Introduction
There have been a number of publications describing the important role of genetic counseling in amyotrophic lateral sclerosis (ALS).1,2 While such attempts at guiding who and who should not undergo genetic testing are welcome, they are put forth in a vacuum as there is no data on where ALS neurologists currently stand in terms of genetic testing and counseling for the disease, and in terms of what is considered to be familial and sporadic ALS.3 We attempt to fill this gap by surveying members of the Northeast Amyotrophic Lateral Sclerosis Consortium (NEALS, www.alsconsortium.org), one of the largest clinical research organizations for ALS.
The survey sought to understand in which situations genetic testing is used, which genes are tested for, and the current and future attitudes of respondents toward genetic testing and counseling.
Methods
The survey was sent via email on June 20th, 2016 to 134 Principal Investigators who are members of the Northeast Amyotrophic Lateral Sclerosis Consortium. The deadline for survey completion was July 29th, 2016. Data was collated and analyzed using Microsoft Excel (Table 1).
Table 1.
Survey questions and responses
| Question | Yes | No | Blank |
|---|---|---|---|
| Do you screen familial ALS cases for genetic mutations for clinical trials? | 31 | 11 | 1 |
| Do you screen sporadic ALS cases for genetic mutations for clinical trials? | 8 | 34 | 1 |
| Do you screen familial ALS cases for genetic mutations in everyday clinical practice? | 40 | 3 | 0 |
| Do you screen familial ALS cases for genetic mutations in everyday clinical practice? | 13 | 30 | 0 |
| Do you use next generation sequencing techniques such as exome sequencing? | 21 | 17 | 1 |
| Do you use genetic panel testing? | 24 | 17 | 0 |
| Do you believe panel testing is cost-effective? | 18 | 22 | 1 |
| Do you provide genetic counseling to patients? | 42 | 1 | 0 |
| Would your attitude toward genetic testing change if an effective gene therapy became available? | 39 | 4 | 0 |
Results
We obtained 43 responses, giving a response rate of nearly one third (32.1%). Responses were obtained from centers throughout the entire United States as well as in Canada, Israel, and Lebanon. The mean number of ALS patients seen at each site on an annual basis was 157, ranging from 20 to 500. Forty (93.0%) respondents screen familial ALS cases for genetic mutations in their routine clinical practice, and 13 (30.2%) screen sporadic cases. Genetic testing rates are surprisingly lower in the context of clinical research: only thirty-one (72.1%) respondents screen familial ALS cases for genetic mutations in preparation for their enrollment in clinical trials, while only 8 (18.6%) screen sporadic cases in clinical trials.
One respondent did not perform genetic testing for clinical trials or everyday clinical practice, and one respondent did not specify which genes the site tested for. Out of the 41 respondents who did specify which genes were tested for, 100% screened for C9ORF72 (Figure 1A). The next most common gene screened for was SOD1 with 31 respondents (75.6%). Next was FUS with 11 respondents (26.8%) and TARDBP/TDP-43 with 10 respondents (24.4%). These were followed by UBQLN2 (8 respondents, 19.5%), OPTN (7 respondents, 17.1%), SQSTM1 (6 respondents, 14.6%), and VCP and PFN1 (5 respondents, 12.2% each). Of note, two respondents reported testing for Ataxin 2 in addition to other genes.
Figure 1.
Results of a survey conducted on genetic testing among members of the Northeast ALS Consortium. (A) Percentage of respondents who test for each gene specified in the survey. The total number of respondents who test for ALS genes was 41. (B) Percentage of respondents who use next generation sequencing, Sanger sequence-based panel testing and genetic counselling in their practice.
Just under half of respondents (21, 48.8%) use next generation sequencing techniques at their sites. More than half of respondents (24, 55.8%) use panel testing (Figure 1B). Interestingly, only 14 out of the 24 respondents (58.3%) who use Sanger sequencing-based panel testing believe it to be cost effective. Most of respondents (42, 97.7%) provide genetic counseling to ALS patients, with only one respondent denying the use of genetic counseling (Figure 1B). Finally, the overwhelming majority of respondents (39, 90.7%) would change their attitude toward genetic testing if an effective therapy became available.
Discussion
The importance of this area is shown by the response to the question on whether future gene therapy trials will influence their practice of genetic testing. Almost uniformly the answer was yes. Our data show that although current efforts at genetic counseling guidelines for ALS patients are important, the pace of discovery in the genetic field means that they have a relatively short shelf life. Guideline documents need to operate in a dynamic manner with yearly updates, rather than being viewed as dogma.
Acknowledgements
This work was supported in part by the Intramural Research Program of the US National Institutes of Health (NIH), National Institute on Aging (Z01-AG000949-02). This research was made possible through the National Institutes of Health (NIH) Medical Research Scholars Program, a public-private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from the Doris Duke Charitable Foundation, The American Association for Dental Research, The Howard Hughes Medical Institute and the Colgate-Palmolive Company, as well as other private donors. For a complete list, please visit the Foundation website at http://fnih.org/work/education-training-0/medical- research-scholars-program. This work was supported in part by the European Community’s Health Seventh Framework Programme (FP7/2007-2013 under grant agreement 259867), the Joint Programme-Neurodegenerative Disease Research (Italian Ministry of Education and University) (Strength Project) and the Vialli and Mauro Foundation for ALS (grant no. 4). Bryan J. Traynor We would also like to thank the Northeast Amyotrophic Lateral Sclerosis Consortium and the neurologists who responded to the survey. Bryan J. Traynor has received research-funding support from Microsoft Research, Merck Inc., the Muscular Dystrophy Association, the ALS Association, the Myasthenia Gravis Foundation, and the Centers for Disease Control and Prevention. Bryan J. Traynor has a patent pending on the clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of C9orf72. Bryan J. Traynor had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
References
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