Defective neutrophil development and specific granule deficiency caused by a homozygous splice-site mutation in SMARCD2

J Allergy Clin Immunol. 2021 Jun;147(6):2381-2385.e2. doi: 10.1016/j.jaci.2020.11.025. Epub 2020 Dec 3.

Abstract

Background: SMARCD2 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily D, member 2) has recently been shown to have a critical role in granulopoiesis in humans, mice, and zebrafish. Our patient presented with delayed cord separation, failure to thrive, and sepsis. Retrospective whole-exome sequencing confirmed a homozygous splice-site mutation in SMARCD2.

Objective: We sought to provide the second description of human SMARCD2 deficiency and the first functional analysis of human primary SMARCD2-deficient cells.

Methods: Heparinized venous blood and bone marrow were collected from the patient after obtaining informed consent. Patient leukocytes and CD34+ cells were then isolated, phenotyped, and assessed functionally.

Results: Circulating neutrophils appeared phenotypically immature, lacking multilobed nuclei, and neutrophil granules lacked lactoferrin but showed normal levels of myeloperoxidase. Neutrophil oxidative burst was preserved in response to phorbol 12-myristate 13-acetate. Patient bone marrow-derived neutrophils and white blood cells showed a severely impaired chemotactic response. Furthermore, white blood cells showed defective in vitro killing of Staphylococcus aureus, consistent with a specific granule deficiency. Finally, patient bone marrow-derived CD34+ cells showed markedly impaired in vitro expansion and differentiation toward the neutrophil lineage. Before her molecular diagnosis, our patient underwent hematopoietic stem cell transplantation and is well 8 years later.

Conclusions: This report highlights an important role for SMARCD2 in human myelopoiesis and the curative effect of hematopoietic stem cell transplantation for the hematopoietic features of SMARCD2 deficiency.

Keywords: CEBPε; Splice-site mutation; chemotaxis; inborn error of immunity; lactoferrin; neutrophil-specific granule deficiency; phagocyte disorder.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers
  • Cell Differentiation / genetics*
  • Cell Differentiation / immunology
  • Chemotaxis, Leukocyte / genetics
  • Chemotaxis, Leukocyte / immunology
  • Chromosomal Proteins, Non-Histone / genetics*
  • Cytotoxicity, Immunologic
  • Female
  • Genetic Predisposition to Disease
  • Homozygote*
  • Humans
  • Immunophenotyping
  • Infant, Newborn
  • Lactoferrin / deficiency*
  • Leukocyte Disorders / diagnosis
  • Leukocyte Disorders / etiology*
  • Mutation*
  • NADPH Oxidases / metabolism
  • Neutrophils / metabolism*
  • Neutrophils / pathology
  • Neutrophils / ultrastructure
  • Pedigree
  • Phenotype
  • RNA Splice Sites*
  • Respiratory Burst / genetics
  • Respiratory Burst / immunology

Substances

  • Biomarkers
  • Chromosomal Proteins, Non-Histone
  • RNA Splice Sites
  • SMARCD2 protein, human
  • NADPH Oxidases
  • Lactoferrin

Supplementary concepts

  • Specific Granule Deficiency