The Clinical and Molecular Assessment of Iranian Families with Severe Congenital Neutropenia, Identification of HYOU1 and SHOC2 as Potential Novel Gene Defects
-
Fatemeh Arab
,
Nima Rezaei
,
Forough Taheri
,
Hamideh Kouhpeikar
,
Elham Rayzan
,
Mona Mirbeyk
,
Davood Zare‐Abdollahi
,
Mohsen Ghadami
Abstract
Neutropenia congenita grave (SCN) is a rare disease with a genetically and clinically heterogeneous nature, usually diagnosed in childhood, with an elevated risk of infections such as otitis, skin infections, pneumonia, deep abscesses, and septicemia. Patients with SCN also have an increased risk of leukemia, and mutations in the ELANE and the HAX1 genes have been observed in those patients.
This study was conducted to genetically screen six Iranian families with SCN who have at least one affected person. In the first step, all exons and intron boundaries of ELANE and HAX1 genes were sequenced in probands. Cases with no pathogenic mutations were tested through whole-exome sequencing (WES).
Analysis showed five different variants in ELANE (c.377 C>T), HAX1 (c.130_131 insA), HYOU1 (c.69 G>C and c.2744 G>A) and SHOC2 (c.4 A>G) genes in four families. We found that two out of six families had mutations in ELANE and HAX1 genes. Moreover, we found two novel mutations at the HYOU1 gene that had not previously been reported, as well as a pathogenic mutation at SHOC2 with multiple phenotypes, that will contribute to determining the genetic basis for SCN.
Our study revealed that WES could help diagnose SCN, improve the classification of neutropenia, and rule out other immunodeficiencies such as autoimmune neutropenia, primary immunodeficiency diseases, and inherited bone marrow failure syndromes.
1. Boxer LA, Newburger PE. A molecular classification of congenital neutropenia syndromes. Pediatr Blood Cancer. 2007;49(5):609-14.
2. Hauck F, Klein C. Pathogenic mechanisms and clinical implications of congenital neutropenia syndromes. Curr Opin Allergy Clin Immunol. 2013;13(6):596-606.
3. Carlsson G, Fasth A. Infantile genetic agranulocytosis, morbus Kostmann: presentation of six cases from the original "Kostmann family" and a review. Acta Paediatr. 2001;90(7):757-64.
4. Boxer LA. Severe congenital neutropenia: genetics and pathogenesis. Trans Am Clin Climatol Assoc. 2006;117:13-32.
5. Skokowa J, Dale DC, Touw IP, Zeidler C, Welte K. Severe congenital neutropenias. Nat Rev Dis Primers. 2017;3(1):1-18.
6. Van den Berg JM, Kuijpers TW. Educational paper: Defects in number and function of neutrophilic granulocytes causing primary immunodeficiency. Eur J Pediatr. 2011;170(11):1369-76.
7. Cho HK, Jeon IS. Different clinical phenotypes in familial severe congenital neutropenia cases with same mutation of the ELANE gene. J Korean Med Sci. 2014;29(3):452-5.
8. Dale DC, Cottle TE, Fier CJ, Bolyard AA, Bonilla MA, Boxer LA, et al. Severe chronic neutropenia: treatment and follow-up of patients in the Severe Chronic Neutropenia International Registry. Am J Hematol. 2003;72(2):82-93.
9. Freedman MH, Bonilla MA, Fier C, Bolyard AA, Scarlata D, Boxer LA, et al. Myelodysplasia syndrome and acute myeloid leukemia in patients with congenital neutropenia receiving G-CSF therapy. Blood. 2000;96(2):429-36.
10. Horwitz M, Benson KF, Person RE, Aprikyan AG, Dale DC. Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis. Nat Genet. 1999;23(4):433-6.
11. Dale DC, Person RE, Bolyard AA, Aprikyan AG, Bos C, Bonilla MA, et al. Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia. Blood. 2000;96(7):2317-22.
12. Nayak RC, Trump LR, Aronow BJ, Myers K, Mehta P, Kalfa T, et al. Pathogenesis of ELANE-mutant severe neutropenia revealed by induced pluripotent stem cells. J Clin Investig. 2015;125(8):3103-16.
