A Novel Homozygous Mutation in G6PC3 Presenting as Cyclic Neutropenia and Severe Congenital Neutropenia in the Same Fami
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A Novel Homozygous Mutation in G6PC3 Presenting as Cyclic Neutropenia and Severe Congenital Neutropenia in the Same Family Abdullah A. Alangari & Abdulrahman Alsultan & Mohamed Elfaki Osman & Shamsa Anazi & Fowzan S. Alkuraya
Received: 18 June 2013 / Accepted: 30 September 2013 / Published online: 9 October 2013 # Springer Science+Business Media New York 2013
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 Chr17:33,901,93845,675,414 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.
A. A. Alangari (*) : A. Alsultan : M. E. Osman Department of Pediatrics, College of Medicine, King Saud University, P.O. Box 2925, Riyadh 11461, Saudi Arabia e-mail: [email protected] S. Anazi : F. S. Alkuraya Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia F. S. Alkuraya Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
Keywords Cyclic neutropenia . severe congenital neutropenia . autozygosity mapping . G6PC3 . congenital heart disease . thrombocytopenia
Introduction Cyclic neutropenia (CyN) is defined as an absolute neutrophil count (ANC) less than 0.5×109/L for at least 3 to 5 days per approximately 21 day cycles [1]. The only known genetic defect in patients with CyN so far is mutated neutrophil elastase (NE) gene (ELANE, formerly known as ELA2) located on chromosome 19p13.3 [2, 3]. This condition is inherited in an autosomal dominant fashion. Glucose 6-phosphatase catalytic subunit-3 (G6PC3) is a ubiquitously expressed enzyme that is involved in the stability of the endoplasmic reticulum (ER) by maintaining cellular energy homeostasis through recycling of ER glucose to the cytoplasm [4]. It is encoded by the gene G6PC3 located on chromosome 17q21. Biallelic mutations in G6PC3 result in an autosomal recessive disease of severe congenital neutropenia (SCN), known as SCN type 4. SCN is defined as an ANC of less than 0.5×109/L present with invasive bacterial infections. It is usually associated with maturation arrest at the promyelocyte/ myelocyte stage
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