Neutropenia, Severe Congenital, 6, Autosomal Recessive

A number sign (#) is used with this entry because autosomal recessive severe congenital neutropenia-6 (SCN6) is caused by homozygous mutation in the JAGN1 gene (616012) on chromosome 3p25.

For a phenotypic description and a discussion of genetic heterogeneity of severe congenital neutropenia, see SCN1 (202700).

Clinical Features

Boztug et al. (2014) reported 14 patients from 9 families with severe congenital neutropenia. Patients presented in early childhood with recurrent bacterial infections of the upper and lower respiratory tract and skin. Laboratory studies showed neutropenia. Bone marrow biopsy showed maturational arrest of granulocytes at the promyelocyte/myelocyte stage. Electron microscopy of patient neutrophils showed an abnormal and enlarged endoplasmic reticulum (ER) with almost complete absence of granules, as well as evidence of increased ER stress. Patient cells showed increased apoptosis compared to control cells. One patient died at age 5 years; the others, aged 5 to 28 years, were alive and well. Two patients underwent hematopoietic bone marrow transplantation.

Inheritance

The transmission pattern of SCN6 in the families reported by Boztug et al. (2014) was consistent with autosomal recessive inheritance. Most of the families were consanguineous.

Molecular Genetics

In 14 patients from 9 families with autosomal recessive SCN6, Boztug et al. (2014) identified 9 different homozygous mutations in the JAGN1 gene (see, e.g., 616012.0001-616012.0005). The mutation in 1 family was found by linkage analysis, followed by candidate gene sequencing and exome and Sanger sequencing; subsequent mutations were found by direct sequencing of the JAGN1 gene in 74 individuals with SCN. Most of the mutations were missense mutations; 1 patient had a truncating mutation. There were no apparent genotype/phenotype correlations. JAGN1-mutant neutrophils showed abnormal N-glycomic profiles with a marked reduction in the fucosylation of all multiantennary glycans. O-glycosylation patterns were normal. Patients showed a poor response to GCSF (CSF3; 138970) treatment, and JAGN1-deficient neutrophils showed decreased amounts of GCSF receptors (CSF3R; 138971), possibly resulting from the N-glycosylation defect.