Clinical genetic testing for patients with autism spectrum disorders
Department of Psychiatry
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
Shen, Yiping; Dies, Kira A.; Holm, Ingrid A.; Bridgemohan, Carolyn; Sobeih, Magdi M.; Caronna, Elizabeth B.; Miller, Karen J.; Frazier, Jean A.; Silverstein, Iris; Picker, Jonathan; Weissman, Laura; Raffalli, Peter; Jeste, Shafali; Demmer, Laurie A.; Peters, Heather K.; Brewster, Stephanie J.; Kowalczyk, Sara J.; Rosen-Sheidley, Beth; McGowan, Caroline; Duda, Andrew W. III; Lincoln, Sharyn A.; Lowe, Kathryn R.; Schonwald, Alison; Robbins, Michael; Hisama, Fuki; Wolff, Robert; Becker, Ronald; Nasir, Ramzi; Urion, David K.; Milunsky, Jeff M.; Rappaport, Leonard; Gusella, James F.; Walsh, Christopher A.; Wu, Bai-Lin; and Miller, David T., "Clinical genetic testing for patients with autism spectrum disorders" (2010). Psychiatry Publications and Presentations. 421.