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; gene panels; gene-disease relationships; genetic testing.

Figure 1.

Year of first discovery of a relationship with amyotrophic lateral sclerosis (ALS), method of discovery, and function of the encoded protein of the genes included on the identified ALS specific commercial clinical genetic tests (N=14) with ≥2 publications reporting rare variants associated with ALS.

Figure 2.. Packed circle plot comparing the number of amyotrophic lateral sclerosis (ALS) specific commercial clinical genetic tests (N=14) each gene was included on.

The size of the circles corresponds to the number of clinical genetic tests the gene was included on, ranging from one to 14 tests. The colour of the circles corresponds to the number of years since the gene’s first association with ALS was made. Grey circles indicate genes that have never been associated with ALS. The year of first association between ALS and the gene is indicated below the gene name, where applicable.

Figure 3.. Pathogenicity classification and variant types reported in ClinVar in genes previously associated with amyotrophic lateral sclerosis (ALS).

All genes found on at least one of the analyzed clinical genetic testing panels (N=14) were included in the analysis. However, only genes with variants reported as associated with “ALS” or “motor neuron disease” in ClinVar are displayed in the figure. (A) Flow chart highlighting the steps taken to obtain and filter the ClinVar variants reported in genes previously associated with ALS. (B) Pathogenicity classification of all variants reported in ClinVar as associated with ALS. The total number of variants reported in ClinVar in DCTN1, FUS, MATR3, SETX, SQSTM1, and VAPB exceeded the y-axis limits of 200; for these genes, the total number of variants found in ClinVar were included on the right side of the bar plot. (C) Variant types of all variants reported in ClinVar as likely pathogenic or pathogenic for ALS. (D) Variant types of all variants reported in ClinVar as being of uncertain significance for ALS. Abbreviations: LP, likely pathogenic; P, pathogenic; VUS, variants of uncertain significance.

Figure 4.. Pathogenicity classification and variant types identified using a commercially available genetic test for amyotrophic lateral sclerosis (ALS).

(A) Pathogenicity classification of variants identified using a commercially available genetic test for ALS. (B) Variant types of all variants identified using a commercially available genetic test for ALS and classified as likely pathogenic or pathogenic. (C) Variant types of all variants identified using a commercially available genetic test for ALS and classified as being of uncertain significance. Abbreviations: LP, likely pathogenic; P, pathogenic; VUS, variants of uncertain significance.