Uncovering the Genetic Landscape of Pediatric Neutropenia: Insights from a Case Series

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Ferguson, Lori Tsang, Mahmut Y Celiker This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7762296/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Neutropenia in children presents with diverse etiologies, including genetic causes that remain incompletely understood. This study investigates the prevalence and clinical relevance of genetic variants in pediatric neutropenia. Methods Genetic testing was performed on 29 children diagnosed with neutropenia using commercial clinical sequencing panels. Variants were assessed for pathogenicity using ACMG guidelines and population frequency data. Results Genetic alterations were identified in 19 patients (66%), with most variants classified as variants of uncertain significance (VUS). Despite inconclusive pathogenicity, the majority of these variants had population frequencies below 0.1%, suggesting a plausible association with neutropenia. Recurrent mutations were observed in VPS13B, MECOM, LYST, RECQL4, and G6PD, with VPS13B being the most frequently affected gene. Conclusion The findings highlight the genetic heterogeneity of childhood neutropenia and the potential clinical utility of early genetic screening. Identification of high-risk mutations, such as those in MECOM, may inform treatment decisions and long-term management. Further research is needed to validate the pathogenicity of rare variants and improve diagnostic precision through expanded genomic databases and collaborative studies. Neutropenia inherited neutropenia pediatric genetic Background Neutropenia is defined as an abnormally low level of neutrophils — absolute neutrophil count (ANC) below 1.5 x 10 3 /µL in peripheral blood. Neutropenia is a condition that can vary in severity, with serious cases carry increased risk of infection 1 or malignancy 2 . It can be acquired through autoimmune disorders such as autoimmune neutropenia 3 or transient suppression from certain infectious and inflammatory conditions 4, 5 , and more severe conditions like Chediak-Higashi syndrome 6 and myelodysplastic syndrome (MDS) 2 . Neutropenia can also be part of inherited bone marrow failure syndromes such as Fanconi’s anemia 7 and Schwachman-Diamond Syndrome 8 . Due to the increased risk of infection and malignancy seen in certain inherited neutropenia syndromes 1, 2 , the etiology of cases needs to be sooner and better determined. A small subset of childhood neutropenia has presumed genetic etiologies 9, 10 , and an early genetic diagnostic test may help identify these cases early. Here we report a variety of genetic alterations found on genetic screening of children with persistent neutropenia. Some of these variants were already known to be associated with neutropenia syndromes 9 ; others were previously unreported but located on genes associated with neutropenia syndromes or on genes with no prior association. We hope that this report will trigger enough interest in further studies to explore the roles of these mutations in neutropenia. Methods Study design and setting The primary aim of the study was to identify and report genetic variants that are found in cases of neutropenia. This is a retrospective review of molecular screening tests done in the evaluation of children with neutropenia in an urban outpatient pediatric hematology-oncology clinic. All patients with an ANC of 1.5 x 10 3 /µL or lower persisting ≥ 3 months were identified by a review of medical records between 2018 and 2025. Those with a known diagnosis of malignancy or known inherited bone marrow failure syndromes were excluded. Genetic testing Peripheral blood or buccal swab samples underwent next-generation sequencing (NGS) in CLIA approved clinical laboratories with test panels that include genes with known association with neutropenia (Invitae Bone Marrow Failure Syndrome Panel, Invitae Phagocytic Disorders Including Neutropenia Panel, include Invitae Primary Immunodeficiency Panel, Invitae Inherited Platelet Disorders Including Thrombocytopenia Panel, and Invitae Fanconi Anemia Panel (Invitae.com) or Mayo Medical Laboratories Congenital Neutropenia Primary Immunodeficiency Gene Panel ( www.mayocliniclabs.com ). Clinical data Clinical data were collected via retrospective chart review from the identified patients (n = 29), The data collected included demographic information (age at diagnosis of neutropenia, sex, ethnicity, family history), characteristics of neutropenia (mild, moderate, or severe; isolated or non-isolated), and any associated clinical findings. Results We reviewed clinical and laboratory data of 29 children who presented with persistent neutropenia and underwent genetic testing. Among them, 19 had a positive genetic testing yield, the details of which are reported here. We also compared clinical characteristics between those with genetic alterations (n = 19) and those without (n = 10) (Table 1 ). Table 1 * Difference in demographics between patients with and without positive genetic yield. Demographics Positive genetic testing (n = 19) Negative genetic testing (n = 10) Sex Female Male 10 (53%) 9 (47%) 3 (30%) 7 (70%) Ethnicity African American East Asian Hispanic Middle Eastern South Asian Eastern European Unknown/Other 1 (5%) 8 (42%) 4 (21%) 4 (21%) 1 (5%) 0 (0%) 1 (5%) Δ 1 (10%) 1 (10%) 2 (20%) 2 (20%) 0 (0%) 2 (20%) 2 (20%) ¥ Age at onset 0–1 y 1–3 y 3–10 y 10–18 y 2 (11%) 9 (47%) 4 (21%) 4 (21%) 1 (10%) 3 (30%) 3 (30%) 3 (30%) Family History Neutropenia Other cytopenia Non-significant 2 (11%) 1 (5%) 16 (84%) 0 (0%) 2 (20%) 8 (80%) Δ Unknown ethnicity. ¥ One patient with Eastern European plus Hispanic ancestry; another patient with East Asian plus African American ancestry. Among those with positive genetic testing results, most were of East Asian descent and had relatively