Genetic defects in patients with primary immunodeficiencies in the Republic of Belarus

Primary immunodeficiency diseases (PID) are a heterogeneous group of genetically determined diseases of the immune system. Patients with a PID are characterized by increased infectious sensitivity, a high rate of development of autoimmune diseases and malignant diseases. All these factors lead to a high incidence of early child mortality.

We identified 191 patients (120 males and 71 female) with genetically confirmed PID, which are represented by 25 nosologies. We found 32 variants that have not been previously described. Most of these variants were small deletions (n = 13) that lead to the synthesis of a shortened protein. Missense variants rank second in frequency (n = 11). Missense mutations lead to changes in the amino acid sequence of the protein. These mutations affect the structure of a protein and change the functional activity of a protein.

1. Picard C., Bobby Gaspar H., Al-Herz W., Bousfina A., Casanoca J. L., Chatila T. [et al.]. International Union of Immunological Societies: 2017 Primary Immunodeficiency Diseases Committee Report on Inborn Errors of Immunity. Journal of Clinical Immunology, 2018, vol. 38, no. 1, pp. 96-128. https://doi.org/10.1007/s10875-017-0464-9

2. Ensembl genome browser 95. Available at: http://www.ensembl.org/index.html (accessed 03.12.2019).

3. Venselaar H., Te Beek T. A. H., Kuipers R. K. P., Hekkelman M. L., Vriend G. Protein structure analysis of mutations causing inheritable diseases. An e-Science approach with life scientist friendly interfaces. BMC Bioinformatics, 2010, vol. 11, no. 1, art. 548. https://doi.org/10.1186/1471-2105-11-548

4. Ryzhkova O. P., Kardymon O. L., Prokhorchuk E. B., Konovalov F. A., Maslennikov A. B., Stepanov V. A. [et. al]. Guidance on the interpretation of human DNA sequence data obtained by mass parallel sequencing (MPS) methods (2018 edition, version 2). Meditsinskaya genetika = Medical genetics, 2019, vol. 18, no. 2. pp. 3-23 (in Russian).

5. Polityko A. D., Khurs O. M., Lir T. Human genomic diseases. Locus analysis 22q11. Molekulyarnaya i prikladnaya genetika = Molecular and applied genetics, 2009, vol. 10, pp. 80-88 (in Russian).

6. Gur’yanova I. E., Korosteleva L. B., Polyakova E. A., Pugacheva V. V., Ermilova T. I., Skopovets E. Ya., Lyubushkin A. V., Zharankova Yu. S., Aleshkevich S. N., Belevtsev M. V. Study of the components of the complement system in differential diagnostics of congenital (hereditary) angioedema. Laboratornaya diagnostika. Vostochnaya Evropa = Laboratory diagnostics. Eastern Europe, 2019, vol. 8, no. 4. pp. 553-563 (in Russian).

7. Bosticardo M., Yamazaki Y., Cowan J., Giardino G., Corsino C., Scalia G. [et al.]. Heterozygous FOXN1 variants cause low TRECs and severe T cell lymphopenia, revealing a crucial role of FOXN1 in supporting early thymopoiesis. American Journal of Human Genetics, 2019, vol. 105, no. 3, pp. 549-561. https://doi.org/10.1016/j.ajhg.2019.07.014

8. Sharapova S. O., Migas A., Guryanova I., Aleshkevich S., Kletski S., Durandy A., Belevtsev M. Late-onset combined immune deficiency associated to skin granuloma due to heterozygous compound mutations in RAG1 gene in a 14 years old male. Human Immunology, 2013, vol. 74, no. 1, rr. 18-22. https://doi.org/10.1016/j.humimm.2012.10.010

9. Sharapova S. O., Migas A. A., Uglova T. A., Byshneva L. N., Belevtsev M. V. Genotype-phenotypic characteristics of patients with Wiskott-Aldrich syndrome. Problemy zdorov’ya i ekologii = Problems of health and ecology, 2011, no. 2, rr. 95-97 (in Russian).

