Clinical Implementation of Gene Panel Testing for Lysosomal Storage Diseases

Overview

Journal Mol Genet Genomic Med

Specialty Genetics

Date 2018 Dec 15

PMID 30548430

Citations 14

Authors

Alexander Gheldof

Sara Seneca

Katrien Stouffs

Willy Lissens

Anna Jansen

Hilde Laeremans

Patrick Verloo

An-Sofie Schoonjans

Marije Meuwissen

Diana Barca

Geert Martens

Linda De Meirleir

Affiliations

Soon will be listed here.

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.

Citing Articles

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References

Scott H, Litjens T, Hopwood J, Morris C . A common mutation for mucopolysaccharidosis type I associated with a severe Hurler syndrome phenotype. Hum Mutat. 1992; 1(2):103-8. DOI: 10.1002/humu.1380010204. View

Li Y, Sekine T, Funayama M, Li L, Yoshino H, Nishioka K . Clinicogenetic study of GBA mutations in patients with familial Parkinson's disease. Neurobiol Aging. 2013; 35(4):935.e3-8. DOI: 10.1016/j.neurobiolaging.2013.09.019. View

Cosma M, Pepe S, Parenti G, Settembre C, Annunziata I, Wade-Martins R . Molecular and functional analysis of SUMF1 mutations in multiple sulfatase deficiency. Hum Mutat. 2004; 23(6):576-81. DOI: 10.1002/humu.20040. View

Park W, OBrien J, Lundquist P, Kraft D, Walsh Vockley C, Karnes P . Identification of 58 novel mutations in Niemann-Pick disease type C: correlation with biochemical phenotype and importance of PTC1-like domains in NPC1. Hum Mutat. 2003; 22(4):313-25. DOI: 10.1002/humu.10255. View

Myerowitz R, Costigan F . The major defect in Ashkenazi Jews with Tay-Sachs disease is an insertion in the gene for the alpha-chain of beta-hexosaminidase. J Biol Chem. 1988; 263(35):18587-9. View

Jones M, Rhodenizer D, da Silva C, Huff I, Keong L, Bean L . Molecular diagnostic testing for congenital disorders of glycosylation (CDG): detection rate for single gene testing and next generation sequencing panel testing. Mol Genet Metab. 2013; 110(1-2):78-85. DOI: 10.1016/j.ymgme.2013.05.012. View

Anikster Y, Lucero C, Touchman J, Huizing M, McDowell G, Shotelersuk V . Identification and detection of the common 65-kb deletion breakpoint in the nephropathic cystinosis gene (CTNS). Mol Genet Metab. 1999; 66(2):111-6. DOI: 10.1006/mgme.1998.2790. View

Danyukova T, Ariunbat K, Thelen M, Brocke-Ahmadinejad N, Mole S, Storch S . Loss of CLN7 results in depletion of soluble lysosomal proteins and impaired mTOR reactivation. Hum Mol Genet. 2018; 27(10):1711-1722. PMC: 5932567. DOI: 10.1093/hmg/ddy076. View

Alfares A, Kelly M, McDermott G, Funke B, Lebo M, Baxter S . Results of clinical genetic testing of 2,912 probands with hypertrophic cardiomyopathy: expanded panels offer limited additional sensitivity. Genet Med. 2015; 17(11):880-8. DOI: 10.1038/gim.2014.205. View

10.

Anson D, Bielicki J, Hopwood J . Correction of mucopolysaccharidosis type I fibroblasts by retroviral-mediated transfer of the human alpha-L-iduronidase gene. Hum Gene Ther. 1992; 3(4):371-9. DOI: 10.1089/hum.1992.3.4-371. View

11.

Kantaputra P, Kayserili H, Guven Y, Kantaputra W, Balci M, Tanpaiboon P . Clinical manifestations of 17 patients affected with mucopolysaccharidosis type VI and eight novel ARSB mutations. Am J Med Genet A. 2014; 164A(6):1443-53. DOI: 10.1002/ajmg.a.36489. View

12.

Coutinho M, Prata M, Alves S . Mannose-6-phosphate pathway: a review on its role in lysosomal function and dysfunction. Mol Genet Metab. 2012; 105(4):542-50. DOI: 10.1016/j.ymgme.2011.12.012. View

13.

Mohammed A, OHare M, Warley A, Tear G, Tuxworth R . in vivo localization of the neuronal ceroid lipofuscinosis proteins, CLN3 and CLN7, at endogenous expression levels. Neurobiol Dis. 2017; 103:123-132. PMC: 5441185. DOI: 10.1016/j.nbd.2017.03.015. View

14.

Koprivica V, Stone D, Park J, Callahan M, Frisch A, Cohen I . Analysis and classification of 304 mutant alleles in patients with type 1 and type 3 Gaucher disease. Am J Hum Genet. 2000; 66(6):1777-86. PMC: 1378059. DOI: 10.1086/302925. View

15.

Velho R, De Pace R, Klunder S, Sperb-Ludwig F, Lourenco C, Schwartz I . Analyses of disease-related GNPTAB mutations define a novel GlcNAc-1-phosphotransferase interaction domain and an alternative site-1 protease cleavage site. Hum Mol Genet. 2015; 24(12):3497-505. PMC: 4498157. DOI: 10.1093/hmg/ddv100. View

16.

Han F, Grimes D, Li F, Wang T, Yu Z, Song N . Mutations in the glucocerebrosidase gene are common in patients with Parkinson's disease from Eastern Canada. Int J Neurosci. 2015; 126(5):415-21. DOI: 10.3109/00207454.2015.1023436. View

17.

Riise Stensland H, Klenow H, Van Nguyen L, Hansen G, Malm D, Nilssen O . Identification of 83 novel alpha-mannosidosis-associated sequence variants: functional analysis of MAN2B1 missense mutations. Hum Mutat. 2011; 33(3):511-20. DOI: 10.1002/humu.22005. View

18.

Gheldof A, Seneca S, Stouffs K, Lissens W, Jansen A, Laeremans H . Clinical implementation of gene panel testing for lysosomal storage diseases. Mol Genet Genomic Med. 2018; 7(2):e00527. PMC: 6393649. DOI: 10.1002/mgg3.527. View

19.

Kousi M, Lehesjoki A, Mole S . Update of the mutation spectrum and clinical correlations of over 360 mutations in eight genes that underlie the neuronal ceroid lipofuscinoses. Hum Mutat. 2011; 33(1):42-63. DOI: 10.1002/humu.21624. View

20.

Qian Y, van Meel E, Flanagan-Steet H, Yox A, Steet R, Kornfeld S . Analysis of mucolipidosis II/III GNPTAB missense mutations identifies domains of UDP-GlcNAc:lysosomal enzyme GlcNAc-1-phosphotransferase involved in catalytic function and lysosomal enzyme recognition. J Biol Chem. 2014; 290(5):3045-56. PMC: 4317033. DOI: 10.1074/jbc.M114.612507. View