early onset of neutropenia. Even when adjusting the ANC to 1x10 3 /µL for East Asian population due to constitutional neutropenia, and adjusting for the population distribution presented to the clinic, East Asian predominance persists. In contrast, those with negative genetic testing results showed no predominant ethnic distribution and had no specific age distribution pattern, though Eastern European descent was only seen in this group. Notably, the majority of patients in both groups reported non-significant family history (Table 1 ). All of these patients initially had incidental findings of neutropenia, mostly during a routine visit with their primary care physician. This suggests that likely no overt symptoms concerning neutropenia were present before a screening complete blood count (CBC). Other cytopenia in addition to neutropenia was observed in 16% of patients (n = 3) with positive genetic testing and 30% (n = 3) of patients with negative genetic testing. The severity of neutropenia was recorded at onset and study conclusion. ANC values from prior external medical records were also included in the analysis. At initial evaluation, which included review of prior available medical records if available, at diagnosis of neutropenia, the neutropenia severity was: mild in 21% of patients (n = 4), moderate in 37% (n = 7), severe in 42% (n = 8). Multiple CBC results over a span of time were recorded for our patients. The last CBC in the chart from these patients prior to concluding this study showed 37% of patients (n = 7) with resolved neutropenia, normal ANC, 5% of patients (n = 1) with mild neutropenia, 47% (n = 9) moderate, and 11% (n = 2) severe (Table 2 ). ANC values from prior external medical records were also included in the analysis. Table 2 Clinical profile of the 19 patients with positive genetic testing yield. Patient Onset age Hematologic Findings Neutropenia Outcome Associated Findings Notes Genetic Alterations Pt 1 1y isolated neutropenia → • history of multiple hospitalizations for pneumonia • latent tuberculosis VPS13B c.1559A > G (p.His520Arg) Pt 2 1y isolated neutropenia ↑, normalized none GFI1 c.1012C > T (p.Arg338Trp) Pt 3 8y isolated neutropenia ↓ none • Pt 3 and Pt 4 are brothers • positive family history: father with low WBC reportedly VPS13B c.5009G > A (p.Trp1670*) Δ VPS13B c.3563C > T (p.Thr1188Met) STAT3 c.576C > G (p.Asn192Lys) Pt 4 7y isolated neutropenia ↑ none • Pt 3 and Pt 4 are brothers • positive family history: father with low WBC reportedly STAT3 c.576C > G (p.Asn192Lys) Pt 5 1y isolated neutropenia ↑, normalized eczema USB1 c.646G > A (p. Gly216Ser) Pt 6 12y isolated neutropenia ↓ • history of absence seizure • autism spectrum disorder • eczema • recurrent oral ulcers patient had a negative chromosome DEB assay BRCA2 c.2959_2961del (p.Asn987del) FANCL c.197A > G (p.Tyr66Cys) MECOM c.2542C > G (p.Arg848Gly) RECQL4 c.3079C > T (p.Leu1027Phe) Pt 7 1y isolated neutropenia ↑ none G6PD c.202G > A (p.Val68Met) ¥ G6PD c.376A > G (p.Asn126Asp) CSF3R c.2434G > A (p.Val812Ile) Pt 8 1y isolated neutropenia ↑ • eczema • history of possible bacterial tracheitis MECOM c.2098G > A (p.Glu700Lys) Pt 9 2y isolated neutropenia ↓ history of forehead skin abscess RECQL4 c.2410C > T (p.Arg804Trp) VPS13B c.5773A > T (p.Thr1925Ser) Pt 10 18y isolated neutropenia ↑, normalized • none CDC42 c.415C > T (p.Pro139Ser) Pt 11 1y • neutropenia • iron deficiency anemia → none positive family history: mom has autoimmune hemolytic anemia, Sjogren’s syndrome, and rheumatoid arthritis LYST c.6154A > G (p.Ile2052Val) Pt 12 2y isolated neutropenia ↑ recurrent oral ulcers FANCI c.1741G > A (p.Glu581Lys) Pt 13 9y isolated neutropenia ↓ none MECOM c.1121A > G (p.Glu374Gly) Pt 14 8mth isolated neutropenia ↑, normalized • failure to thrive • short stature • eczema LYST c.11393A > G (p.Tyr3798Cys) AP3D1 c.2663_2668dup (p.Ala888_Pro889dup) Pt 15 10y isolated neutropenia → • global developmental delay • short stature • history of multiple hospitalizations for pneumonia patient was diagnosed with Cohen Syndrome VPS13B c.9405 + 2T > C (Splice donor) ¶ VPS13B c.8465A > G (p.Tyr2822Cys) ARPC1B c.713C > T (p.Ala238Val) DOCK8 Gain (Exons 21–48) PRKDC c.5571 + 5C > T (Intronic) SI c.1420T > C (p.Tyr474His) TICAM1 c.1238G > A (p.Arg413Gln) TYK2 c.727C > T (p.Arg243Trp) Pt 16 6y • neutropenia • congenital thrombocytopenia • megaloblastic anemia ↓ • global developmental delay • dysmorphic features, including cleft palate, wide-set eyes • patient was diagnosed with KAT6A-related neurodevelopmental disorder with multiple anomalies • BMB: did not support malignancy nor MDS RUNX1 c.965C > G (p.Ser322*) § FERMT3 c.1954C > T (p.Leu652Phe) TINF2 c.1292del (p.Pro431Leufs*31) Pt 17 1y isolated neutropenia ↑, normalized none FPR1 c.646A > G (p.Ile216Val) Pt 18 17y • neutropenia • persistent thrombocytopenia • normocytic anemia ↑, normalized • recurrent prolonged epistaxis BMB: did not support malignancy nor MDS TERT c.3323C > A (p.Pro1108Gln) WAS c.1189C > G (p.Pro397Ala) Pt 19 2mth isolated neutropenia ↑, normalized • G6PD deficiency • eczema G6PD c.202G > A (p.Val68Met) ¥ G6PD c.376A > G (p.Asn126Asp) WBC: white blood count; DEB: diepoxybutane; BMB: bone marrow biopsy; MDS: myelodysplastic syndrome. ↑: improved; →: unchanged; ↓: worsened. The genetic alterations without a footnote are all reported as variants of unknown significance (VUS). Δ Pathogenic but has not been previously reported in individuals affected with VPS13B-related conditions. ¥ Pathogenic. This variant has been previously reported in individuals affected with G6PD deficiency. ¶ Likely Pathogenic but has not been previously reported in individuals affected with VPS13B-related conditions. § Pathogenic. This variant has been reported in individuals with autosomal dominant familial platelet disorder with predisposition to myeloid malignancy. At study conclusion, of the 