Clinical Genetic Testing for Patients With Autism Spectrum Disorders

Abstract

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 changesin7.3%(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.

Neuronal cell adhesion genes

“…Finally, although the common risk genes identified by our analysis are of limited clinical utility, more highly penetrant mutations although individually rare may be diagnostically significant across these neurodevelopmental disorders as is already being realised in ASDs. 29 …”

Autism genetic testing: a qualitative study of awareness, attitudes, and experiences among parents of children with autism spectrum disorders

“…The diagnostic yield of ASD genetic testing varies from 0.5% to 18%, depending on the type of testing. [7][8][9][10] Although genetic testing is now a standard of care and an integral part of evaluation of ASD, a genetic cause is identified in <25% of patients with ASD. 11 With the advancement of genomic technologies, another potential test-massively parallel sequencing (e.g., whole-exome and whole-genome sequencing analysis)-is gradually moving from the research laboratory to clinical settings for the identification of single genes associated with ASD.…”

Genetic architecture, epigenetic influence and environment exposure in the pathogenesis of Autism

“…Stobbe et al [9] collected 23 adult patients (range 18-45 years) with confirmed autism. CNVs were demonstrated in 9 of 23 (39.1%) of patients, compared with 18.2% in published pediatric cases of ASDs [10], which suggested that the adult ASD population is enriched for genomic imbalance and rare CNVs. Girirajan et al identified recurrent CNVs, including DPP10, PLCB1, TRPM1, NRXN1, FHIT, and HYDIN, that are enriched in autism by focusing on gene-disruptive events.…”