou
The Centre for Applied Genomics, Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Zhuozhi
Z
Wang
The Centre for Applied Genomics, Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
John
J
Wei
The Centre for Applied Genomics, Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Jennifer L
JL
Howe
The Centre for Applied Genomics, Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Matthew J
MJ
Gazzellone
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.
Lynette
L
Lau
The Centre for Applied Genomics, Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Wilson W L
WW
Sung
Provincial Medical Genetics Program, Eastern Health, St John's, Newfoundland and Labrador, Canada.
Kathy
K
Whitten
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.
Cathy
C
Vardy
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.
Victoria
V
Crosbie
The Centre for Applied Genomics, Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Brian
B
Tsang
The Centre for Applied Genomics, Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Lia
L
D'Abate
The Centre for Applied Genomics, Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Winnie W L
WW
Tong
Child Health Program, Eastern Health, St John's, Newfoundland and Labrador, Canada.
Sandra
S
Luscombe
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.
Tyna
T
Doyle
Department of Pediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada.
Melissa T
MT
Carter
Centre for Addiction and Mental Health, The Hospital for Sick Children, University of Toronto, Toronto, Canada.
Peter
P
Szatmari
Disciplines of Genetics and Medicine, Memorial University of Newfoundland, St John's, Newfoundland and Labrador, Canada.
Susan
S
Stuckless
The Centre for Applied Genomics, Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
Daniele
D
Merico
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.
Dimitri J
DJ
Stavropoulos
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.
Stephen W
SW
Scherer
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.
Bridget A
BA
Fernandez
D020817:Asperger Syndrome / Q000175:diagnosis / Q000235:genetics; D001321:Autistic Disorder / Q000175:diagnosis / Q000235:genetics; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D002675:Child, Preschool; D059472:Exome; D005260:Female; D006801:Humans; D008297:Male; D046228:Microarray Analysis / Q000379:methods* / Q000706:statistics & numerical data; D025202:Molecular Diagnostic Techniques / Q000379:methods* / Q000706:statistics & numerical data; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis / Q000706:statistics & numerical data; D010641:Phenotype; D017422:Sequence Analysis, DNA / Q000379:methods; D020539:Sequence Analysis, Protein / Q000379:methods