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.
Shen
Yiping
Y
Autism Consortium, Boston, Massachusetts, USA.
Dies
Kira A
KA
Holm
Ingrid A
IA
Bridgemohan
Carolyn
C
Sobeih
Magdi M
MM
Caronna
Elizabeth B
EB
Miller
Karen J
KJ
Frazier
Jean A
JA
Silverstein
Iris
I
Picker
Jonathan
J
Weissman
Laura
L
Raffalli
Peter
P
Jeste
Shafali
S
Demmer
Laurie A
LA
Peters
Heather K
HK
Brewster
Stephanie J
SJ
Kowalczyk
Sara J
SJ
Rosen-Sheidley
Beth
B
McGowan
Caroline
C
Duda
Andrew W
AW
Lincoln
Sharyn A
SA
Lowe
Kathryn R
KR
Schonwald
Alison
A
Robbins
Michael
M
Hisama
Fuki
F
Wolff
Robert
R
Becker
Ronald
R
Nasir
Ramzi
R
Urion
David K
DK
Milunsky
Jeff M
JM
Rappaport
Leonard
L
Gusella
James F
JF
Walsh
Christopher A
CA
Wu
Bai-Lin
BL
Miller
David T
DT
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