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.
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The data that support the findings of this study is submitted to ClinVar (https://www.ncbi.nlm.nih.gov/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.
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).
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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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). https://doi.org/10.1038/s41431-021-00898-7