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Syndromic variants of congenital neutropenia may be due to mutations in genes controlling glucose metabolism (SLC37A4, G6PC3) or lysosomal function (LYST, RAB27A, ROBLD3\/p14, AP3B1, VPS13B). Furthermore, defects in genes encoding ribosomal proteins (SBDS, RMRP) and mitochondrial proteins (AK2, TAZ) are associated with congenital neutropenia syndromes. Despite remarkable progress in the field, many patients with congenital neutropenia cannot yet definitively be classified by genetic terms. This review addresses diagnostic and therapeutic aspects of congenital neutropenia and covers recent molecular and pathophysiological insights of selected congenital neutropenia syndromes.<\/jats:p>","DOI":"10.1182\/asheducation-2009.1.344","type":"journal-article","created":{"date-parts":[[2009,12,11]],"date-time":"2009-12-11T15:35:31Z","timestamp":1260545731000},"page":"344-350","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":40,"title":["Congenital neutropenia"],"prefix":"10.1182","volume":"2009","author":[{"given":"Christoph","family":"Klein","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","reference":[{"key":"2019111704434521100_R1","unstructured":"Kostmann R. Heredita\u0308r reticulos - en ny systemsjukdom. Svenska Laekartidningen. 1950;47:2861\u20132868."},{"key":"2019111704434521100_R2","doi-asserted-by":"crossref","unstructured":"Kostmann R. Infantile genetic agranulocytosis; agranulocytosis infantilis hereditaria. Acta Paediatr Suppl. 1956;45:1\u201378.","DOI":"10.1111\/j.1651-2227.1956.tb06875.x"},{"key":"2019111704434521100_R3","doi-asserted-by":"crossref","unstructured":"Reich D, Nalls MA, Kao WH, et al. Reduced neutrophil count in people of African descent is due to a regulatory variant in the Duffy antigen receptor for chemokines gene. PLoS Genet. 2009;5:e1000360.","DOI":"10.1371\/journal.pgen.1000360"},{"key":"2019111704434521100_R4","doi-asserted-by":"crossref","unstructured":"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;23:433\u2013436.","DOI":"10.1038\/70544"},{"key":"2019111704434521100_R5","doi-asserted-by":"crossref","unstructured":"Dale DC, Person RE, Bolyard AA, et al. Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia. 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