13. Klein C, Grudzien M, Appaswamy G, Germeshausen M, Sandrock I, Schäffer AA, et al. HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease). Nat Genet. 2007;39(1):86-92.
14. Donadieu J, Fenneteau O, Beaupain B, Mahlaoui N, Chantelot CB. Congenital neutropenia: diagnosis, molecular bases and patient management. Orphanet J Rare Dis. 2011;6(1):26.
15. Arunachalam AK, Suresh H, Edison ES, Korula A, Aboobacker FN, George B, et al. Screening of genetic variants in ELANE mutation negative congenital neutropenia by next generation sequencing. J Clin Pathol. 2020;73(6):322-7.
16. Picard C, Al-Herz W, Bousfiha A, Casanova JL, Chatila T, Conley ME, et al. Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015. J Clin Immunol. 2015;35(8):696-726.
17. Rezaei N, Moazzami K, Aghamohammadi A, Klein C. Neutropenia and primary immunodeficiency diseases. Int Rev Immunol. 2009;28(5):335-66.
18. Furutani E, Newburger PE, Shimamura A. Neutropenia in the age of genetic testing: advances and challenges. Am J Hematol. 2019;94(3):384-93.
19. Zeidler C, Schwinzer B, Welte K. Severe congenital neutropenia: trends in diagnosis and therapy. Klin Padiatr. 2000;212(4):145-52.
20. Rehman AU, Sepahi N, Bedoni N, Ravesh Z, Salmaninejad A, Cancellieri F, et al. Whole exome sequencing in 17 consanguineous Iranian pedigrees expands the mutational spectrum of inherited retinal dystrophies. Sci Rep. 2021;11(1):1-9.
21. Bouma G, Ancliff PJ, Thrasher AJ, Burns SO. Recent advances in the understanding of genetic defects of neutrophil number and function. Br J Haematol. 2010;151(4):312-26.
22. Untergasser A, Cutcutache I, Koressaar T, Ye J, Faircloth BC, Remm M, et al. Primer3—new capabilities and interfaces. Nucleic Acids Res. 2012;40(15):e115-e.
23. Connelly JA, Choi SW, Levine JE. Hematopoietic stem cell transplantation for severe congenital neutropenia. Curr Opin Hematol. 2012;19(1):44.
24. McNulty SN, Evenson MJ, Riley M, Yoest JM, Corliss MM, Heusel JW, et al. A Next-Generation Sequencing Test for Severe Congenital Neutropenia: Utility in a Broader Clinicopathologic Spectrum of Disease. J Mol Diagn. 2021;23(2):200-11.
25. Horwitz MS, Corey SJ, Grimes HL, Tidwell T. ELANE mutations in cyclic and severe congenital neutropenia: genetics and pathophysiology. Hematol Oncol Clin North Am. 2013;27(1):19-vii.
26. Ancliff PJ, Gale RE, Liesner R, Hann IM, Linch DC. Mutations in the ELA2 gene encoding neutrophil elastase are present in most patients with sporadic severe congenital neutropenia but only in some patients with the familial form of the disease. Blood. 2001;98(9):2645-50.
27. Makaryan V, Zeidler C, Bolyard AA, Skokowa J, Rodger E, Kelley ML, et al. The diversity of mutations and clinical outcomes for ELANE-associated neutropenia. Curr Opin Hematol. 2015;22(1):3.
28. Dale DC, Bolyard AA, Schwinzer BG, Pracht G, Bonilla MA, Boxer L, et al. The severe chronic neutropenia international registry: 10-year follow-up report. Support Cancer Ther. 2006;3(4):220-31.
29. Klein C, Grudzien M, Appaswamy G, Germeshausen M, Sandrock I, Schäffer AA, et al. HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease). Nat Genet. 2007;39(1):86-92.
30. Alizadeh Z, Fazlollahi MR, Houshmand M, Maddah M, Chavoshzadeh Z, Hamidieh AA, et al. Different pattern of gene mutations in Iranian patients with severe congenital neutropenia (including 2 new mutations). Iran J Allergy Asthma Immunol. 2013;12(1):82-96.
