Extended spectrum of human glucose-6-phosphatase catalytic subunit 3 deficiency: Novel genotypes and phenotypic variability in severe congenital neutropenia

Kaan Boztug, Philip S. Rosenberg, Marie Dorda, Siddharth Banka, Thomas Moulton, Julie Curtin, Nima Rezaei, John Corns, Jeffrey W. Innis, Zekai Avci, Hung Chi Tran, Isabelle Pellier, Paolo Pierani, Rachel Fruge, Nima Parvaneh, Setareh Mamishi, Rajen Mody, Phil Darbyshire, Jayashree Motwani, Jennie MurrayGeorge R. Buchanan, William G. Newman, Blanche P. Alter, Laurence A. Boxer, Jean Donadieu, Karl Welte, Christoph Klein

Research output: Contribution to journalArticle

Abstract

Objective: To delineate the phenotypic and molecular spectrum of patients with a syndromic variant of severe congenital neutropenia (SCN) due to mutations in the gene encoding glucose-6-phosphatase catalytic subunit 3 (G6PC3). Study design: Patients with syndromic SCN were characterized for associated malformations and referred to us for G6PC3 mutational analysis. Results: In a cohort of 31 patients with syndromic SCN, we identified 16 patients with G6PC3 deficiency including 11 patients with novel biallelic mutations. We show that nonhematologic features of G6PC3 deficiency are good predictive indicators for mutations in G6PC3. Additionally, we demonstrate genetic variability in this disease and define novel features such as growth hormone deficiency, genital malformations, disrupted bone remodeling, and abnormalities of the integument. G6PC3 mutations may be associated with hydronephrosis or facial dysmorphism. The risk of transition to myelodysplastic syndrome/acute myeloid leukemia may be lower than in other genetically defined SCN subgroups. Conclusions: The phenotypic and molecular spectrum in G6PC3 deficiency is wider than previously appreciated. The risk of transition to myelodysplastic syndrome or acute myeloid leukemia may be lower in G6PC3 deficiency compared with other subgroups of SCN.

Original languageEnglish (US)
JournalJournal of Pediatrics
Volume160
Issue number4
DOIs
StatePublished - Apr 2012
Externally publishedYes

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health

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    Boztug, K., Rosenberg, P. S., Dorda, M., Banka, S., Moulton, T., Curtin, J., Rezaei, N., Corns, J., Innis, J. W., Avci, Z., Tran, H. C., Pellier, I., Pierani, P., Fruge, R., Parvaneh, N., Mamishi, S., Mody, R., Darbyshire, P., Motwani, J., ... Klein, C. (2012). Extended spectrum of human glucose-6-phosphatase catalytic subunit 3 deficiency: Novel genotypes and phenotypic variability in severe congenital neutropenia. Journal of Pediatrics, 160(4). https://doi.org/10.1016/j.jpeds.2011.09.019