Novel genetic etiologies of severe congenital neutropenia

Abstract

Severe congenital neutropenia (SCN) comprises a heterogenous group of primary immunodeficiency disorders collectively characterized by paucity of mature neutrophils. In recent years, progress has been made with respect to the elucidation of genetic causes underlying syndromic and non-syndromic variants of SCN. Most cases of autosomal dominant SCN are associated with mutations in the neutrophil elastase (ELA-2/ELANE) gene, autosomal recessive forms of this disorder can be caused by mutations in the gene encoding the mitochondrial protein HAX-1. Rarely, SCN can be caused by mutations in the gene encoding the transcription factor GFI1 or activating mutations in the Wiskott-Aldrich syndrome (WAS) gene, respectively. More recently, a complex disorder associating SCN and developmental aberrations was identified, caused by mutations in the glucose-6-phosphatase catalytic subunit 3 (G6PC3) gene. Despite our increasing knowledge of the genetic etiologies of SCN, the molecular pathophysiology underlying these disorders remains only partially understood.