Clinical genetic testing for patients with autism spectrum disorders


Yiping Shen, Harvard Medical School
Kira A. Dies, Harvard Medical School
Ingrid A. Holm, Harvard Medical School
Carolyn Bridgemohan, Harvard Medical School
Magdi M. Sobeih, Harvard Medical School
Elizabeth B. Caronna, Boston University School of Medicine
Karen J. Miller, Tufts Medical Center
Jean A. Frazier, University of Massachusetts Medical SchoolFollow
Iris Silverstein, Massachusetts General Hospital
Jonathan Picker, Harvard Medical School
Laura Weissman, Harvard Medical School
Peter Raffalli, Harvard Medical School
Shafali Jeste, Harvard Medical School
Laurie A. Demmer, University of Massachusetts Medical School
Heather K. Peters, Harvard Medical School
Stephanie J. Brewster, Harvard Medical School
Sara J. Kowalczyk, Boston University School of Medicine
Beth Rosen-Sheidley, Tufts Medical Center
Caroline McGowan, Children's Hospital Boston
Andrew W. Duda III, Massachusetts General Hospital
Sharyn A. Lincoln, Children's Hospital Boston
Kathryn R. Lowe, Children's Hospital Boston
Alison Schonwald, Harvard Medical School
Michael Robbins, Harvard Medical School
Fuki Hisama, Harvard Medical School
Robert Wolff, Harvard Medical School
Ronald Becker, Harvard Medical School
Ramzi Nasir, Harvard Medical School
David K. Urion, Harvard Medical School
Jeff M. Milunsky, Boston University School of Medicine
Leonard Rappaport, Harvard Medical School
James F. Gusella, Harvard Medical School
Christopher A. Walsh, Harvard Medical School
Bai-Lin Wu, Fudan University
David T. Miller, Harvard Medical School

UMMS Affiliation

Department of Psychiatry

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Adolescent; Child; Child Development Disorders, Pervasive; Child, Preschool; Cohort Studies; Female; *Genetic Testing; Humans; Infant; Karyotyping; Male; Microarray Analysis; Young Adult




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.

DOI of Published Version



Pediatrics. 2010 Apr;125(4):e727-35. Epub 2010 Mar 15. Link to article on publisher's site

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