Clinical genetic testing for patients with autism spectrum disorders.
BACKGROUND
Multiple lines of evidence indicate a strong genetic contribution to autism spectrum disorders (ASDs). Current guidelines for clinical genetic testing recommend a G-banded karyotype to detect chromosomal abnormalities and fragile X DNA testing, but guidelines for chromosomal microarray analysis have not been established.


METHODS
A cohort of 933 patients received clinical genetic testing for a diagnosis of ASD between January 2006 and December 2008. Clinical genetic testing included G-banded karyotype, fragile X testing, and chromosomal microarray (CMA) to test for submicroscopic genomic deletions and duplications. Diagnostic yield of clinically significant genetic changes was compared.


RESULTS
Karyotype yielded abnormal results in 19 of 852 patients (2.23% [95% confidence interval (CI): 1.73%-2.73%]), fragile X testing was abnormal in 4 of 861 (0.46% [95% CI: 0.36%-0.56%]), and CMA identified deletions or duplications in 154 of 848 patients (18.2% [95% CI: 14.76%-21.64%]). CMA results for 59 of 848 patients (7.0% [95% CI: 5.5%-8.5%]) were considered abnormal, which includes variants associated with known genomic disorders or variants of possible significance. CMA results were normal in 10 of 852 patients (1.2%) with abnormal karyotype due to balanced rearrangements or unidentified marker chromosome. CMA with whole-genome coverage and CMA with targeted genomic regions detected clinically relevant copy-number changes in 7.3% (51 of 697) and 5.3% (8 of 151) of patients, respectively, both higher than karyotype. With the exception of recurrent deletion and duplication of chromosome 16p11.2 and 15q13.2q13.3, most copy-number changes were unique or identified in only a small subset of patients.


CONCLUSIONS
CMA had the highest detection rate among clinically available genetic tests for patients with ASD. Interpretation of microarray data is complicated by the presence of both novel and recurrent copy-number variants of unknown significance. Despite these limitations, CMA should be considered as part of the initial diagnostic evaluation of patients with ASD.
Autism Consortium, Boston, Massachusetts, USA.
Yiping
Y
Shen
Kira A
KA
Dies
Ingrid A
IA
Holm
Carolyn
C
Bridgemohan
Magdi M
MM
Sobeih
Elizabeth B
EB
Caronna
Karen J
KJ
Miller
Jean A
JA
Frazier
Iris
I
Silverstein
Jonathan
J
Picker
Laura
L
Weissman
Peter
P
Raffalli
Shafali
S
Jeste
Laurie A
LA
Demmer
Heather K
HK
Peters
Stephanie J
SJ
Brewster
Sara J
SJ
Kowalczyk
Beth
B
Rosen-Sheidley
Caroline
C
McGowan
Andrew W
AW
Duda
Sharyn A
SA
Lincoln
Kathryn R
KR
Lowe
Alison
A
Schonwald
Michael
M
Robbins
Fuki
F
Hisama
Robert
R
Wolff
Ronald
R
Becker
Ramzi
R
Nasir
David K
DK
Urion
Jeff M
JM
Milunsky
Leonard
L
Rappaport
James F
JF
Gusella
Christopher A
CA
Walsh
Bai-Lin
BL
Wu
David T
DT
Miller
D000293:Adolescent; D002648:Child; D002659:Child Development Disorders, Pervasive / Q000175:diagnosis* / Q000235:genetics*; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D005820:Genetic Testing / Q000379:methods; D006801:Humans; D007223:Infant; D007621:Karyotyping / Q000379:methods; D008297:Male; D046228:Microarray Analysis / Q000379:methods; D055815:Young Adult