31. Haapaniemi EM, Fogarty CL, Keskitalo S, Katayama S, Vihinen H, Ilander M, et al. Combined immunodeficiency and hypoglycemia associated with mutations in hypoxia upregulated 1. J Allergy Clin Immunol. 2017;139(4):1391-3. e11.
32. Donadieu J, Beaupain B, Fenneteau O, Bellanné‐Chantelot C. Congenital neutropenia in the era of genomics: classification, diagnosis, and natural history. Br J Haematol. 2017;179(4):557-74.
33. Baldassarre G, Mussa A, Banaudi E, Rossi C, Tartaglia M, Silengo M, et al. Phenotypic variability associated with the invariant SHOC2 c. 4A> G (p. Ser2Gly) missense mutation. Am J Med Genet A. 2014;164(12):3120-5.
34. Komatsuzaki S, Aoki Y, Niihori T, Okamoto N, Hennekam RC, Hopman S, et al. Mutation analysis of the SHOC2 gene in Noonan-like syndrome and in hematologic malignancies. J Hum Genet. 2010;55(12):801-9.
35. Cordeddu V, Di Schiavi E, Pennacchio LA, Ma'ayan A, Sarkozy A, Fodale V, et al. Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair. Nat Genet. 2009;41(9):1022-6.
36. Jang H, Oakley E, Forbes-Osborne M, Kesler MV, Norcross R, Morris AC, et al. Hematopoietic and neural crest defects in zebrafish shoc2 mutants: a novel vertebrate model for Noonan-like syndrome. Hum Mol Genet. 2019;28(3):501-14.
37. Tartaglia M, Gelb BD, Zenker M. Noonan syndrome and clinically related disorders. Best Pract Res Clin Endocrinol Metab. 2011;25(1):161-79.
38. Tidyman WE, Rauen KA. The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation. Curr Opin Genet Dev. 2009;19(3):230-6.
39. Zenker M. Clinical manifestations of mutations in RAS and related intracellular signal transduction factors. Curr Opin Pediatr. 2011;23(4):443-51.
40. Almaninejad A, Gowhari A, Hosseini S, Aslani S, Yousefi M, Bahrami T, et al. Genetics and immunodysfunction underlying Behçet’s disease and immunomodulant treatment approaches. J Immunotoxicol. 2017;14(1):137-51.
41. Salmaninejad A, Zamani MR, Shabgah AG, Hosseini S, Mollaei F, Hosseini N, et al. Behçet’s disease: An immunogenetic perspective. J Cell Physiol. 2019;234(6):8055-74.
2. Hauck F, Klein C. Pathogenic mechanisms and clinical implications of congenital neutropenia syndromes. Curr Opin Allergy Clin Immunol. 2013;13(6):596-606.
3. Carlsson G, Fasth A. Infantile genetic agranulocytosis, morbus Kostmann: presentation of six cases from the original "Kostmann family" and a review. Acta Paediatr. 2001;90(7):757-64.
4. Boxer LA. Severe congenital neutropenia: genetics and pathogenesis. Trans Am Clin Climatol Assoc. 2006;117:13-32.
5. Skokowa J, Dale DC, Touw IP, Zeidler C, Welte K. Severe congenital neutropenias. Nat Rev Dis Primers. 2017;3(1):1-18.
6. Van den Berg JM, Kuijpers TW. Educational paper: Defects in number and function of neutrophilic granulocytes causing primary immunodeficiency. Eur J Pediatr. 2011;170(11):1369-76.
7. Cho HK, Jeon IS. Different clinical phenotypes in familial severe congenital neutropenia cases with same mutation of the ELANE gene. J Korean Med Sci. 2014;29(3):452-5.
8. Dale DC, Cottle TE, Fier CJ, Bolyard AA, Bonilla MA, Boxer LA, et al. Severe chronic neutropenia: treatment and follow-up of patients in the Severe Chronic Neutropenia International Registry. Am J Hematol. 2003;72(2):82-93.