19 patients with positive genetic testing, the severity of neutropenia improved in 11 (58%), unchanged in 3 (16%), worsened for 5 (26%); whereas of the 10 patients with negative genetic testing, 6 (60%) improved, 4 (40%) unchanged, none worsened. Of note, ANC values at study conclusion were single endpoint measurements and may not reflect trends. Of the 19 patients with positive genetic testing results, 53% of patients (n = 10) had a history of one or more of the following symptoms: eczema, oral ulcers, seizure, serious bacterial infection, failure to thrive, short stature, global developmental delay, and dysmorphic features (Table 2 ). These symptoms are reported here, given that they have been documented in patients with neutropenia 11–16 . Considering that these symptoms are not rare as an isolated finding in the general pediatric population, there is a considerable possibility that these symptoms were present with no correlation to the neutropenia our patients had. The correlations between neutropenia and these symptoms remain unclear in our patients, they are still significant clinical findings that require careful assessment or further evaluation. The method utilized by the genetic testing laboratories included in this study adheres to ACMG recommendations 17 . Unless otherwise specified, pathogenicity classifications of the following variants in each gene are reported as per the respective laboratory interpretation. The genetic testing revealed that several patients had variants in the same genes that may be associated with neutropenia (Table 3) , including VPS13B (also referred to as COH1 ), MECOM , LYST , RECQL4 , and G6PD. VPS13B variants are associated with Cohen syndrome 16, 18 , in which neutropenia is common. In our study, 6 VPS13B variants were identified. MECOM mutations are related to Radioulnar synostosis with amegakaryocytic thrombocytopenia 2 19 , a BMFS. LYST mutations are linked to Chediak-Higashi syndrome, characterized by immunodeficiency with neutropenia, in severe cases, pancytopenia 6, 20, 21 . RECQL4 mutations can cause Baller-Gerold syndrome, RAPADILINO syndrome, and Rothmund-Thomson syndrome, type 2 (RTS2). While no direct link with neutropenia is reported, RAPADILINO syndrome and RTS2 predispose to cancer and potential bone marrow failure 22, 23 . No current evidence suggests a relation between G6PD with neutropenia. Discussion Our findings underscore the genetic heterogeneity and diagnostic challenges in pediatric neutropenia. Two thirds of children with neutropenia showed a genetic variation in genes that are thought to be relevant in neutropenia. For the majority of patients, the genetic testing was not conclusive, as most of the genetic alterations were classified as VUS; however, population frequencies of these mutations are well below 0.1% (excluding G6PD ) which supports a plausible relationship between the genetic findings and neutropenia. Among all the identified genetic mutations, VPS13B , MECOM , LYST , RECQL4, G6PD appeared in more than one case. Mutations in VPS13B was the most frequent finding, and in one case a homozygous missense variant in VPS13B (NM_017890.4:c.9405 + 2T > C, Splice donor) was identified as likely pathogenic although this particular variant has not been previously reported in Cohen syndrome. Identifying genetic causes of neutropenia helps with treatment selection and follow-up planning in patients with inherited or congenital neutropenia 24, 25 . For example, most patients with MECOM-associated syndrome experience progressive bone marrow failure and require allogeneic hematopoietic bone marrow transplant 26, 27 . Early detection of pathogenic MECOM mutation would warrant closer follow-up and theoretically improve the outcome of the patient. Also, genetic diagnostics may have an immediate clinical utility in neonatal testing to determine at-risk neonates, adding room for future research in prevention and management. Conclusion This study underscores the genetic complexity of childhood neutropenia, with two-thirds of patients exhibiting rare variants in genes implicated in phagocyte function and bone marrow failure. Although most variants were classified as of uncertain significance, their low population frequencies and recurrence across multiple cases suggest a potential pathogenic role. Our findings emphasize the need for expanded genomic databases, functional validation studies, and collaborative efforts between clinical and research institutions to better define the role of these variants in disease pathogenesis. Declarations Conflict Interest Statement: All authors declare no conflict of interest Data-sharing statement: Available upon request Funding: None This research was approved by the IRB of Maimonides Medical Center and consent was not required for publication. All available data will be anonymized and made available upon request Authors declare there are no competing interest associated with this research Author’s contributions: Chen Chen: Data analysis and interpretation, writing of manuscript Faith Ferguson: Collection, analysis, and interpretation of data Lori Tsang: Collection, analysis, and interpretation of data Mahmut Çeliker: Study design, supervision of data collection and analysis, interpretation References 1. Melvan JN, Bagby GJ, Welsh DA, Nelson S, Zhang P. Neonatal sepsis and neutrophil insufficiencies. Int Rev Immunol. 2010;29(3):315–348. 2. Rosenberg PS, Alter BP, Link DC, et al. Neutrophil elastase mutations and risk of leukaemia in severe congenital neutropenia. Br J Haematol. 2008;140(2):210–213. 3. Fioredda F, Dufour C, Hoglund P, Papadaki HA, Palmblad J. Autoimmune Neutropenias: Update on Clinical and Biological Features in Children and Adults. Hemasphere. 2023;7(1):e814. 4. Tschernin D, Fruchtman Y, Sergienko R, et al. 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Semin Hematol. 2013;50(3):198–206. 