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A new molecular genetic mechanism for the pathogenesis of Niemann-Pick disease type C was discovered

Researchers at the FSBI RCMG Laboratory of Hereditary Metabolic Diseases and Functional Genomics first described a rare new molecular genetic mechanism for the pathogenesis of Niemann-Pick disease type C. This mechanism lies in the joint effect of rare and frequent synonymous variants in the NPC1 gene, which leads to splicing disruption. Using minigen expression techniques they showed that only the presence of both variants in cis-position led to the activation of a hidden splicing site in exon 18 of the NPC1 gene, which resulted in exon shortening at mRNA level. Using quantitative mRNA analysis and histochemistry methods the authors also showed that the detected complex allele c.[272727 C > T;2793 C > T] was hypomorphic and associated with the adult form of Niemann-Pick disease type C.

This paper focuses the researchers’ attention on the importance of analyzing “raw” data obtained by next-generation sequencing methods because polymorphic variants, often filtered out during data processing, can have a direct modifying effect on the rare variants detected. Neglecting this fact may lead to difficulties and discrepancies in molecular genetic diagnosis or even misdiagnosis. The European Journal of Human Genetics published the results (Q2, Impact Factor: 3.657)


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 

https://www.nature.com/articles/s41431-021-00898-7