9. Freedman MH, Bonilla MA, Fier C, Bolyard AA, Scarlata D, Boxer LA, et al. Myelodysplasia syndrome and acute myeloid leukemia in patients with congenital neutropenia receiving G-CSF therapy. Blood. 2000;96(2):429-36.
10. Horwitz M, Benson KF, Person RE, Aprikyan AG, Dale DC. Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis. Nat Genet. 1999;23(4):433-6.
11. Dale DC, Person RE, Bolyard AA, Aprikyan AG, Bos C, Bonilla MA, et al. Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia. Blood. 2000;96(7):2317-22.
12. Nayak RC, Trump LR, Aronow BJ, Myers K, Mehta P, Kalfa T, et al. Pathogenesis of ELANE-mutant severe neutropenia revealed by induced pluripotent stem cells. J Clin Investig. 2015;125(8):3103-16.
13. Klein C, Grudzien M, Appaswamy G, Germeshausen M, Sandrock I, Schäffer AA, et al. HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease). Nat Genet. 2007;39(1):86-92.
14. Donadieu J, Fenneteau O, Beaupain B, Mahlaoui N, Chantelot CB. Congenital neutropenia: diagnosis, molecular bases and patient management. Orphanet J Rare Dis. 2011;6(1):26.
15. Arunachalam AK, Suresh H, Edison ES, Korula A, Aboobacker FN, George B, et al. Screening of genetic variants in ELANE mutation negative congenital neutropenia by next generation sequencing. J Clin Pathol. 2020;73(6):322-7.
16. Picard C, Al-Herz W, Bousfiha A, Casanova JL, Chatila T, Conley ME, et al. Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015. J Clin Immunol. 2015;35(8):696-726.
17. Rezaei N, Moazzami K, Aghamohammadi A, Klein C. Neutropenia and primary immunodeficiency diseases. Int Rev Immunol. 2009;28(5):335-66.
18. Furutani E, Newburger PE, Shimamura A. Neutropenia in the age of genetic testing: advances and challenges. Am J Hematol. 2019;94(3):384-93.
19. Zeidler C, Schwinzer B, Welte K. Severe congenital neutropenia: trends in diagnosis and therapy. Klin Padiatr. 2000;212(4):145-52.
20. Rehman AU, Sepahi N, Bedoni N, Ravesh Z, Salmaninejad A, Cancellieri F, et al. Whole exome sequencing in 17 consanguineous Iranian pedigrees expands the mutational spectrum of inherited retinal dystrophies. Sci Rep. 2021;11(1):1-9.
21. Bouma G, Ancliff PJ, Thrasher AJ, Burns SO. Recent advances in the understanding of genetic defects of neutrophil number and function. Br J Haematol. 2010;151(4):312-26.
22. Untergasser A, Cutcutache I, Koressaar T, Ye J, Faircloth BC, Remm M, et al. Primer3—new capabilities and interfaces. Nucleic Acids Res. 2012;40(15):e115-e.
23. Connelly JA, Choi SW, Levine JE. Hematopoietic stem cell transplantation for severe congenital neutropenia. Curr Opin Hematol. 2012;19(1):44.
24. McNulty SN, Evenson MJ, Riley M, Yoest JM, Corliss MM, Heusel JW, et al. A Next-Generation Sequencing Test for Severe Congenital Neutropenia: Utility in a Broader Clinicopathologic Spectrum of Disease. J Mol Diagn. 2021;23(2):200-11.
25. Horwitz MS, Corey SJ, Grimes HL, Tidwell T. ELANE mutations in cyclic and severe congenital neutropenia: genetics and pathophysiology. Hematol Oncol Clin North Am. 2013;27(1):19-vii.
26. Ancliff PJ, Gale RE, Liesner R, Hann IM, Linch DC. Mutations in the ELA2 gene encoding neutrophil elastase are present in most patients with sporadic severe congenital neutropenia but only in some patients with the familial form of the disease. Blood. 2001;98(9):2645-50.
27. Makaryan V, Zeidler C, Bolyard AA, Skokowa J, Rodger E, Kelley ML, et al. The diversity of mutations and clinical outcomes for ELANE-associated neutropenia. Curr Opin Hematol. 2015;22(1):3.
