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Variant modifier of the severity of spinal muscular atrophy 5q C.859G>C SMN2 in Russian patients
https://doi.org/10.25557/2073-7998.2024.09.32-37
Abstract
Background. The research and study spinal muscular atrophy (SMA 5q) severity modifiers in different patient cohorts remains a crucial task. In practice it is not possible to explain the clinical diversity of SMA 5q only by variations of SMN2 copies. For the c.859G>C variant in exon 7 of SMN2, several studies have described an association with a milder clinical phenotype of SMA due to increased inclusion of exon 7 in the SMN2 gene transcript and generation of more functional SMN protein.
Aim: to explore the modifying effect of the c.859G>C variant in the clinical structure of SMA 5q in Russian patients.
Materials. The search for the c.859G>C p. (Gly287Arg) variant in SMN2 gene was performed in 488 unrelated patients referred for molecular genetic diagnostics of spinal muscular atrophy from 2020 to 2022 to the laboratory of DNA diagnostics in the Research Center for Medical Genetics, Moscow. The control group consisted of 200 DNA samples from residents of the Russian Federation with 2 copies of SMN1 and 2 copies of SMN2.
Methods. Multiplex ligation-dependent probe amplification (MLPA).
Results. The frequency of c.859G>C SMN2 in Russian patients was 0.2%. In summary, it is not possible to assess the effect of c.859G>C as a factor modifying the phenotype of SMA due to the extremely low frequency of this variant.
Supporting agencies: The research was carried out within the state assignment of Ministry of Science and Higher Education of the Russian Federation for RCMG.
About the Authors
E. E. Lotnik
Research Centre for Medical Genetics
Russian Federation
Russian Federation
Ekaterina Lotnik
1, Moskvorechye st., Moscow, 115522
M. A. Akhkiamova
Research Centre for Medical Genetics
Russian Federation
Russian Federation
1, Moskvorechye st., Moscow, 115522
V. V. Zabnenkova
Research Centre for Medical Genetics
Russian Federation
Russian Federation
1, Moskvorechye st., Moscow, 115522
K. A. Mikhalchuk
Research Centre for Medical Genetics
Russian Federation
Russian Federation
1, Moskvorechye st., Moscow, 115522
A. V. Polyakov
Research Centre for Medical Genetics
Russian Federation
Russian Federation
1, Moskvorechye st., Moscow, 115522
O. A. Schagina
Research Centre for Medical Genetics
Russian Federation
Russian Federation
1, Moskvorechye st., Moscow, 115522
References
1. Brzustowicz L.M., Lehner T., Castilla et al. Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q11.2 – q13.3. Nature. 1990; 344: 540-541.
2. Sumner C.J. Molecular mechanisms of spinal muscular atrophy. J Child Neurol. 2007;22(8):979-89. doi: 10.1177/0883073807305787.
3. Rossiyskiye klinicheskiye rekomendatsii «Proksimal’naya spinal’naya myshechnaya atrofiya 5q», 2023. [Elektronnyy resurs] [Russian clinical guidelines “Proximal spinal muscular atrophy 5q”, 2023. [Electronic resource]. Access mode https://cr.minzdrav.gov.ru/schema/593_3 Date of application: 04/01/2024. (In Russ.)
4. Sugarman E.A., Nagan N., Zhu H. et al. Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: Clinical laboratory analysis of >72400 specimens. Eur J Hum Genet 2012;20:27– 32. DOI: 10.1038/ejhg.2011.134
5. Mikhalchuk K., Shchagina O., Chukhrova A., et al. Pilot Program of Newborn Screening for 5q Spinal Muscular Atrophy in the Russian Federation. Int J Neonatal Screen. 2023;9(2):29. doi: 10.3390/ijns9020029.
6. Voronin S.V., Zakharova E.Yu., Baydakova G.V., et al. Rasshirennyy neonatal’nyy skrining na nasledstvennyye zabolevaniya v Rossii: pervyye itogi i perspektivy [Advanced neonatal screening for hereditary diseases in Russia: first results and future prospects]. Pediatriya im. G.N. Speranskogo [Pediatria n.a. G.N. Speransky]. 2024; 103 (1): 16-29. DOI: 10.24110/0031-403X-2024-103-1-16-29 (In Russ.)
