Congenital Neutropenia Research Articles

Attempts to identify the molecular cause of autoinflammatory recurrent fever

Systemic autoinflammatory diseases caused by dysregulation of the innate immunity are a known cause of recurrent fevers. We present the molecular diagnosis results of 12 children with recurrent fever, analyzing the correlation between molecular findings and clinical symptoms. No pathogenic variants confirming autoinflammatory disease were found. One child was diagnosed with SRP54 deficiency, linked to congenital neutropenia with a cyclic pattern. Variants of uncertain significance were found in 6 patients in genes associated with autoinflammatory disorders, though two lacked clinical correlation. Variants of uncertain significance in the NLRC4 gene were detected in 2 patients with periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome, in the PLSG2 gene in 1 child with systemic juvenile idiopathic arthritis, and in the MEFV gene in 1 patient with syndrome of uncertain recurrent fever. COVID-19 was identified as a triggering factor in 54.5% of cases. Further research is needed to clarify the role of genetic variants and environmental factors in recurrent fevers.

A large cohort from an immunology reference center and an algorithm for the follow-up of chronic neutropenia.

Chronic neutropenia causes involve nutritional deficiencies and inborn errors of immunity(IEI), such as severe congenital neutropenia. To classify common chronic neutropenia causes in a pediatric immunology unit. We enrolled 109 chronic neutropenia patients admitted to a pediatric immunology department between 2002-2022. We recorded clinical/laboratory features and genetic characteristics. The male/female ratio was 63/46. Fifty-eight patients had parental consanguinity(57.4%). 26.6% (n = 29) patients had at least one individual in their family with neutropenia. Common symtpoms at presentation were upper respiratory tract infections(URTI)(31.1%), oral aphthae(23.6%), skin infections(23.6%), pneumonia(20.8%), and recurrent abscesses(12.3%). Common infections during follow-up were URTI(56.8%), pneumonia(33%), skin infections(25.6%), gastroenteritis(18.3%), and recurrent abscesses(14,6%). Common long-term complications were dental problems(n = 51), osteoporosis(n = 22), growth retardation(n = 14), malignancy(n = 16)[myelodysplastic syndrome(n = 10), large granulocytic leukemia(n = 1), acute lymphoblastic leukemia(n = 1), Hodgkin lymphoma(n = 1), EBV-related lymphoma(n = 1), leiomyosarcoma(n = 1), and thyroid neoplasm(n = 1)]. We performed a genetic study in 86 patients, and 69(71%) got a genetic diagnosis. Common gene defects were HAX-1(n = 26), ELA-2 (ELANE)(n = 10), AP3B1(n = 4), and ADA-2(n = 4) gene defects. The IEI ratio(70.6%) was high. GCSF treatment(93.4%), immunoglobulin replacement therapy(18.7%), and HSCT(15.9%) were the treatment options. The mortality rate was 12.9%(n = 14). The most common long term complications were dental problems that is three times more common in patients with known genetic mutations. We prepared an algorithm for chronic neutropenia depending on the present cohort. An important rate of inborn errors of immunity, especially combined immunodeficiency(11.9%) was presented in addition to congenital phagocytic cell defects. Early diagnosis will allow us tailor the disease-specific treatment options sooner, preventing irreversible consequences.

Successful repurposing of empagliflozin to treat neutropenia in a severe congenital neutropenia patient with G6PC3 mutations

Successful repurposing of empagliflozin to treat neutropenia in a severe congenital neutropenia patient with G6PC3 mutations

Severe Congenital Neutropenia with ELANE gene mutation, on G-CSF therapy; a case report

Abstract Introduction/Objective Severe congenital neutropenia (SCN) is a genetic syndrome characterized by a deficiency of mature neutrophils in the bone marrow and peripheral blood. The disease is caused by various gene mutations, with ELANE gene mutations accounting for 50% to 60% of cases. Methods/Case Report We report a case of a 12-year-old male patient with severe congenital neutropenia, positive for the ELANE gene mutation. He has a history of recurrent infections and unexplained fevers since childhood. He has been receiving G-CSF treatment for ten years but is now exhibiting a diminished response to it. Analysis of the bone marrow biopsy reveals trilineage hematopoiesis, maturing myeloid with a rise in eosinophils, maturing erythroid, megakaryocytes normal in number and morphology with significantly reduced iron reserves in normocellular bone marrow. On immunostaining, CD34, CD14, or CD117 stains were negative. Neither monocytes nor granulocytes were CD56 positive. Increased monocyte counts coincide with partial CD14 loss. Lymphocytes make up 10% of all cells and consist of Polytypic B-cells, natural killer cells, and a heterogeneous population of T-cells with a normal CD4 to CD8 ratio. Hence, myelodysplastic syndrome was ruled out. Results (if a Case Study enter NA) NA Conclusion This case report provides valuable insights into the limited knowledge of congenital neutropenia with ELANE mutation on G-CSF therapy. It highlights the importance of ruling out Myelodysplastic syndrome in patients with severe congenital neutropenia and ELANE gene mutation treated with G-CSF therapy.

