Genetic etiologies of severe congenital neutropenia

Abstract

Purpose of review: To review recent advances in severe congenital neutropenia (SCN) syndromes.

Recent findings: The majority of patients with SCN bear monoallelic mutations in the neutrophil elastase (ELANE) gene. Biallelic mutations in the antiapoptotic gene HAX1 were identified in patients with autosomal recessive SCN. G6PC3 deficiency is a syndromic variant of SCN associating congenital neutropenia with various developmental defects including cardiac or urogenital malformations. The pathophysiology of these distinct genetic variants of SCN is complex. Increased apoptosis of neutrophil granulocytes may be caused by various molecular mechanisms including destabilization of the mitochondrial membrane potential and/or activation of the so-called 'unfolded protein response'.

Summary: SCN represents a heterogenous group of disorders that may be caused by genetic defects in ELANE, GFI1, HAX1, G6PC3 or activating mutations in the Wiskott-Aldrich syndrome (WAS) gene. Ongoing research will uncover additional genetic defects in SCN patients.