A number sign (#) is used with this entry because of evidence that autosomal dominant severe congenital neutropenia-9 (SCN9) is caused by heterozygous mutation in the CLPB gene (616254) on chromosome 11q13.

Autosomal dominant severe congenital neutropenia-9 (SCN9) is characterized by onset of neutropenia in the first years of life. Most patients have recurrent infections; bone marrow examination shows a myeloid maturation arrest. Rare patients may exhibit additional features such as seizures, learning difficulties, or cataracts, which are more commonly observed in patients with MGCA7 (616271). However, patients with SCN9 do not have 3-methylglutaconic aciduria, and most have normal neurologic function (Warren et al., 2022).

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

Warren et al. (2022) reported 10 unrelated patients with severe congenital neutropenia associated with heterozygous missense mutations in the CLPB gene. The patients were ascertained from several large patient cohorts who underwent exome sequencing. All patients were diagnosed by 2.5 years of age, and most had recurrent infections. Most received G-CSF therapy. Bone marrow examination showed a myeloid maturation arrest in all patients. Three patients had neurologic involvement, including epilepsy, learning difficulties, and developmental delay. One adult patient had cataracts. One patient developed a myeloid malignancy and died. None of 5 patients tested had 3-methylglutaconic aciduria.

The heterozygous mutations in the CLPB gene that were identified in 2 patients with SCN9 by Warren et al. (2022) were demonstrated to have occurred de novo.

In 10 unrelated individuals with SCN9, Warren et al. (2022) identified 6 different heterozygous missense mutations in the CLPB gene (see, e.g., 616254.0014-616254.0016). The mutations, which were found by exome sequencing, were not present in the gnomAD database. In 2 patients, the mutations occurred de novo; family studies were not available for the other patients. All of the mutations occurred at conserved residues in the C-terminal ATP-binding pocket of CLPB. Knockdown of CLPB in CD34+ hematopoietic cells resulted in significantly fewer mature neutrophils and increased numbers of granulocyte precursors, indicating that CLPB is required for normal granulocyte differentiation. In vitro studies in transfected CD34+ cells showed that the CLPB variants tested impaired granulocytic differentiation and enhanced apoptosis without affecting the cell cycle or causing ER stress. Mixing studies indicated a dominant-negative effect of the mutations on CLPB ATPase activity and disaggregase activity. Additional studies showed that the tested ATP-binding pocket variants impaired mitochondrial respiration, suggesting a possible mechanistic link between mitochondrial dysfunction and defective granulopoiesis. In addition, 3 patients with cyclic neutropenia were found to carry a heterozygous R628C variant in the CLPB gene; functional studies of this variant were not performed.