Inherited Predispositions to Myeloid Neoplasms: Pathogenesis and Clinical Implications.

Myeloid neoplasms with and without preexisting platelet disorders frequently develop in association with an underlying germline predisposition. Germline alterations affecting ANKRD26, CEBPA, DDX41, ETV6, and RUNX1 are associated with nonsyndromic predisposition to the development of myeloid neoplasms including acute myeloid leukemia and myelodysplastic syndrome. However, germline predisposition to myeloid neoplasms is also associated with a wide range of other syndromes, including SAMD9/9L associated predisposition, GATA2 deficiency, RASopathies, ribosomopathies, telomere biology disorders, Fanconi anemia, severe congenital neutropenia, Down syndrome, and others. In the fifth edition of the World Health Organization (WHO) series on the classification of tumors of hematopoietic and lymphoid tissues, myeloid neoplasms associated with germline predisposition have been recognized as a separate entity. Here, we review several disorders from this WHO entity as well as other related conditions with an emphasis on the molecular pathogenesis of disease and accompanying somatic alterations. Finally, we provide an overview of establishing the molecular diagnosis of these germline genetic conditions and general recommendations for screening and management of the associated hematologic conditions.

Comparison of Gene-Editing Approaches for Severe Congenital Neutropenia-Causing Mutations in the ELANE Gene.

Safety considerations for gene therapies of inherited preleukemia syndromes, including severe congenital neutropenia (CN), are paramount. We compared several strategies for CRISPR/Cas9 gene editing of autosomal-dominant ELANE mutations in CD34+ cells from two CN patients head-to-head. We tested universal and allele-specific ELANE knockout, ELANE mutation correction by homology-directed repair (HDR) with AAV6, and allele-specific HDR with ssODN. All strategies were not toxic, had at least 30% editing, and rescued granulopoiesis in vitro. In contrast to published data, allele-specific indels in the last exon of ELANE also restored granulopoiesis. Moreover, by implementing patient-derived induced pluripotent stem cells for GUIDE-Seq off-target analysis, we established a clinically relevant "personalized" assessment of off-target activity of gene editing on the background of the patient's genome. We found that allele-specific approaches had the most favorable off-target profiles. Taken together, a well-defined head-to-head comparison pipeline for selecting the appropriate gene therapy is essential for diseases, with several gene editing strategies available.

De Novo Deep Intron ELANE Mutation Resulting in Severe Congenital Neutropenia.

Severe congenital neutropenia (SCN) comprises a diverse range of rare hematological disorders characterized by recurrent, often life-threatening infections that manifest within the first months of life. Mutations in the ELANE gene are the most prevalent cause of SCN. While over 230 mutations in ELANE have been documented, including substitutions, frameshifts, nonsense mutations, and splice site alterations, the occurrence of deep intronic mutations has not been previously reported. Herein, we present the case of a young girl who exhibited recurrent fever, respiratory infections, skin abscesses, and gingivitis shortly after birth. Laboratory analysis revealed markedly diminished neutrophil levels alongside elevated monocyte and eosinophil counts. Bone marrow examination disclosed a halt in myelopoiesis maturation. ELANE gene full-length sequencing identified a novel de novo deep intron mutation in ELANE (c.598 + 79G > T), subsequently confirmed by Sanger sequencing. cDNA sequencing of the patient demonstrated aberrant gene splicing. Utilizing a mini-gene splicing assay for ELANE intronic variants, we identified a mutant ELANE allele (c.597 + 1_597 + 83ins) leading to the creation of a premature termination codon (p.Gly200ValfsTer40). Confocal microscopy revealed heightened expression of myeloperoxidase and neutrophil elastase in the patient, suggesting a potential role for the unfolded protein response in the pathogenesis of the deep intron ELANE mutation. In summary, our findings illustrate the first reported instance of de novo deep intron ELANE mutations associated with SCN, underscoring the importance of exploring deep intronic regions in SCN patients lacking identifiable disease-causing gene mutations.

