Clinical implementation of gene panel testing for lysosomal storage diseases.
4MU-based enzymatic testing
diagnostic testing
gene panel sequencing
lysosomal storage disease
next-generation sequencing
Journal
Molecular genetics & genomic medicine
ISSN: 2324-9269
Titre abrégé: Mol Genet Genomic Med
Pays: United States
ID NLM: 101603758
Informations de publication
Date de publication:
02 2019
02 2019
Historique:
received:
20
07
2018
revised:
26
10
2018
accepted:
07
11
2018
pubmed:
15
12
2018
medline:
12
4
2019
entrez:
15
12
2018
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 30548430
doi: 10.1002/mgg3.527
pmc: PMC6393649
doi:
Banques de données
GENBANK
['NM_000147.4', 'NM_000528.3', 'NM_001171988.1', 'NM_005908.3', 'NM_003465.2', 'NM_000310.3', 'NM_001909.4', 'NM_000391.3', 'NM_001042432.1', 'NM_006493.3', 'NM_017882.2', 'NM_152778.2', 'NM_018941.3', 'NM_004937.2', 'NM_001122606.1', 'NM_000169.2', 'NM_177924.4', 'NM_000308.3', 'NM_001005742.2', 'NM_000404.3', 'NM_001167607.1', 'NM_000521.3', 'NM_000520.5', 'NM_000153.3', 'NM_000487.5', 'NM_000203.5', 'NM_001166550.3', 'NM_000199.4', 'NM_000263.3', 'NM_152419.2', 'NM_002076.3', 'NM_000512.4', 'NM_000046.4', 'NM_001293105.1', 'NM_153281.1', 'NM_000434.3', 'NM_024312.4', 'NM_032520.4', 'NM_182760.3', 'NM_001007593.2', 'NM_000271.4', 'NM_001363688.1', 'NM_001814.5', 'NM_001079804.2', 'NM_002778.3', 'NM_000396.3', 'NM_012434.4', 'NM_000262.2', 'NM_000351.5', 'NM_001127605.2']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e00527Informations de copyright
© 2018 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.
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