28. Dale DC, Bolyard AA, Schwinzer BG, Pracht G, Bonilla MA, Boxer L, et al. The severe chronic neutropenia international registry: 10-year follow-up report. Support Cancer Ther. 2006;3(4):220-31.
29. Klein C, Grudzien M, Appaswamy G, Germeshausen M, Sandrock I, Schäffer AA, et al. HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease). Nat Genet. 2007;39(1):86-92.
30. Alizadeh Z, Fazlollahi MR, Houshmand M, Maddah M, Chavoshzadeh Z, Hamidieh AA, et al. Different pattern of gene mutations in Iranian patients with severe congenital neutropenia (including 2 new mutations). Iran J Allergy Asthma Immunol. 2013;12(1):82-96.
31. Haapaniemi EM, Fogarty CL, Keskitalo S, Katayama S, Vihinen H, Ilander M, et al. Combined immunodeficiency and hypoglycemia associated with mutations in hypoxia upregulated 1. J Allergy Clin Immunol. 2017;139(4):1391-3. e11.
32. Donadieu J, Beaupain B, Fenneteau O, Bellanné‐Chantelot C. Congenital neutropenia in the era of genomics: classification, diagnosis, and natural history. Br J Haematol. 2017;179(4):557-74.
33. Baldassarre G, Mussa A, Banaudi E, Rossi C, Tartaglia M, Silengo M, et al. Phenotypic variability associated with the invariant SHOC2 c. 4A> G (p. Ser2Gly) missense mutation. Am J Med Genet A. 2014;164(12):3120-5.
34. Komatsuzaki S, Aoki Y, Niihori T, Okamoto N, Hennekam RC, Hopman S, et al. Mutation analysis of the SHOC2 gene in Noonan-like syndrome and in hematologic malignancies. J Hum Genet. 2010;55(12):801-9.
35. Cordeddu V, Di Schiavi E, Pennacchio LA, Ma'ayan A, Sarkozy A, Fodale V, et al. Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair. Nat Genet. 2009;41(9):1022-6.
36. Jang H, Oakley E, Forbes-Osborne M, Kesler MV, Norcross R, Morris AC, et al. Hematopoietic and neural crest defects in zebrafish shoc2 mutants: a novel vertebrate model for Noonan-like syndrome. Hum Mol Genet. 2019;28(3):501-14.
37. Tartaglia M, Gelb BD, Zenker M. Noonan syndrome and clinically related disorders. Best Pract Res Clin Endocrinol Metab. 2011;25(1):161-79.
38. Tidyman WE, Rauen KA. The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation. Curr Opin Genet Dev. 2009;19(3):230-6.
39. Zenker M. Clinical manifestations of mutations in RAS and related intracellular signal transduction factors. Curr Opin Pediatr. 2011;23(4):443-51.
40. Almaninejad A, Gowhari A, Hosseini S, Aslani S, Yousefi M, Bahrami T, et al. Genetics and immunodysfunction underlying Behçet’s disease and immunomodulant treatment approaches. J Immunotoxicol. 2017;14(1):137-51.
41. Salmaninejad A, Zamani MR, Shabgah AG, Hosseini S, Mollaei F, Hosseini N, et al. Behçet’s disease: An immunogenetic perspective. J Cell Physiol. 2019;234(6):8055-74.
| Files | ||
| Issue | Vol 21 No 3 (2022) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v21i3.9808 | |
| Keywords | ||
| ELANE protein HAX1 protein HYOU1 protein Severe congenital neutropenia SHOC2 protein Whole exome sequencing | ||
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How to Cite
1.
Arab F, Rezaei N, Taheri F, Kouhpeikar H, Rayzan E, Mirbeyk M, Zare‐Abdollahi D, Ghadami M. The Clinical and Molecular Assessment of Iranian Families with Severe Congenital Neutropenia, Identification of HYOU1 and SHOC2 as Potential Novel Gene Defects. Iran J Allergy Asthma Immunol. 2022;21(3):344-354.