Abstract 15: Invasive Aspergillus Niger Infection Cured after V Hematopoietic Stem Cell Transplantation in a Pediatric Patient with Severe Congenital Neutropenia

Abstract 15: Invasive Aspergillus Niger Infection Cured after V Hematopoietic Stem Cell Transplantation in a Pediatric Patient with Severe Congenital Neutropenia

Forty years of human G-CSF: A short history in time.

Human G-CSF was identified in 1984 at Memorial Sloan-Kettering Cancer Centre, New York. Based on these findings, recombinant G-CSF was developed by Amgen, Thousand Oaks. In 1987, clinical trials began using recombinant G-CSF in cancer patients following chemotherapy to reduce the duration of neutropenia and in patients with congenital neutropenia (CN) to increase the number of neutrophils. It has changed the quality of life for many cancer patients and saved the lives of many patients with (CN).

Protein Network Alterations in G-CSF Treated Severe Congenital Neutropenia Patients and Beneficial Effects of Oral Health Intervention.

Severe congenital neutropenia (SCN) is a raredisorder characterized by diminished neutrophil levels. Despite granulocytecolony-stimulating factor (G-CSF) treatment, SCN patients remain still prone tosevere infections, including periodontal disease-a significant oral healthrisk. This study investigates the host proteome and metaproteome in saliva andgingival crevicular fluid (GCF) of G-CSF-treated patients. We used label-free quantitative proteomics on saliva and GCF samples from SCN patients before (n=10, mean age: 10.7±6.6 years) and after a 6-month oral hygiene intervention (n=9,mean age: 11.6±5.27 years), and from 12 healthy controls. We quantified 894 proteins in saliva (648 human,246 bacterial) and 756 proteins in GCF (493 human, 263 bacterial). Predominant bacterial genera included Streptococcus, Veillonella, Selenomonas, Corynebacterium, Porphyromonas, and Prevotella. SCN patients showed reduced antimicrobial peptides (AMPs) and elevated complement proteins compared tohealthy controls. Oral hygiene intervention improved oral epithelial conditionsand reduced both AMPs and complement proteins. SCN patients have aunique proteomic profile with reduced AMPs and increased complement proteins, contributing to infection susceptibility. Oral hygiene intervention not onlyimproved oral health in SCN patients but also offers potential overall therapeuticbenefits.

Expanding the genetic landscape of congenital neutropenia: CXCR2 mutations in three families revealed through whole exome sequencing.

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Oral health management in children with severe congenital neutropenia with periodontitis: Case report.

Severe congenital neutropenia (SCN) is a rare and heterogeneous genetic disease. By describing the diagnosis and treatment of a child with SCN and periodontitis, this case provides a reference for the oral health management of a child with SCN and periodontitis. We describe a boy with clinical manifestations of oral bleeding, neutropenia, recurrent fever, and other recurrent infections. The absolute neutrophil count (ANC) was <0.50 × 109/L most of the time. Morphological examination of bone marrow cells showed active granulocyte hyperplasia and dysmaturation. According to the clinical manifestations, hematological examination and gene detection results, the child was diagnosed as SCN with chronic periodontitis. Periodontal treatment was performed after informed consent was obtained from the child guardian. These included supragingival and subgingival cleaning, hydrogen peroxide and saline irrigation, placement of iodoglycerin in the gingival sulcus, and oral hygiene instruction. Hematopoietic stem cell transplantation (HSCT) was performed later. One month after initial periodontal treatment, oral hygiene was well maintained and gingival swelling had subsided. Probing depth (PD) index on periodontal probing and bleeding was significantly reduced. However, there was no significant change in blood routine and other indicators before and after periodontal treatment. Once SCN is diagnosed, individualized treatment plans can be developed according to the characteristics of the disease and its impact on oral health, which can effectively control the interaction between SCN and periodontal disease and reduce the occurrence of serious infection.

Molecular and clinical characterization of a founder mutation causing G6PC3 deficiency.

