Clinical Genetic Testing for Patients With Autism Spectrum Disorders

Published online March 15, 2010
PEDIATRICS (doi:10.1542/peds.2009-1684) This Article

Articles
Clinical Genetic Testing for Patients With Autism Spectrum Disorders

Yiping Shen, PhDa,b,c,d, Kira A. Dies, ScMa,c, Ingrid A. Holm, MD, MPHa,c,e,f, Carolyn Bridgemohan, MDa,c,g, Magdi M. Sobeih, MD, PhDa,c,h, Elizabeth B. Caronna, MDa,i, Karen J. Miller, MDa,j, Jean A. Frazier, MDa,k,l, Iris Silverstein, MDa,m, Jonathan Picker, MBChB, PhDa,c,n, Laura Weissman, MDa,c,g, Peter Raffalli, MDa,c,h, Shafali Jeste, MDa,c,h, Laurie A. Demmer, MDa,j, Heather K. Peters, MSa,e, Stephanie J. Brewster, MSa,e, Sara J. Kowalczyk, MA, MPHa,i, Beth Rosen-Sheidley, MSa,j, Caroline McGowan, MSa,n, Andrew W. Duda, III, MSa,m, Sharyn A. Lincoln, MSa,n, Kathryn R. Lowe, MSa,e, Alison Schonwald, MDa,c,g, Michael Robbins, MDa,c,h, Fuki Hisama, MDa,c,n, Robert Wolff, MDa,c,h, Ronald Becker, MDa,c,g, Ramzi Nasir, MD, MPHa,c,g, David K. Urion, MDa,c,h, Jeff M. Milunsky, MDa,i,o, Leonard Rappaport, MDa,c,g, James F. Gusella, PhDa,c,d, Christopher A. Walsh, MD, PhDa,c,n, Bai-Lin Wu, PhD, MMeda,b,c,p, David T. Miller, MD, PhDa,b,c,n, on behalf of the Autism Consortium Clinical Genetics/DNA Diagnostics Collaboration

a. Autism Consortium, Boston, Massachusetts;
b. Department of Laboratory Medicine,
e. Program in Genomics,
f. Manton Center for Orphan Disease Research,
g. Developmental Medicine Center,
h. Department of Neurology, and
n. Division of Genetics, Children's Hospital Boston, Boston, Massachusetts;
c. Harvard Medical School, Boston, Massachusetts;
d. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts;
i. Department of Pediatrics and
o. Clinical Genetics, Boston University School of Medicine, Massachusetts;
j. Floating Hospital for Children, Tufts Medical Center, Boston, Massachusetts;
k. University of Massachusetts Medical School, Worcester, Massachusetts;
l. UMass Memorial Medical Center, Worcester, Massachusetts;
m. Massachusetts General Hospital for Children LADDERS Clinic, Boston, Massachusetts; and
p. Institutes of Biomedical Science, Pediatric Hospital, Shanghai Medical College, Fudan University, Shanghai, China

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.

Patients and 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.

Key Words: array CGH • aCGH • autism spectrum disorder • ASD • language delay • microdeletion • microduplication • neuropsychiatric disorders

Abbreviations: ADI-R = Autism Diagnostic Interview-Revised

Accepted Oct 28, 2009.

abstract: http://pediatrics.aappublications.org/cgi/content/abstract/peds.2009-1684v1

full-text:
http://pediatrics.aappublications.org/cgi/reprint/peds.2009-1684v1