25. Connelly JA, Walkovich K. Diagnosis and therapeutic decision-making for the neutropenic patient. Hematology Am Soc Hematol Educ Program. 2021;2021(1):492–503. 26. Germeshausen M, Ancliff P, Estrada J, et al. MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia. Blood Adv. 2018;2(6):586–596. 27. Lozano Chinga MM, Bertuch AA, Afify Z, et al. Expanded phenotypic and hematologic abnormalities beyond bone marrow failure in MECOM-associated syndromes. Am J Med Genet A. 2023;191(7):1826–1835. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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18:07:17","extension":"html","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":60509,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7762296/v1/8eb398710d8e26a65ff98b13.html"},{"id":96912995,"identity":"10672869-4329-4dbe-b661-bd8fc28dfe19","added_by":"auto","created_at":"2025-11-27 13:48:23","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":702082,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7762296/v1/2f381fd2-caba-4efd-b470-d5dbc1b99798.pdf"}],"financialInterests":"","formattedTitle":"Uncovering the Genetic Landscape of Pediatric Neutropenia: Insights from a Case Series","fulltext":[{"header":"Background","content":"\u003cp\u003eNeutropenia is defined as an abnormally low level of neutrophils \u0026mdash; absolute neutrophil count (ANC) below 1.5 x 10\u003csup\u003e3\u003c/sup\u003e/\u0026micro;L in peripheral blood. Neutropenia is a condition that can vary in severity, with serious cases carry increased risk of infection\u003csup\u003e1\u003c/sup\u003e or malignancy\u003csup\u003e2\u003c/sup\u003e. It can be acquired through autoimmune disorders such as autoimmune neutropenia\u003csup\u003e3\u003c/sup\u003e or transient suppression from certain infectious and inflammatory conditions\u003csup\u003e4, 5\u003c/sup\u003e, and more severe conditions like Chediak-Higashi syndrome\u003csup\u003e6\u003c/sup\u003e and myelodysplastic syndrome (MDS)\u003csup\u003e2\u003c/sup\u003e. Neutropenia can also be part of inherited bone marrow failure syndromes such as Fanconi\u0026rsquo;s anemia\u003csup\u003e7\u003c/sup\u003e and Schwachman-Diamond Syndrome\u003csup\u003e8\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eDue to the increased risk of infection and malignancy seen in certain inherited neutropenia syndromes\u003csup\u003e1, 2\u003c/sup\u003e, the etiology of cases needs to be sooner and better determined. A small subset of childhood neutropenia has presumed genetic etiologies\u003csup\u003e9, 10\u003c/sup\u003e, and an early genetic diagnostic test may help identify these cases early.\u003c/p\u003e\u003cp\u003eHere we report a variety of genetic alterations found on genetic screening of children with persistent neutropenia. Some of these variants were already known to be associated with neutropenia syndromes\u003csup\u003e9\u003c/sup\u003e; others were previously unreported but located on genes associated with neutropenia syndromes or on genes with no prior association. We hope that this report will trigger enough interest in further studies to explore the roles of these mutations in neutropenia.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy design and setting\u003c/h2\u003e\u003cp\u003eThe primary aim of the study was to identify and report genetic variants that are found in cases of neutropenia. This is a retrospective review of molecular screening tests done in the evaluation of children with neutropenia in an urban outpatient pediatric hematology-oncology clinic. All patients with an ANC of 1.5 x 10\u003csup\u003e3\u003c/sup\u003e/\u0026micro;L or lower persisting\u0026thinsp;\u0026ge;\u0026thinsp;3 months were identified by a review of medical records between 2018 and 2025. Those with a known diagnosis of malignancy or known inherited bone marrow failure syndromes were excluded.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eGenetic testing\u003c/h3\u003e\n\u003cp\u003ePeripheral blood or buccal swab samples underwent next-generation sequencing (NGS) in CLIA approved clinical laboratories with test panels that include genes with known association with neutropenia (Invitae Bone Marrow Failure Syndrome Panel, Invitae Phagocytic Disorders Including Neutropenia Panel, include Invitae Primary Immunodeficiency Panel, Invitae Inherited Platelet Disorders Including Thrombocytopenia Panel, and Invitae Fanconi Anemia Panel (Invitae.com) or Mayo Medical Laboratories Congenital Neutropenia Primary Immunodeficiency Gene Panel (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e\u003ca href=\"http://www.mayocliniclabs.com\" target=\"_blank\"\u003ewww.mayocliniclabs.com\u003c/a\u003e\u003c/span\u003e\u003cspan address=\"http://www.mayocliniclabs.com\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e ).\u003c/p\u003e\n\u003ch3\u003eClinical data\u003c/h3\u003e\n\u003cp\u003e Clinical data were collected via retrospective chart review from the identified patients (n\u0026thinsp;=\u0026thinsp;29), The data collected included demographic information (age at diagnosis of neutropenia, sex, ethnicity, family history), characteristics of neutropenia (mild, moderate, or severe; isolated or non-isolated), and any associated clinical findings.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eWe reviewed clinical and laboratory data of 29 children who presented with persistent neutropenia and underwent genetic testing. Among them, 19 had a positive genetic testing yield, the details of which are reported here. We also compared clinical characteristics between those with genetic alterations (n\u0026thinsp;=\u0026thinsp;19) and those without (n\u0026thinsp;=\u0026thinsp;10) (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003ctable id=\"Tab1\" style=\"width: 821px;\" border=\"1\" class=\"fr-table-selection-hover\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003e\u003cstrong\u003e*\u003c/strong\u003eDifference in demographics between patients with and without positive genetic yield.