G6PC3 deficiency is a monogenic immunometabolic disorder that causes syndromic congenital neutropenia. Patients display heterogeneous extra-hematological manifestations, contributing to delayed diagnosis. Here, we investigated the origin and functional consequence of the G6PC3 c.210delC variant found in patients of Mexican origin. Based on the shared haplotypes amongst carriers of the c.210delC mutation, we estimated that this variant originated from a founder effect in a common ancestor. Furthermore, by ancestry analysis, we concluded that it originated in the indigenous Mexican population. At the protein level, we showed that this frameshift mutation leads to an aberrant protein expression in overexpression and patient-derived cells. G6PC3 pathology is driven by the intracellular accumulation of the metabolite 1,5-anhydroglucitol-6-phosphate (1,5-AG6P) that inhibits glycolysis. We characterized how the variant c.210delC impacts glycolysis by performing extracellular flux assays on patient-derived cells. When treated with 1,5-anhydroglucitol (1,5-AG), the precursor to 1,5-AG6P, patient-derived cells exhibited markedly reduced engagement of glycolysis. Finally, we compared the clinical presentation of patients with the mutation c.210delC and all other G6PC3 deficient patients reported in the literature to date, and we found that c.210delC carriers display all prominent clinical features observed in prior G6PC3 deficient patients. In conclusion, G6PC3 c.210delC is a loss-of-function mutation that arose from a founder effect in the indigenous Mexican population. These findings may facilitate the diagnosis of additional patients in this geographical area. Moreover, the in vitro 1,5-AG-dependent functional assay used in our study could be employed to assess the pathogenicity of additional G6PC3 variants.

Clinical Profile of Adults with Inherited Bone Marrow Failure Syndromes: Results of an Ambispective Clinical Single-Center Study

BACKGROUND. Inherited bone marrow failure syndromes (IBMFS) is a heterogenous group of rare genetically determined diseases with variable hematologic and nonhematologic manifestations. The implementation of highly specific methods of genetic diagnosis advanced the understanding of IBMFS and allowed its application also beyond pediatrics. That presupposes an awareness of clinical features and reference points for recognizing IBMFS in adults. AIM. To describe the clinical profile of adult IBMFS patients. MATERIALS &amp; METHODS. This ambispective single-center study enrolled 35 patients (10 women and 25 men) with IBMFS. Patients were aged 18–51 years (median 26 years). The following IBMFS were identified: congenital dyskeratosis (n = 10; 28 %), Diamond-Blackfan anemia (n = 9; 26 %), Fanconi anemia (n = 7; 20 %), GATA2 deficiency (n = 3; 8 %), Shwachman-Diamond syndrome (n = 1; 3 %), GATA2 deficiency (n = 1; 3 %), amegakaryocytic thrombocytopenia (n = 1; 3 %), bone marrow failure syndrome type 3 (n = 1; 3 %), severe congenital neutropenia (n = 1; 3 %), bone marrow failure with SAMD9 mutation (n = 1; 3 %). These diseases were analyzed in terms of hematologic and nonhematologic manifestations as well as main diagnosis stages and factors that contribute to recognizing IBMFS. RESULTS. Monolinear cytopenia, bilinear cytopenia, and pancytopenia were identified at hematologic onset in 18 (52 %), 6 (17 %), and 11 (31 %) patients, respectively. The median age of patients by hematologic onset was 15 years (range 0–43 years), in 14 (40 %) patients cytopenia was newly diagnosed at the age of &gt; 18 years. In 23 (63 %) patients hypocellular bone marrow was reported, 7 (20 %) and 5 (14 %) patients had pure red cell aplasia and multilineage myelodysplasia, respectively. Chromosomal aberrations were identified in 2 patients. Paroxysmal nocturnal hemoglobinuria clone was detected in none of 27 examined patients. In 12 (34 %) patients, the criteria for non-severe aplastic anemia were met. Temporary partial or complete spontaneous hematologic recovery was observed in 6 (17 %) patients. Abnormalities with partial or complete organ dysfunctions were identified in 14 patients, whereas all patients showed minor congenital defects. All 7 Fanconi anemia patients and 9 out of 10 congenital dyskeratosis patients demonstrated organ damage specific to these diseases. Family history predominantly showing malignant neoplasms in relatives was reported in 15 (43 %) patients. Initial hematological examination yielded suspect of IBMFS in 12 (34 %) patients with the median time to diagnosis of 6 months. In 23 (66 %) patients, hematologic defects with cytopenia were erroneously accounted for by various acquired diseases, which led to a delayed correct diagnosis (median 7 years). The key factors in suspecting IBMFS were organ abnormalities and positive family history. The IBMFS diagnosis was verified by the next-generation sequencing (NGS) in 29 (83 %) patients and by other specific methods in 4 (11 %) patients. In 2 patients, the diagnosis was established on the basis of complete clinical criteria alone. CONCLUSION. IBMFS is a matter of current concern and a difficult-to-recognize clinical challenge in adult hematology patients. Differential diagnosis of acquired and congenital bone marrow failure needs to be performed irrespective of patient’s age. A detailed physical examination of patients, family history, and critical analysis of clinical profile and disease course allow for early suspicion of IBMFS. Suspected IBMFS is an indication for referral of patients to specialized centers and performing genetic diagnostics including NGS.