7. Lorson C.L., Hahnen E., Androphy E.J., Wirth B. A single nucleotide in the SMN gene regulates splicing and is responsible for spinal muscular atrophy. Proc Natl Acad Sci U S A. 1999;96(11):6307-11. doi: 10.1073/pnas.96.11.6307.
8. Akhkiamova M.A., Shchagina O.A., Polyakov A.V. Faktory, modifitsiruyushchiye techeniye spinal’noy myshechnoy atrofii 5q [Factors modifying the course of spinal muscular atrophy 5q]. Nervno-myshechnyye bolezni [Neuromuscular Diseases]. 2023;13(4):62-73. (In Russ.)
9. Ruhno C., McGovern V.L., Avenarius M.R., et al. Complete sequencing of the SMN2 gene in SMA patients detects SMN gene deletion junctions and variants in SMN2 that modify the SMA phenotype. Hum Genet. 2019;138(3):241-256. doi: 10.1007/s00439-019-01983-0.
10. Wadman R.I., Jansen M.D., Curial C.A.D., et al. Analysis of FUS, PFN2, TDP-43, and PLS3 as potential disease severity modifiers in spinal muscular atrophy. Neurol Genet. 2019;6(1):e386. doi: 10.1212/NXG.0000000000000386.
11. Jedrzejowska M., Milewski M., Zimowski J., et al. Phenotype modifiers of spinal muscular atrophy: the number of SMN2 gene copies, deletion in the NAIP gene and probably gender influence the course of the disease. Acta Biochim Pol. 2009;56(1):103-8.
12. Vezain M., Saugier-Veber P., Goina E., et al. A rare SMN2 variant in a previously unrecognized composite splicing regulatory element induces exon 7 inclusion and reduces the clinical severity of spinal muscular atrophy. Hum Mutat. 2010;31(1):E1110-25. doi: 10.1002/humu.21173. .
13. Odabaş S.P., Bal E., Yelgen G., et al. (2022). Exon7 Targeted CRISPR-Prime Editing Approaches for SMN2 Gene Editing in Spinal Muscular Atrophy (SMA) Disease Can Increase In Vitro SMN Expression. bioRxiv 2022.03.21.484406; doi: https://doi.org/10.1101/2022.03.21.484406
14. Blasco-Pérez L., Costa-Roger M., Leno-Colorado J. Deep molecular characterization of milder spinal muscular atrophy patients carrying the c.859G>C variant in SMN2. Int J Mol Sci 2022;23(15):82– 9. DOI: 10.3390/ijms23158289
15. Prior T.W., Krainer A.R., Hua Y., et al. A positive modifier of spinal muscular atrophy in the SMN2 gene. Am J Hum Genet. 2009;85(3):408-13. doi: 10.1016/j.ajhg.2009.08.002.
16. Bernal S., Alías L., Barceló M.J., et al. The c.859G>C variant in the SMN2 gene is associated with types II and III SMA and originates from a common ancestor. J Med Genet. 2010;47(9):640-2. doi: 10.1136/jmg.2010.079004.
17. Genome Aggregation Database (gnomAD). [Electronic resource]. Access mode: https://gnomad.broadinstitute.org/variant/5-69372372-G-C?dataset=gnomad_r2_1 Date of application: 01.05.2024
18. Calucho M., Bernal S., Alías L., et al. Correlation between SMA type and SMN2 copy number revisited: An analysis of 625 unrelated Spanish patients and a compilation of 2834 reported cases. Neuromuscul Disord. 2018;28(3):208-215. doi: 10.1016/j.nmd.2018.01.003.
Review
For citations:
Lotnik E.E., Akhkiamova M.A., Zabnenkova V.V., Mikhalchuk K.A., Polyakov A.V., Schagina O.A. Variant modifier of the severity of spinal muscular atrophy 5q C.859G>C SMN2 in Russian patients. Medical Genetics. 2024;23(9):32-37. (In Russ.) https://doi.org/10.25557/2073-7998.2024.09.32-37
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