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth style=\"width: 20.5356%;\" align=\"left\"\u003e\n \u003cp\u003eDemographics\u003c/p\u003e\n \u003c/th\u003e\n \u003cth style=\"width: 38.6605%;\" align=\"left\"\u003e\n \u003cp\u003ePositive genetic testing (n\u0026thinsp;=\u0026thinsp;19)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth style=\"width: 327px;\" align=\"left\"\u003e\n \u003cp\u003eNegative genetic testing (n\u0026thinsp;=\u0026thinsp;10)\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 20.5356%;\" align=\"left\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38.6605%;\" align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e10 (53%)\u003c/p\u003e\n \u003cp\u003e9 (47%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 327px;\" align=\"left\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003cp\u003e3 (30%)\u003c/p\u003e\n \u003cp\u003e7 (70%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 20.5356%;\" align=\"left\"\u003e\n \u003cp\u003eEthnicity\u003c/p\u003e\n \u003cp\u003eAfrican American\u003c/p\u003e\n \u003cp\u003eEast Asian\u003c/p\u003e\n \u003cp\u003eHispanic\u003c/p\u003e\n \u003cp\u003eMiddle Eastern\u003c/p\u003e\n \u003cp\u003eSouth Asian\u003c/p\u003e\n \u003cp\u003eEastern European\u003c/p\u003e\n \u003cp\u003eUnknown/Other\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38.6605%;\" align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1 (5%)\u003c/p\u003e\n \u003cp\u003e8 (42%)\u003c/p\u003e\n \u003cp\u003e4 (21%)\u003c/p\u003e\n \u003cp\u003e4 (21%)\u003c/p\u003e\n \u003cp\u003e1 (5%)\u003c/p\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003cp\u003e1 (5%)\u003csup\u003e\u0026Delta;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 327px;\" align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1 (10%)\u003c/p\u003e\n \u003cp\u003e1 (10%)\u003c/p\u003e\n \u003cp\u003e2 (20%)\u003c/p\u003e\n \u003cp\u003e2 (20%)\u003c/p\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003cp\u003e2 (20%)\u003c/p\u003e\n \u003cp\u003e2 (20%)\u003csup\u003e\u0026yen;\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 20.5356%;\" align=\"left\"\u003e\n \u003cp\u003eAge at onset\u003c/p\u003e\n \u003cp\u003e0\u0026ndash;1 y\u003c/p\u003e\n \u003cp\u003e1\u0026ndash;3 y\u003c/p\u003e\n \u003cp\u003e3\u0026ndash;10 y\u003c/p\u003e\n \u003cp\u003e10\u0026ndash;18 y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38.6605%;\" align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2 (11%)\u003c/p\u003e\n \u003cp\u003e9 (47%)\u003c/p\u003e\n \u003cp\u003e4 (21%)\u003c/p\u003e\n \u003cp\u003e4 (21%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 327px;\" align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1 (10%)\u003c/p\u003e\n \u003cp\u003e3 (30%)\u003c/p\u003e\n \u003cp\u003e3 (30%)\u003c/p\u003e\n \u003cp\u003e3 (30%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 20.5356%;\" align=\"left\"\u003e\n \u003cp\u003eFamily History\u003c/p\u003e\n \u003cp\u003eNeutropenia\u003c/p\u003e\n \u003cp\u003eOther cytopenia\u003c/p\u003e\n \u003cp\u003eNon-significant\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 38.6605%;\" align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2 (11%)\u003c/p\u003e\n \u003cp\u003e1 (5%)\u003c/p\u003e\n \u003cp\u003e16 (84%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 327px;\" align=\"left\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003cp\u003e2 (20%)\u003c/p\u003e\n \u003cp\u003e8 (80%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 802px;\" colspan=\"3\"\u003e\u0026Delta; Unknown ethnicity. \u0026yen; One patient with Eastern European plus Hispanic ancestry; another patient with East Asian plus African American ancestry.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eAmong those with positive genetic testing results, most were of East Asian descent and had relatively early onset of neutropenia. Even when adjusting the ANC to 1x10\u003csup\u003e3\u003c/sup\u003e/\u0026micro;L for East Asian population due to constitutional neutropenia, and adjusting for the population distribution presented to the clinic, East Asian predominance persists. In contrast, those with negative genetic testing results showed no predominant ethnic distribution and had no specific age distribution pattern, though Eastern European descent was only seen in this group. Notably, the majority of patients in both groups reported non-significant family history (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eAll of these patients initially had incidental findings of neutropenia, mostly during a routine visit with their primary care physician. This suggests that likely no overt symptoms concerning neutropenia were present before a screening complete blood count (CBC). Other cytopenia in addition to neutropenia was observed in 16% of patients (n\u0026thinsp;=\u0026thinsp;3) with positive genetic testing and 30% (n\u0026thinsp;=\u0026thinsp;3) of patients with negative genetic testing.\u003c/p\u003e\n\u003cp\u003eThe severity of neutropenia was recorded at onset and study conclusion. ANC values from prior external medical records were also included in the analysis. At initial evaluation, which included review of prior available medical records if available, at diagnosis of neutropenia, the neutropenia severity was: mild in 21% of patients (n\u0026thinsp;=\u0026thinsp;4), moderate in 37% (n\u0026thinsp;=\u0026thinsp;7), severe in 42% (n\u0026thinsp;=\u0026thinsp;8). Multiple CBC results over a span of time were recorded for our patients. The last CBC in the chart from these patients prior to concluding this study showed 37% of patients (n\u0026thinsp;=\u0026thinsp;7) with resolved neutropenia, normal ANC, 5% of patients (n\u0026thinsp;=\u0026thinsp;1) with mild neutropenia, 47% (n\u0026thinsp;=\u0026thinsp;9) moderate, and 11% (n\u0026thinsp;=\u0026thinsp;2) severe (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). ANC values from prior external medical records were also included in the analysis.