Absence of Neutropenia in Patients With Early Exon Nonsense Mutations in ELANE : Clinical Evidence to Support Gene Therapy Approaches for Severe Congenital Neutropenia.

Severe congenital neutropenia is an inherited bone marrow failure disorder characterized by profoundly low neutrophil counts and promyelocytic maturation arrest in bone marrow. Severe congenital neutropenia is most often caused by heterozygous ELANE mutations. In vitro and mouse xenograft studies using CRISPR/Cas9 have shown that introduction of frameshift/nonsense mutations in mutant ELANE may restore neutrophil counts, providing a model for gene therapy. Here, we present 2 children with inherited nonsense mutations in ELANE analogous to those proposed for gene therapy. Their normal peripheral blood neutrophil counts provide support for this approach through human "experiments of nature."

ДИФФЕРЕНЦИАЛЬНАЯ ДИАГНОСТИКА ПРИОБРЕТЕННОЙ АПЛАСТИЧЕСКОЙ АНЕМИИ У ДЕТЕЙ: АНАЛИЗ ДАННЫХ РЕГИСТРОВОГО ИССЛЕДОВАНИЯ

Acquired aplastic anemia (AA) is still the diagnosis of exclusion. The purpose of the research was to identify clinical and laboratory signs that do not correspond to acquired AA allowing to diagnose other diseases accompanied by cytopenia. Materials and methods used: Authors represent the results of diagnostic search in pediatric patients (0 to 18 y/o) with a suspected diagnosis of acquired AA who underwent remote diagnosis in the laboratories of the National Scientific and Practical Center for Pediatric Hematology, Oncology and Immunology named after Dmitry Rogachev (Moscow, Russia) as part of the Register Study in Sep. 1, 2017-May 1, 2022. Results: in retrospective analysis of 523 children records, 104 (20%) patients had other diagnoses. In 29 (27.9%) patients were diagnosed with inherited bone marrow failure syndromes (IBMFS), in 11 (10.6%) with myelodysplastic syndrome, in 11 (10.6%) with deficiency anemia, in 10 (9.6%) with congenital unspecified AA, in 7 (6.7%) with immune cytopenia, in 7 (6.7%) with inborn defects of immunity, in 6 (5.8%) with secondary AA, in 6 (5.8%) with acute leukemia, in 2 (1.9%) with paroxysmal nocturnal hemoglobinuria and in 15 (14.4%) cases with other unspecified diseases. Fanconi anemia (n=15/29 patients) was the most common disease in the IBMFS group; this group had also included: dyskeratosis congenita (n=9), Schwachman-Diamond syndrome (n=2), amegakaryocytic thrombocytopenia (n=2), Diamond-Blackfan anemia in combination with congenital neutropenia (n=1). Conclusion: differential diagnosis of acquired AA can be difficult though it is undoubtedly must-do for successful treatment. Verification of other alternative diseases, including genetically determined syndromes, contributes to the choice of optimal patient management tactics.

Clinical relevance of SCN and CyN induced by ELANE mutations: a systematic review.

According to the PRISMA criteria, a systematic review has been conducted to investigate the clinical relevance between patients with severe congenital neutropenia (SCN) and cyclic congenital neutropenia (CyN) induced by ELANE mutations. We have searched PubMed, EMBASE, Web of Science, Scopus, Cochrane, CNKI, Wanfang Medicine, and VIP for ELANE mutation related literature published from 1997 to 2022. Using Microsoft Excel collect and organize data, SPSS 25, GraphPad Prism 8.0.1, and Omap analyze and plot statistical. Compare the gender, age, geography, mutation sites, infection characteristics, treatment, and other factors of SCN and CyN patients induced by ELANE mutations, with a focus on exploring the relationship between genotype and clinical characteristics, genotype and prognosis. This study has included a total of 467 patients with SCN and 90 patients with CyN. The onset age of SCN and CyN are both less than 1 year old, and the onset and diagnosis age of SCN are both younger than CyN. The mutation of ELANE gene is mainly missense mutation, and hot spot mutations include S126L, P139L, G214R, c.597+1G>A. The high-frequency mutations with severe outcomes are A57V, L121H, L121P, c.597+1G>A, c.597+1G>T, S126L, C151Y, C151S, G214R, C223X. Respiratory tract, skin and mucosa are the most common infection sites, Staphylococcus aureus, Pseudomonas aeruginosa and Escherichia coli are the most common. Patients with refractory G-CSF are more likely to develop severe outcomes. The commonly used pre-treatment schemes for transplantation are Bu-Cy-ATG and Flu-Bu-ATG. The prognosis of transplantation is mostly good, but the risk of GVHD is high. https://www.crd.york.ac.uk/PROSPERO/. PROSPERO, identifier CRD42023434656.

