Blood Adv. 2025 10 07. pii: bloodadvances.2025016507. [Epub ahead of print]
Thijs van Bergen,
Dennis Bosch,
Christine Bellanné-Chantelot,
Roger Mulet-Lazaro,
Jacob R Bledsoe,
Lanpeng Chen,
Hans W J de Looper,
Claire van Dijk,
Mariëtte Ter Borg,
Eric Bindels,
Remco Hoogenboezem,
Onno Roovers,
Patricia A Olofsen,
Marije Bartels,
Joris M van Montfrans,
Puck Breed,
Elisabeth Salzer,
Marloes G Holierhoek,
Brigittie Nelken,
Blandine Beaupain,
Mark Daniel Fleming,
Akiko Shimamura,
Marc H G P Raaijmakers,
Jean Donadieu,
Peter E Newburger,
Ivo P Touw,
Anna M Aalbers.
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.