Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2018 Mar;6(2):171-185.
doi: 10.1002/mgg3.354. Epub 2017 Dec 21.

Genetic testing including targeted gene panel in a diverse clinical population of children with autism spectrum disorder: Findings and implications

Louisa Kalsner  1   2 , Jennifer Twachtman-Bassett  1 , Kristin Tokarski  2 , Christine Stanley  3 , Thyde Dumont-Mathieu  1   2 , Justin Cotney  2 , Stormy Chamberlain  2
Affiliations

Genetic testing including targeted gene panel in a diverse clinical population of children with autism spectrum disorder: Findings and implications

Louisa Kalsner et al. Mol Genet Genomic Med. 2018 Mar.

Abstract

Background: Genetic testing of children with autism spectrum disorder (ASD) is now standard in the clinical setting, with American College of Medical Genetics and Genomics (ACMGG) guidelines recommending microarray for all children, fragile X testing for boys and additional gene sequencing, including PTEN and MECP2, in appropriate patients. Increasingly, testing utilizing high throughput sequencing, including gene panels and whole exome sequencing, are offered as well.

Methods: We performed genetic testing including microarray, fragile X testing and targeted gene panel, consistently sequencing 161 genes associated with ASD risk, in a clinical population of 100 well characterized children with ASD. Frequency of rare variants identified in individual genes was compared with that reported in the Exome Aggregation Consortium (ExAC) database.

Results: We did not diagnose any conditions with complete penetrance for ASD; however, copy number variants believed to contribute to ASD risk were identified in 12%. Eleven children were found to have likely pathogenic variants on gene panel, yet, after careful analysis, none was considered likely causative of disease. KIRREL3 variants were identified in 6.7% of children compared to 2% in ExAC, suggesting a potential role for KIRREL3 variants in ASD risk. Children with KIRREL3 variants more often had minor facial dysmorphism and intellectual disability. We also observed an increase in rare variants in TSC2. However, analysis of variant data from the Simons Simplex Collection indicated that rare variants in TSC2 occur more commonly in specific racial/ethnic groups, which are more prevalent in our population than in the ExAC database.

Conclusion: The yield of genetic testing including microarray, fragile X (boys) and targeted gene panel was 12%. Gene panel did not increase diagnostic yield; however, we found an increase in rare variants in KIRREL3. Our findings reinforce the need for racial/ethnic diversity in large-scale genomic databases used to identify variants that contribute to disease risk.

Keywords: KIRREL3; TSC2; autism spectrum disorder; microarray; racial/ethnic diversity; targeted gene panel.

PubMed Disclaimer

References

    1. Alarcon, M. , Abrahams, B. S. , Stone, J. L. , Duvall, J. A. , Perederiy, J. V. , Bomar, J. M. , … Geschwind, D. H. (2008). Linkage, association, and gene‐expression analyses identify CNTNAP2 as an autism‐susceptibility gene. American Journal of Human Genetics, 82(1), 150–159. https://doi.org/10.1016/j.ajhg.2007.09.005 - DOI - PMC - PubMed
    1. Alvarez‐Mora, M. I. , Calvo Escalona, R. , Puig Navarro, O. , Madrigal, I. , Quintela, I. , Amigo, J. , … Rodriguez‐Revenga, L. (2016). Comprehensive molecular testing in patients with high functioning autism spectrum disorder. Mutation Research, 784–785, 46–52. https://doi.org/10.1016/j.mrfmmm.2015.12.006 - DOI - PubMed
    1. American Psychiatric Association (2013). Diagnostic and statistical manual of mental disorders: DSM‐5 (5th ed.). Washington, DC: American Psychiatric Association.
    1. Auton, A. , Brooks, L. D. , Durbin, R. M. , Garrison, E. P. , Kang, H. M. , Korbel, J. O. , … Abecasis, G. R. (2015). A global reference for human genetic variation. Nature, 526(7571), 68–74. https://doi.org/10.1038/nature15393 - DOI - PMC - PubMed
    1. Bahl, S. , Chiang, C. , Beauchamp, R. L. , Neale, B. M. , Daly, M. J. , Gusella, J. F. , … Ramesh, V. (2013). Lack of association of rare functional variants in TSC1/TSC2 genes with autism spectrum disorder. Molecular Autism, 4(1), 5 https://doi.org/10.1186/2040-2392-4-5 - DOI - PMC - PubMed

Publication types

MeSH terms