Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Additive effect of frequent polymorphism and rare synonymous variant alters splicing in twin patients with Niemann-Pick disease type C


Niemann-Pick disease type C (NP-C) (OMIM#257220) is a rare lysosomal storage disorder caused by pathogenic variants in either the NPC1 or NPC2 genes. It manifests with a wide spectrum of clinical symptoms and variable age of onset. We studied the impact of the frequent polymorphic variant c.2793 C > T (p.Asn931 = ), located in the donor splice site (SS) of NPC1 exon 18 on the penetrance of the rare synonymous variant c.2727 C > T (p.Cys909 = ), identified in two 55 y.o. twins with an adult onset form of NP-C. The patients’ diagnosis was supported by biochemical analysis and positive filipin test. Analysis of the patients’ cDNA showed that the c.2727 C > T variant leads to cryptic donor SS activation and frameshift deletion in the NPC1 exon 18. However, the minigene assay demonstrated that this exon shortening takes place only in the presence of the frequent polymorphic variant c.2793 C > T. Results of the transcript specific qPCR showed that only the presence in the NPC1 exon 18 of both variants leads to significant decrease of wild type (WT) transcript isoform.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Patients’ mRNA analysis and filipin staining.
Fig. 2: Functional analysis of the complex allele.


  1. 1.

    Patterson MC, Hendriksz CJ, Walterfang M, Sedel F, Vanier MT, Wijburg F, et al. Recommendations for the diagnosis and management of Niemann-Pick disease type C: an update. Mol Genet Metab. 2012;106:330–44.

    CAS  Article  Google Scholar 

  2. 2.

    Vance JE. Lipid imbalance in the neurological disorder, Niemann-Pick C disease. FEBS Lett. 2006;580:5518–24.

    CAS  Article  Google Scholar 

  3. 3.

    Burlina A. Niemann-Pick disease type C: introduction and main clinical features. J Neurol. 2014;261:S525–7.

    Article  Google Scholar 

  4. 4.

    Geberhiwot T, Moro A, Dardis A, Ramaswami U, Sirrs S, Marfa MP, et al. Consensus clinical management guidelines for Niemann-Pick disease type C. Orphanet J Rare Dis. 2018;13:50.

    Article  Google Scholar 

  5. 5.

    Jahnova H, Dvorakova L, Vlaskova H, Hulkova H, Poupetova H, Hrebicek M, et al. Observational, retrospective study of a large cohort of patients with Niemann-Pick disease type C in the Czech Republic: a surprisingly stable diagnostic rate spanning almost 40 years. Orphanet J Rare Dis. 2014;9:140.

    Article  Google Scholar 

  6. 6.

    Wassif CA, Cross JL, Iben J, Sanchez-Pulido L, Cougnoux A, Platt FM, et al. High incidence of unrecognized visceral/neurological late-onset Niemann-Pick disease, type C1, predicted by analysis of massively parallel sequencing data sets. Genet Med. 2016;18:41–8.

    CAS  Article  Google Scholar 

  7. 7.

    Stampfer M, Theiss S, Amraoui Y, Jiang X, Keller S, Ory DS, et al. Niemann-Pick disease type C clinical database: cognitive and coordination deficits are early disease indicators. Orphanet J Rare Dis. 2013;8:35.

    Article  Google Scholar 

  8. 8.

    Vanier MT, Latour P. Laboratory diagnosis of Niemann–Pick disease type C: The filipin staining test. Methods Cell Biol. 2015;126:357–75.

    CAS  Article  Google Scholar 

  9. 9.

    Lucarelli M, Narzi L, Pierandrei S, Bruno SM, Stamato A, d’Avanzo M, et al. A new complex allele of the CFTR gene partially explains the variable phenotype of the L997F mutation. Genet Med. 2010;12:548–55.

    CAS  Article  Google Scholar 

  10. 10.

    Romey MC, Guittard C, Chazalette JP, Frossard P, Dawson KP, Patton MA, et al. Complex allele [-102T>A+S549R(T>G)] is associated with milder forms of cystic fibrosis than allele S549R(T>G) alone. Hum Genet. 1999;105:145–50.

    CAS  PubMed  Google Scholar 

  11. 11.

    Salles MV, Motta FL, Dias da Silva E, Varela P, Costa KA, Filippelli-Silva R, et al. Novel Complex ABCA4 Alleles in Brazilian Patients With Stargardt Disease: Genotype-Phenotype Correlation. Invest Ophthalmol Vis Sci. 2017;58:5723–30.

    CAS  Article  Google Scholar 

  12. 12.

    Shroyer NF, Lewis RA, Lupski JR. Complex inheritance of ABCR mutations in Stargardt disease: linkage disequilibrium, complex alleles, and pseudodominance. Hum Genet. 2000;106:244–8.

    CAS  Article  Google Scholar 

  13. 13.

    Zaum AK, Stuve B, Gehrig A, Kolbel H, Schara U, Kress W, et al. Deep intronic variants introduce DMD pseudoexon in patient with muscular dystrophy. Neuromuscul Disord. 2017;27:631–4.

    Article  Google Scholar 

Download references


The data that support the findings of this study is submitted to ClinVar ( (Accession number—VCV000867233.3). A part of the research was done using equipment of Core Facility of Koltzov Institute of Developmental Biology RAS.


The research was carried out within the state assignment of the Ministry of Science and Higher Education of the Russian Federation for RCMG.

Author information



Corresponding author

Correspondence to Igor Bychkov.

Ethics declarations

Conflict of interest

The authors declare no competing interests.


The study was approved by the local ethics committee of the Federal State Budgetary Institution “Research Centre for Medical Genetics” (the approval number 2015-5/3).

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Bychkov, I., Filatova, A., Perelman, G. et al. Additive effect of frequent polymorphism and rare synonymous variant alters splicing in twin patients with Niemann-Pick disease type C. Eur J Hum Genet (2021).

Download citation


Quick links