Germline LCP1 mutations cause immunodeficiency with neutropenia, monocytopenia, lymphopenia and defective cytokinesis.

Abstract

Severe congenital neutropenia (SCN) is characterized by neutropenia, recurrent infections and an increased leukemia risk. Multiple genetic defects underlying SCN have been identified, but a genetic diagnosis is still lacking in a significant proportion of patients. Here, we report four independent pedigrees with heterozygous variants in LCP1. Variants c.740-1G>T and c.740-20_744del resulted in the same alternatively spliced RNA product, causing an in-frame deletion (p.A247_E254del). Variant c.509C>T in the third pedigree resulted in p.S170L, and variant c.806T>C in the fourth pedigree in p.L269P. Affected individuals suffer from neutropenia, poor or complete lack of response to G-CSF treatment, and variable degrees of lymphopenia, hypogammaglobulinemia, and monocytopenia. Patients with A247_E254del and p.L269P presented with tetraploid cells in the bone marrow, indicative of disturbed cytokinesis. In one of these kindreds, two individuals developed acute leukemia. G-CSF non-responsiveness and defective cell cycling were repaired upon correction of the LCP1 A247_E254del variant in patient-derived induced pluripotent stem cells, supporting the monogenic origin of the disease. Indicative of their gain-of-function, both A247_E254del and S170L variants increased F-actin bundling and formation of abnormal protrusions. Single-cell transcriptome analysis of A247_E254del bone marrow-derived hematopoietic stem and progenitor cells (HSPCs) showed deregulation of signaling pathways controlling mitosis in multi-lineage and lymphoid-primed HSPC subsets. We conclude that activating LCP1 variants cause a new hematopoietic disorder with autosomal dominant inheritance. Depending on the consequences of the LCP1 variants for protein structure, patients may suffer from G-CSF refractory severe neutropenia, lymphopenia, hypogammaglobulinemia, monocytopenia, and defective cytokinesis.