Abstract
Purpose
Patients with autosomal recessive cyclic neutropenia have no known causative genetic defect yet.
Methods
Autozygosity mapping on two branches of an extended multiplex consanguineous family presenting with cyclic neutropenia or severe congenital neutropenia to look for candidate gene, followed by candidate gene selection and sequencing.
Results
A single autozygous interval on Chr17:33,901,938-45,675,414 that is exclusively shared by the affected members was identified. This interval spans 11.8 Mb and contains 30 genes. Review of these genes highlighted G6PC3 as the most likely candidate given its known role in neutrophil biology. Direct sequencing revealed a novel homozygous mutation (NM_138387.3, c.974T > G, p.Leu325Arg). Two of our patients had associated congenital defects that are known to occur in patients with G6PC3 mutations, including congenital heart disease and intermittent thrombocytopenia.
Conclusion
Biallelic G6PC3 defects should be considered in patients with autosomal recessive cyclic neutropenia, especially those with typical associated congenital defects.
This is a preview of subscription content, log in via an institution to check access.
References
Haurie C, Dale DC, Mackey MC. Cyclical neutropenia and other periodic hematological disorders: a review of mechanisms and mathematical models. Blood. 1998;92(8):2629–40.
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. doi:10.1038/70544.
Horwitz MS, Duan Z, Korkmaz B, Lee HH, Mealiffe ME, Salipante SJ. Neutrophil elastase in cyclic and severe congenital neutropenia. Blood. 2007;109(5):1817–24. doi:10.1182/blood-2006-08-019166.
Jun HS, Lee YM, Cheung YY, McDermott DH, Murphy PM, De Ravin SS, et al. Lack of glucose recycling between endoplasmic reticulum and cytoplasm underlies cellular dysfunction in glucose-6-phosphatase-beta-deficient neutrophils in a congenital neutropenia syndrome. Blood. 2010;116(15):2783–92. doi:10.1182/blood-2009-12-258491.
Klein C. Genetic defects in severe congenital neutropenia: emerging insights into life and death of human neutrophil granulocytes. Annu Rev Immunol. 2011;29:399–413. doi:10.1146/annurev-immunol-030409-101259.
Ward AC, Dale DC. Genetic and molecular diagnosis of severe congenital neutropenia. Curr Opin Hematol. 2009;16(1):9–13. doi:10.1097/MOH.0b013e32831952de.
Boztug K, Appaswamy G, Ashikov A, Schäffer AA, Salzer U, Diestelhorst J, et al. A syndrome with congenital neutropenia and mutations in G6PC3. N Engl J Med. 2009;360(1):32–43. doi:10.1056/NEJMoa0805051.
Alkuraya FS. Discovery of rare homozygous mutations from studies of consanguineous pedigrees. Current protocols in human genetics / editorial board, Jonathan L Haines [et al]. 2012;Chapter 6:Unit6 12. doi:10.1002/0471142905.hg0612s75.
Haurie C, Dale DC, Mackey MC. Occurrence of periodic oscillations in the differential blood counts of congenital, idiopathic, and cyclical neutropenic patients before and during treatment with G-CSF. Exp Hematol. 1999;27(3):401–9.
Boztug K, Rosenberg PS, Dorda M, Banka S, Moulton T, Curtin J, et al. Extended spectrum of human glucose-6-phosphatase catalytic subunit 3 deficiency: novel genotypes and phenotypic variability in severe congenital neutropenia. J Pediatr. 2012;160(4):679–683.e2. doi:10.1016/j.jpeds.2011.09.019.
Donadieu J, Fenneteau O, Beaupain B, Mahlaoui N, Chantelot CB. Congenital neutropenia: diagnosis, molecular bases and patient management. Orphanet J Rare Dis. 2011;6:26. doi:10.1186/1750-1172-6-26.
Smith BN, Evans C, Ali A, Ancliff PJ, Hayee Bah, Segal AW, et al. Phenotypic heterogeneity and evidence of a founder effect associated with G6PC3 mutations in patients with severe congenital neutropenia. Br J Haematol. 2012;158(1):146–9.
Banka S, Wynn R, Newman WG. Variability of bone marrow morphology in G6PC3 mutations: is there a genotype-phenotype correlation or age-dependent relationship? Am J Hematol. 2011;86(2):235–7. doi:10.1002/ajh.21930.
McDermott DH, De Ravin SS, Jun HS, Liu Q, Priel DA, Noel P, et al. Severe congenital neutropenia resulting from G6PC3 deficiency with increased neutrophil CXCR4 expression and myelokathexis. Blood. 2010;116(15):2793–802. doi:10.1182/blood-2010-01-265942.
Newburger PE, Pindyck TN, Zhu Z, Bolyard AA, Aprikyan AAG, Dale DC, et al. Cyclic neutropenia and severe congenital neutropenia in patients with a shared ELANE mutation and paternal haplotype: evidence for phenotype determination by modifying genes. Pediatr Blood Cancer. 2010;55(2):314–7. doi:10.1002/pbc.22537.
Acknowledgments
The authors extend their appreciation to the Deanship of Scientific Research at King Saud University for funding the work through the research group project No. RGP-VPP-190
Conflict of interest
None of the authors has any potential financial conflict of interest related to this manuscript.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Alangari, A.A., Alsultan, A., Osman, M.E. et al. A Novel Homozygous Mutation in G6PC3 Presenting as Cyclic Neutropenia and Severe Congenital Neutropenia in the Same Family. J Clin Immunol 33, 1403–1406 (2013). https://doi.org/10.1007/s10875-013-9945-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10875-013-9945-7