Severe congenital neutropenia (SCN) is a heterogeneous group of disorders characterized by low counts of neutrophils in peripheral blood. Several genes are responsible for SCN and genotype-phenotype correlation has been established in most of them.
We reported a 2-year-old boy with chronic neutropenia who presented at the age of two weeks with anal abscesses. Immunological analysis showed normal lymphocyte subpopulations and immunoglobulins levels. Tests for autoantibodies and the neutrophil oxidative burst were normal.
Custom Next-Generation Sequencing (NGS) panel of 10 gens associated with SCN was performed.
NGS revealed two monoallelic variants of uncertain clinical significance in two different candidate genes: p.Val57Met and p.Phe338Leu in JAGN1 and SLC37A4, respectively. Both variants have low allele frequency (<0.001) and in silico tools predicted a deleterious effect on protein function.
Due to advances in genetic testing through NGS, the knowledge about the relationship between genes and diseases and the evidence for digenic inheritance has increased in recent years. However, the genetic basis of neutropenia remains unknown in a substantial proportion of children. Here, we described a patient with chronic neutropenia and carrier of two potentially pathogenic monoallelic variants in two candidate genes. SCN is considered a monogenic disease however, a recent study suggests that an additional variant in a second causal gene could produce an impact on clinical phenotype. These data prompt us to hypothesize that the combination of these variants could produce a synergistic effect causing chronic neutropenia. Future studies are needed to explore the synergic effect of monoallelic variants in different SCN related genes.