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. 2019 Feb;7(2):e00527.
doi: 10.1002/mgg3.527. Epub 2018 Dec 11.

Clinical implementation of gene panel testing for lysosomal storage diseases

Alexander Gheldof  1   2 , Sara Seneca  1   2 , Katrien Stouffs  1   2 , Willy Lissens  1   2 , Anna Jansen  3 , Hilde Laeremans  4 , Patrick Verloo  5 , An-Sofie Schoonjans  6 , Marije Meuwissen  7 , Diana Barca  8   9 , Geert Martens  10 , Linda De Meirleir  3
Affiliations

Clinical implementation of gene panel testing for lysosomal storage diseases

Alexander Gheldof et al. Mol Genet Genomic Med. 2019 Feb.

Abstract

Background: The diagnostic workup in patients with a clinical suspicion of lysosomal storage diseases (LSD) is often difficult due to the variability in the clinical phenotype. The gold standard for diagnosis of LSDs consists of enzymatic testing. However, due to the sequential nature of this methodology and inconsistent genotype-phenotype correlations of certain LSDs, finding a diagnosis can be challenging.

Method: We developed and clinically implemented a gene panel covering 50 genes known to cause LSDs when mutated. Over a period of 18 months, we analyzed 150 patients who were referred for LSD testing and compared these results with the data of patients who were previously enrolled in a scheme of classical biochemical testing.

Results: Our panel was able to determine the molecular cause of the disease in 22 cases (15%), representing an increase in diagnostic yield compared to biochemical tests developed for 21 LSDs (4.6%). We were furthermore able to redirect the diagnosis of a mucolipidosis patient who was initially suspected to be affected with galactosialidosis. Several patients were identified as being affected with neuronal ceroid lipofuscinosis, which cannot readily be detected by enzyme testing. Finally, several carriers of pathogenic mutations in LSD genes related to the disease phenotype were identified as well, thus potentially increasing the diagnostic yield of the panel as heterozygous deletions cannot be detected.

Conclusion: We show that the implementation of a gene panel for LSD diagnostics results in an increased yield in comparison to classical biochemical testing. As the panel is able to cover a wider range of diseases, we propose to implement this methodology as a first-tier test in cases of an aspecific LSD presentation, while enzymatic testing remains the first choice in patients with a more distinctive clinical presentation. Positive panel results should however still be enzymatically confirmed whenever possible.

Keywords: 4MU-based enzymatic testing; diagnostic testing; gene panel sequencing; lysosomal storage disease; next-generation sequencing.

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Conflict of interest statement

AG received supporting grants from Shire and Sanofi for the validation of the panel.

Figures

Figure 1
Figure 1
(a) Average coverage of the 609 exons in the LSD gene panel. For each exon, the average coverage was calculated by adding the read depth of each base divided by the total exon length. (b) Graphical overview of percentage of coverage per exon. For each exon, this was calculated by dividing the number of bases with a coverage above 30× by the total number of bases. Five hundred and forty‐eight of a total of 609 exons have a coverage of 100% (fully covered). For three exons, <10% of their nucleotides are covered above 30×
Figure 2
Figure 2
(a) Age distribution of the patients who were tested with the LSD gene panel. (b) Age distribution of the patients in whom a diagnosis was found and where heterozygous mutations were found
See this image and copyright information in PMC

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