Clinical testing panels for ALS: global distribution, consistency, and challenges

Abstract

Objective: In 2021, the Clinical Genome Resource (ClinGen) amyotrophic lateral sclerosis (ALS) spectrum disorders Gene Curation Expert Panel (GCEP) was established to evaluate the strength of evidence for genes previously reported to be associated with ALS. Through this endeavor, we will provide standardized guidance to laboratories on which genes should be included in clinical genetic testing panels for ALS. In this manuscript, we aimed to assess the heterogeneity in the current global landscape of clinical genetic testing for ALS. Methods: We reviewed the National Institutes of Health (NIH) Genetic Testing Registry (GTR) and members of the ALS GCEP to source frequently used testing panels and compare the genes included on the tests. Results: 14 clinical panels specific to ALS from 14 laboratories covered 4 to 54 genes. All panels report on ANG, SOD1, TARDBP, and VAPB; 50% included or offered the option of including C9orf72 hexanucleotide repeat expansion (HRE) analysis. Of the 91 genes included in at least one of the panels, 40 (44.0%) were included on only a single panel. We could not find a direct link to ALS in the literature for 14 (15.4%) included genes. Conclusions: The variability across the surveyed clinical genetic panels is concerning due to the possibility of reduced diagnostic yields in clinical practice and risk of a missed diagnoses for patients. Our results highlight the necessity for consensus regarding the appropriateness of gene inclusions in clinical genetic ALS tests to improve its application for patients living with ALS and their families.

Keywords:

• Amyotrophic lateral sclerosis
• clinical laboratories
• genetic testing
• gene-disease relationships
• gene panels

Acknowledgements

A.A.D. is supported by the Canadian Institute of Health Research Banting Postdoctoral Fellowship program. H.M is supported by GlaxoSmithKline and the KCL funded centre for Doctoral Training (CDT) in Data-Driven Health. I.B. is supported by the National Health and Medical Research Council of Australia [1176913]. W.v.R. is supported by funding provided by the Dutch Research Council (NWO) [VENI scheme grant 09150161810018] and Prinses Beatrix Spierfonds [neuromuscular fellowship grant W.F19-03]. This work was supported in part by the Intramural Research Programs of the NIH, National Institute on Aging (Z01-AG000949- 02). B.J.T. received additional support from the Center for Disease Control and Prevention, the Muscular Dystrophy Association, Microsoft Research, the Packard Center for ALS Research at Johns Hopkins, and the ALS Association.

Disclosure statement

W.v.R. has sponsored research agreements with Biogen. BJT holds patents on the clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of C9orf72.

Additional information

Funding

This publication was supported [in part] by the National Human Genome Research Institute of the National Institutes of Health through the following grant: UNC/Kaiser - U24HG009650. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.