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n \u003cdiv class=\"colspec\" align=\"left\"\u003e\u0026nbsp;\u003c/div\u003e\n \u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eClinical profile of the 19 patients with positive genetic testing yield.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePatient\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eOnset age\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eHematologic Findings\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNeutropenia Outcome\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAssociated Findings\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNotes\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGenetic Alterations\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePt 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eisolated neutropenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026rarr;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026bull; history of multiple hospitalizations for pneumonia\u003c/p\u003e\n \u003cp\u003e\u0026bull; latent tuberculosis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVPS13B c.1559A\u0026thinsp;\u0026gt;\u0026thinsp;G (p.His520Arg)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePt 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eisolated neutropenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026uarr;, normalized\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003enone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGFI1 c.1012C\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Arg338Trp)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePt 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eisolated neutropenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026darr;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003enone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026bull; Pt 3 and Pt 4 are brothers\u003c/p\u003e\n \u003cp\u003e\u0026bull; positive family history: father with low WBC reportedly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eVPS13B c.5009G\u0026thinsp;\u0026gt;\u0026thinsp;A (p.Trp1670*)\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e\u0026Delta;\u003c/strong\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003eVPS13B c.3563C\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Thr1188Met)\u003c/p\u003e\n \u003cp\u003eSTAT3 c.576C\u0026thinsp;\u0026gt;\u0026thinsp;G (p.Asn192Lys)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePt 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eisolated neutropenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026uarr;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003enone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026bull; Pt 3 and Pt 4 are brothers\u003c/p\u003e\n \u003cp\u003e\u0026bull; positive family history: father with low WBC reportedly\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSTAT3 c.576C\u0026thinsp;\u0026gt;\u0026thinsp;G (p.Asn192Lys)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePt 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eisolated neutropenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026uarr;, normalized\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eeczema\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eUSB1 c.646G\u0026thinsp;\u0026gt;\u0026thinsp;A (p. Gly216Ser)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePt 6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eisolated neutropenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026darr;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026bull; history of absence seizure\u003c/p\u003e\n \u003cp\u003e\u0026bull; autism spectrum disorder\u003c/p\u003e\n \u003cp\u003e\u0026bull; eczema\u003c/p\u003e\n \u003cp\u003e\u0026bull; recurrent oral ulcers\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epatient had a negative chromosome DEB assay\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBRCA2 c.2959_2961del (p.Asn987del)\u003c/p\u003e\n \u003cp\u003eFANCL c.197A\u0026thinsp;\u0026gt;\u0026thinsp;G (p.Tyr66Cys)\u003c/p\u003e\n \u003cp\u003eMECOM c.2542C\u0026thinsp;\u0026gt;\u0026thinsp;G (p.Arg848Gly)\u003c/p\u003e\n \u003cp\u003eRECQL4 c.3079C\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Leu1027Phe)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePt 7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eisolated neutropenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026uarr;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003enone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eG6PD c.202G\u0026thinsp;\u0026gt;\u0026thinsp;A (p.Val68Met)\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e\u0026yen;\u003c/strong\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003eG6PD c.376A\u0026thinsp;\u0026gt;\u0026thinsp;G (p.Asn126Asp)\u003c/p\u003e\n \u003cp\u003eCSF3R c.2434G\u0026thinsp;\u0026gt;\u0026thinsp;A (p.Val812Ile)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePt 8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eisolated neutropenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026uarr;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026bull; eczema\u003c/p\u003e\n \u003cp\u003e\u0026bull; history of possible bacterial tracheitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMECOM c.2098G\u0026thinsp;\u0026gt;\u0026thinsp;A (p.Glu700Lys)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePt 9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eisolated neutropenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026darr;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ehistory