10. Vihinen M., Arredondo-Vega F. X., Casanova J. L., Etzioni A., Giliani S., Hammarstrom L. [et al.]. Primary immunodeficienciecy mutation databases. Advances in Genetics, 2001, vol. 43, rr. 103-108. https://doi.org/10.1016/s0065-2660(01)43005-7

11. Jin Y., Mazza C., Christie J. R., Giliani S., Fiorini M., Mella P. [et al.]. Mutations of the Wiskott-Aldrich syndrome protein (WASP): hotspots, effect on transcription, and translation and phenotype/genotype correlation. Blood, 2004, vol. 104, rr. 4010-4019. https://doi.org/10.1182/blood-2003-05-1592

12. Thrasher A. J. New insights into the biology of Wiskott-Aldrich syndrome (WAS). Hematology. American Society of Hematology. Education Program, 2009, vol. 2009, no. 1, rr. 132-138. https://doi.org/10.1182/asheducation-2009.1.132

13. Campbell C., Mitui M., Eng L., Coutinho G., Thorstenson Y., Gatti R. A. ATM mutations on distinct SNP and STR haplotypes in ataxia-telangiectasia patients of differing ethnicities reveal ancestral founder effects. Human Mutation, 2003, vol. 21, no. 1, pp. 80-85. https://doi.org/10.1002/humu.10156

14. Perlman S., Becker-Catania S., Gatti R. A. Ataxia-Telangiectasia: diagnosis and treatment. Seminars in Pediatric Neurology, 2003, vol. 10, no. 3, pp. 173-182. https://doi.org/10.1016/s1071-9091(03)00026-3

15. Chun H. H., Gatti R. A. Ataxia-telangiectasia, an evolving phenotype. DNA Repair, 2004, vol. 13, no. 8-9, pp. 1187- 1196. https://doi.org/10.1016/j.dnarep.2004.04.010

16. Sharapova S. O., Valochnik A. V., Guryanova I. E., Sakovich I. S., Aleinikova O. V. Novel biallelic ATM mutations coexist with a mosaic form of triple X syndrome in an 11-year-old girl at remission after T cell acute leukemia. Immunogenetics, 2018, vol. 70, no. 9, pp. 613-617. https://doi.org/10.1007/s00251-018-1056-4

17. Sharapova S. O., Pashchenko O. E., Migas A. A., Gur’yanova I. E., Kondratenko I. V., Belevtsev M. V., Aleinikova O. V. Immunological status of children with congenital agammaglobulinemia. Vestsi Natsyyanal’nai akademii navuk Belarusi. Seriya meditsinskikh navuk = Proceedings of the National Academy of Sciences of Belarus. Medical series, 2013, no. 2, pp. 19-29 (in Russian).

18. Valiaho J., Smith C. I., Vihinen M. BTKbase: the mutation database for X-linked agammaglobulinemia. Human Mutation, 2006, vol. 27, no. 12, pp. 1209-1217. https://doi.org/10.1002/humu.20410

19. Lopez-Granados E., Perez de Diego R., Ferreira Cerdan A., Fontan Casariego G., Garcia Rodriguez M. C. A genotype-phenotype correlation study in a group of 54 patients with X-linked agammaglobulinemia. The Journal of Allergy and Clinical Immunology, 2005, vol. 116, no. 3, pp. 690-697. https://doi.org/10.1016/j.jaci.2005.04.043

20. Toth B., Volokha A., Mihas A., Pac M., Bernatowska E., Kondratenko I. [et al.]. Genetic and demographic features of X-linked agammaglobulinemia in Eastern and Central Europe A cohort study. Molecular Immunology, 2009, vol. 46, no. 10, pp. 2140-2146. https://doi.org/10.1016/j.molimm.2009.03.012

21. Michalovich D., Nejentsev S. Activated PI3 kinase delta syndrome: from genetics to therapy. Frontiers in Immunology, 2018, vol. 9, art. 369. https://doi.org/10.3389/fimmu.2018.00369

22. Lucas C. L., Chandra A., Nejentsev S., Condliffe A. M., Okkenhaug K. PI3Kδ and primary immunodeficiencies. Nature Reviews. Immunology, 2016, vol. 16, no. 11, pp. 702-714. https://doi.org/10.1038/nri.2016.93

23. Jirapongsananuruk O., Niemela J. E., Malech H. L., Fleisher T. A. CYBB mutation analysis in X-linked chronic granulomatous disease. Clinical Immunology, 2002, vol. 104, no. 1, pp. 73-76. https://doi.org/10.1006/clim.2002.5230

24. Roos D., Kuhns D. B., Maddalena A., Roesler J., Lopez J. A., Ariga T. Hematologically important mutations: X-linked chronic granulomatous disease (third update). Blood Cells, Molecules and Diseases, 2010, vol. 45, no. 3, pp. 246- 265. https://doi.org/10.1016/j.bcmd.2010.07.012

25. Sharapova S. O., Haapaniemi E., Sakovich I. S., Rojas J., Gamez-Diaz L., Mareika Y. E. [et al.]. Novel LRBA mutation and possible germinal mosaicism in a Slavic family. Journal of Clinical Immunology, 2018, vol. 38, no. 4, pp. 471-474. https://doi.org/10.1007/s10875-018-0515-x