Am J Med Genet A. 2021 Oct;185(10):2922-2928. doi: 10.1002/ajmg.a.62372. Epub 2021 Jun 02.

Temporal trends and yield of clinical diagnostic genetic testing in adult neurology.

American journal of medical genetics. Part A

Michael H Guo, Tanya M Bardakjian, Morgan R Brzozowski, Steven S Scherer, Colin Quinn, Lauren Elman, Jennifer Orthmann-Murphy, Thomas F Tropea, Colin A Ellis, Pedro Gonzalez-Alegre

PMID: 34075706 DOI: 10.1002/ajmg.a.62372

Abstract

While genetics evaluation is increasingly utilized in adult neurology patients, its usage and efficacy are not well characterized. Here, we report our experience with 1461 consecutive patients evaluated in an adult neurogenetics clinic at a large academic medical center between January 2015 and March 2020. Of the 1461 patients evaluated, 1215 patients were referred for the purposes of identifying a genetic diagnosis for an undiagnosed condition, 90.5% of whom underwent genetic testing. The modalities of genetic testing utilized varied across referral diagnostic categories, including a range of utilization of whole exome sequencing (WES) as an initial test in 13.9% of neuromuscular patients to 52.9% in white matter disorder patients. The usage of WES increased over time, from 7.7% of initial testing in 2015 to a peak of 27.3% in 2019. Overall, genetic testing yielded a causal genetic diagnosis in 30.7% of patients. This yield was higher in certain referring diagnosis categories, such as neuromuscular (39.0%) and epilepsy (29.8%). Our study demonstrates that evaluation at an adult neurogenetics referral center can yield diagnoses in a substantial fraction of patients. Additional research will be needed to determine optimal genetic testing strategies and cost effectiveness of adult neurogenetics evaluation.

© 2021 Wiley Periodicals LLC.

Keywords: clinical genetics; genetic counseling; neurogenetics; whole exome sequencing

References

1. Bardakjian, T. M., Helbig, I., Quinn, C., Elman, L. B., McCluskey, L. F., Scherer, S. S., & Gonzalez-Alegre, P. (2018). Genetic test utilization and diagnostic yield in adult patients with neurological disorders. Neurogenetics, 19, 105-110. - PubMed
2. Córdoba, M., Rodriguez-Quiroga, S. A., Vega, P. A., Salinas, V., Perez-Maturo, J., Amartino, H., Vásquez-Dusefante, C., Medina, N., González-Morón, D., & Kauffman, M. A. (2018). Whole exome sequencing in neurogenetic odysseys: An effective, cost- and time-saving diagnostic approach. PLoS One, 13, e0191228. - PubMed
3. Fernández, I. S., Loddenkemper, T., Gaínza-Lein, M., Sheidley, B. R., & Poduri, A. (2019). Diagnostic yield of genetic tests in epilepsy: A meta-analysis and cost-effectiveness study. Neurology, 92, E418-E428. - PubMed
4. Fogel, B. L., Satya-Murti, S., & Cohen, B. H. (2016). Clinical exome sequencing in neurologic disease. Neurology Clinical Practice, 6, 164-176. - PubMed
5. Gorcenco, S., Ilinca, A., Almasoudi, W., Kafantari, E., Lindgren, A. G., & Puschmann, A. (2020). New generation genetic testing entering the clinic. Parkinsonism & Related Disorders, 73, 72-84. - PubMed
6. Guerreiro, R., Brás, J., Hardy, J., & Singleton, A. (2014). Next generation sequencing techniques in neurological diseases: Redefining clinical and molecular associations. Human Molecular Genetics, 23, R47-R53. - PubMed
7. Harris, P. A., Taylor, R., Minor, B. L., Elliott, V., Fernandez, M., O-Neal, L., McLeod, L., Delacqua, G., Delacqua, F., Kirby, J., Duda, S. N., & REDCap Consortium (2019). The REDCap consortium: Building an international community of software platform partners. Journal of Biomedical Informatics, 95, 103208. https://doi.org/10.1016/j.jbi.2019.103208 - PubMed
8. Harris, P. A., Taylor, R., Thielke, R., Payne, J., Gonzalez, N., & Conde, J. G. (2009). Research electronic data capture (REDCap)--A metadata-driven methodology and workflow process for providing translational research informatics support. Journal of Biomedical Informatics, 42, 377-381. - PubMed
9. Haskell, G. T., Adams, M. C., Fan, Z., Amin, K., Guzman Badillo, R. J., Zhou, L., Bizon, C., Chahin, N., Greenwood, R. S., Milko, L. V., Shiloh-Malawsky, Y., Crooks, K. R., Strande, N., Tennison, M., Tilley, C. R., Brandt, A., Wilhelmsen, K. C., Weck, K., Evans, J. P., & Berg, J. S. (2018). Diagnostic utility of exome sequencing in the evaluation of neuromuscular disorders. Neurology Genetics, 4, E212. - PubMed
10. Krenn, M., Wagner, M., Strom, T. M., Auff, E., & Zimprich, F. (2017). Diagnostic yield of whole-exome sequencing in neurological diaseases. Journal of the Neurological Sciences, 381, 160. - PubMed
11. Marques Matos, C., Alonso, I., & Leão, M. (2019). Diagnostic yield of next-generation sequencing applied to neurological disorders. Journal of Clinical Neuroscience, 67, 14-18. - PubMed
12. R Core Team. (2019). R: A language and environment for statistical computing. R Foundation for Statistical Computing. Vienna, Austria: R Core Team. https://www.R-project.org/ - PubMed
13. Shakya, S., Kumari, R., Suroliya, V., Tyagi, N., Joshi, A., Garg, A., Singh, I., Puthanveedu, D. K., Cherian, A., Mukerji, M., Srivastava, A. K., & Faruq, M. (2019). Whole exome and targeted gene sequencing to detect pathogenic recessive variants in early onset cerebellar ataxia. Clinical Genetics, 96, 566-574. - PubMed
14. Srivastava, S., Love-Nichols, J. A., Ledbetter, D. H., Martin, C. L., Chung, W. K., Firth, H. V., Frazier, T., Hansen, R. L., Prock, L., Brunner, H., Hoang, N., Scherer, S. W., Sahin, M., Miller, D. T., & NDD Exome Scoping Review Work Group. (2019). Meta-analysis and multidisciplinary consensus statement: Exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders. Genetics in Medicine, 21, 2413-2421. - PubMed
15. Vanderver, A., Simons, C., Helman, G., Crawford, J., Wolf, N. I., Bernard, G., Pizzino, A., Schmidt, J. L., Takanohashi, A., Miller, D., Khouzam, A., Rajan, V., Ramos, E., Chowdhury, S., Hambuch, T., Ru, K., Baillie, G. J., Grimmond, S. M., Caldovic, L., Devaney, J., … Taft, R. J. (2016). Whole exome sequencing in patients with white matter abnormalities. Annals of Neurology, 79(6), 1031-1037. https://doi.org/10.1002/ana.24650 - PubMed
16. Winder, T. L., Tan, C. A., Klemm, S., White, H., Westbrook, J. M., Wang, J. Z., Entezam, A., Truty, R., Nussbaum, R. L., McNally, E. M., & Aradhya, S. (2020). Clinical utility of multigene analysis in over 25,000 patients with neuromuscular disorders. Neurology Genetics, 6, e412. - PubMed

Publication Types

• Journal Article