A JAGN1-associated severe congenital neutropenia zebrafish model revealed an altered G-CSFR signaling and UPR activation

AbstractA variety of autosomal recessive mutations in the JAGN1 gene cause severe congenital neutropenia (CN). However, the underlying pathomechanism remains poorly understood, mainly because of the limited availability of primary hematopoietic stem cells from JAGN1-CN patients and the absence of animal models. In this study, we aimed to address these limitations by establishing a zebrafish model of JAGN1-CN. We found 2 paralogs of the human JAGN1 gene, namely jagn1a and jagn1b, which play distinct roles during zebrafish hematopoiesis. Using various approaches such as morpholino-based knockdown, CRISPR/Cas9–based gene editing, and misexpression of a jagn1b harboring a specific human mutation, we successfully developed neutropenia while leaving other hematopoietic lineages unaffected. Further analysis of our model revealed significant upregulation of apoptosis and genes involved in the unfolded protein response (UPR). However, neither UPR nor apoptosis is the primary mechanism that leads to neutropenia in zebrafish. Instead, Jagn1b has a critical role in granulocyte colony-stimulating factor receptor signaling and steady-state granulopoiesis, shedding light on the pathogenesis of neutropenia associated with JAGN1 mutations. The establishment of a zebrafish model for JAGN1-CN represents a significant advancement in understanding the specific pathologic pathways underlying the disease. This model provides a valuable in vivo tool for further investigation and exploration of potential therapeutic strategies.

Agranulocytosis: from diagnosis to selecting treatment tactics

Neutropenia is a condition accompanied by a decrease in an absolute neutrophil count (of band and segmented neutrophils) in the peripheral blood to less than 1.0 × 109/l in children under 1 year of age and less than 1.5 × 109/l in children over one year of age and adults. Among neutropenia types, congenital (genetically determined), acquired, and chronic benign neutropenia of childhood are distinguished. Agranulocytosis is a decrease in the level of neutrophils in peripheral blood to less than 0.5 × 109/l.

Genetic backgrounds and clinical characteristics of congenital neutropenias in Israel.

Congenital neutropenias are characterized by severe infections and a high risk of myeloid transformation; the causative genes vary across ethnicities. The Israeli population is characterized by an ethnically diverse population with a high rate of consanguinity. To evaluate the clinical and genetic spectrum of congenital neutropenias in Israel. We included individuals with congenital neutropenias listed in the Israeli Inherited Bone Marrow Failure Registry. Sanger sequencing was performed for ELANE or G6PC3, and patients with wild-type ELANE/G6PC3 were referred for next-generation sequencing. Sixty-five patients with neutropenia were included. Of 51 patients with severe congenital neutropenia, 34 were genetically diagnosed, most commonly with variants in ELANE (15 patients). Nine patients had biallelic variants in G6PC3, all of consanguineous Muslim Arab origin. Other genes involved were SRP54, JAGN1, TAZ, and SLC37A4. Seven patients had cyclic neutropenia, all with pathogenic variants in ELANE, and seven had Shwachman-Diamond syndrome caused by biallelic SBDS variants. Eight patients (12%) developed myeloid transformation, including six patients with an unknown underlying genetic cause. Nineteen (29%) patients underwent hematopoietic stem cell transplantation, mostly due to insufficient response to treatment with granulocyte-colony stimulating factor or due to myeloid transformation. The genetic spectrum of congenital neutropenias in Israel is characterized by a high prevalence of G6PC3 variants and an absence of HAX1 mutations. Similar to other registries, for 26% of the patients, a molecular diagnosis was not achieved. However, myeloid transformation was common in this group, emphasizing the need for close follow-up.