of forehead skin abscess\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eRECQL4 c.2410C\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Arg804Trp)\u003c/p\u003e\n \u003cp\u003eVPS13B c.5773A\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Thr1925Ser)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePt 10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eisolated neutropenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026uarr;, normalized\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026bull; none\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCDC42 c.415C\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Pro139Ser)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePt 11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026bull; neutropenia\u003c/p\u003e\n \u003cp\u003e\u0026bull; iron deficiency anemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026rarr;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003enone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epositive family history: mom has autoimmune hemolytic anemia, Sjogren\u0026rsquo;s syndrome, and rheumatoid arthritis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLYST c.6154A\u0026thinsp;\u0026gt;\u0026thinsp;G (p.Ile2052Val)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePt 12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eisolated neutropenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026uarr;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003erecurrent oral ulcers\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFANCI c.1741G\u0026thinsp;\u0026gt;\u0026thinsp;A (p.Glu581Lys)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePt 13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eisolated neutropenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026darr;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003enone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMECOM c.1121A\u0026thinsp;\u0026gt;\u0026thinsp;G (p.Glu374Gly)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePt 14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8mth\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eisolated neutropenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026uarr;, normalized\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026bull; failure to thrive\u003c/p\u003e\n \u003cp\u003e\u0026bull; short stature\u003c/p\u003e\n \u003cp\u003e\u0026bull; eczema\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eLYST c.11393A\u0026thinsp;\u0026gt;\u0026thinsp;G (p.Tyr3798Cys)\u003c/p\u003e\n \u003cp\u003eAP3D1 c.2663_2668dup (p.Ala888_Pro889dup)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePt 15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eisolated neutropenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026rarr;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026bull; global developmental delay\u003c/p\u003e\n \u003cp\u003e\u0026bull; short stature\u003c/p\u003e\n \u003cp\u003e\u0026bull; history of multiple hospitalizations for pneumonia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003epatient was diagnosed with Cohen Syndrome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eVPS13B c.9405\u0026thinsp;+\u0026thinsp;2T\u0026thinsp;\u0026gt;\u0026thinsp;C (Splice donor)\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e\u0026para;\u003c/strong\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003eVPS13B c.8465A\u0026thinsp;\u0026gt;\u0026thinsp;G (p.Tyr2822Cys)\u003c/p\u003e\n \u003cp\u003eARPC1B c.713C\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Ala238Val)\u003c/p\u003e\n \u003cp\u003eDOCK8 Gain (Exons 21\u0026ndash;48)\u003c/p\u003e\n \u003cp\u003ePRKDC c.5571\u0026thinsp;+\u0026thinsp;5C\u0026thinsp;\u0026gt;\u0026thinsp;T (Intronic)\u003c/p\u003e\n \u003cp\u003eSI c.1420T\u0026thinsp;\u0026gt;\u0026thinsp;C (p.Tyr474His)\u003c/p\u003e\n \u003cp\u003eTICAM1 c.1238G\u0026thinsp;\u0026gt;\u0026thinsp;A (p.Arg413Gln)\u003c/p\u003e\n \u003cp\u003eTYK2 c.727C\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Arg243Trp)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePt 16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026bull; neutropenia\u003c/p\u003e\n \u003cp\u003e\u0026bull; congenital thrombocytopenia\u003c/p\u003e\n \u003cp\u003e\u0026bull; megaloblastic anemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026darr;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026bull; global developmental delay\u003c/p\u003e\n \u003cp\u003e\u0026bull; dysmorphic features, including cleft palate, wide-set eyes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026bull; patient was diagnosed with KAT6A-related neurodevelopmental disorder with multiple anomalies\u003c/p\u003e\n \u003cp\u003e\u0026bull; BMB: did not support malignancy nor MDS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eRUNX1 c.965C\u0026thinsp;\u0026gt;\u0026thinsp;G (p.Ser322*)\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e\u0026sect;\u003c/strong\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003eFERMT3 c.1954C\u0026thinsp;\u0026gt;\u0026thinsp;T (p.Leu652Phe)\u003c/p\u003e\n \u003cp\u003eTINF2 c.1292del (p.Pro431Leufs*31)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePt 17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eisolated neutropenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026uarr;, normalized\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003enone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFPR1 c.646A\u0026thinsp;\u0026gt;\u0026thinsp;G (p.Ile216Val)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePt 18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17y\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026bull; neutropenia\u003c/p\u003e\n \u003cp\u003e\u0026bull; persistent thrombocytopenia\u003c/p\u003e\n \u003cp\u003e\u0026bull; normocytic anemia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026uarr;, normalized\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026bull; recurrent prolonged epistaxis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBMB: did not support malignancy nor MDS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTERT c.3323C\u0026thinsp;\u0026gt;\u0026thinsp;A (p.Pro1108Gln)\u003c/p\u003e\n \u003cp\u003eWAS c.1189C\u0026thinsp;\u0026gt;\u0026thinsp;G (p.Pro397Ala)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ePt 19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2mth\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eisolated neutropenia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026uarr;, normalized\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026bull; G6PD deficiency\u003c/p\u003e\n \u003cp\u003e\u0026bull; eczema\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eG6PD c.202G\u0026thinsp;\u0026gt;\u0026thinsp;A (p.Val68Met)\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e\u0026yen;\u003c/strong\u003e\u003c/sup\u003e\u003c/p\u003e\n \u003cp\u003eG6PD c.376A\u0026thinsp;\u0026gt;\u0026thinsp;G (p.Asn126Asp)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\"\u003eWBC: white blood count; DEB: diepoxybutane; BMB: bone marrow biopsy; MDS: myelodysplastic syndrome. \u0026uarr;: improved; \u0026rarr;: unchanged; \u0026darr;: worsened. The genetic alterations without a footnote are all reported as variants of unknown significance (VUS). \u0026Delta; Pathogenic but has not been previously reported in individuals affected with VPS13B-related conditions. \u0026yen; Pathogenic. This variant has been previously reported in individuals affected with G6PD deficiency. \u0026para; Likely Pathogenic but has not been previously reported in individuals affected with VPS13B-related conditions. \u0026sect; Pathogenic. This variant has been reported in individuals with autosomal dominant familial platelet disorder with predisposition to myeloid malignancy.\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eAt study conclusion, of the 19 patients with positive genetic testing, the severity of neutropenia improved in 11 (58%), unchanged in 3 (16%), worsened for 5 (26%); whereas of the 10 patients with negative genetic testing, 6 (60%) improved, 4 (40%) unchanged, none worsened. Of note, ANC values at study conclusion were single endpoint measurements and may not reflect trends.\u003c/p\u003e\n\u003cp\u003eOf the 19 patients with positive genetic testing results, 53% of patients (n\u0026thinsp;=\u0026thinsp;10) had a history of one or more of the following symptoms: eczema, oral ulcers, seizure, serious bacterial infection, failure to thrive, short stature, global developmental delay, and dysmorphic features (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). These symptoms are reported here, given that they have been documented in patients with neutropenia\u003csup\u003e11\u0026ndash;16\u003c/sup\u003e. Considering that these symptoms are not rare as an isolated finding in the general pediatric population, there is a considerable possibility that these symptoms were present with no correlation to the neutropenia our patients had. The correlations between neutropenia and these symptoms remain unclear in our patients, they are still significant clinical findings that require careful assessment or further evaluation.\u003c/p\u003e\n\u003cp\u003eThe method utilized by the genetic testing laboratories included in this study adheres to ACMG recommendations\u003csup\u003e17\u003c/sup\u003e. Unless otherwise specified, pathogenicity classifications of the following variants in each gene are reported as per the respective laboratory interpretation.\u003c/p\u003e\n\u003cp\u003eThe genetic testing revealed that several patients had variants in the same genes that may be associated with neutropenia \u003cstrong\u003e(Table\u0026nbsp;3)\u003c/strong\u003e, including \u003cem\u003eVPS13B\u003c/em\u003e (also referred to as \u003cem\u003eCOH1\u003c/em\u003e), \u003cem\u003eMECOM\u003c/em\u003e, \u003cem\u003eLYST\u003c/em\u003e, \u003cem\u003eRECQL4\u003c/em\u003e, and \u003cem\u003eG6PD. VPS13B\u003c/em\u003e variants are associated with Cohen syndrome\u003csup\u003e16, 18\u003c/sup\u003e, in which neutropenia is common. In our study, 6 \u003cem\u003eVPS13B\u003c/em\u003e variants were identified. \u003cem\u003eMECOM\u003c/em\u003e mutations are related to Radioulnar synostosis with amegakaryocytic thrombocytopenia 2\u003csup\u003e19\u003c/sup\u003e, a BMFS. \u003cem\u003eLYST\u003c/em\u003e mutations are linked to Chediak-Higashi syndrome, characterized by immunodeficiency with neutropenia, in severe cases, pancytopenia\u003csup\u003e6, 20, 21\u003c/sup\u003e. \u003cem\u003eRECQL4\u003c/em\u003e mutations can cause Baller-Gerold syndrome, RAPADILINO syndrome, and Rothmund-Thomson syndrome, type 2 (RTS2). While no direct link with neutropenia is reported, RAPADILINO syndrome and RTS2 predispose to cancer and potential bone marrow failure\u003csup\u003e22, 23\u003c/sup\u003e. No current evidence suggests a relation between \u003cem\u003eG6PD\u003c/em\u003e with neutropenia.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur findings underscore the genetic heterogeneity and diagnostic challenges in pediatric neutropenia. Two thirds of children with neutropenia showed a genetic variation in genes that are thought to be relevant in neutropenia. For the majority of patients, the genetic testing was not conclusive, as most of the genetic alterations were classified as VUS; however, population frequencies of these mutations are well below 0.1% (excluding \u003cem\u003eG6PD\u003c/em\u003e) which supports a plausible relationship between the genetic findings and neutropenia.\u003c/p\u003e\u003cp\u003eAmong all the identified genetic mutations, \u003cem\u003eVPS13B\u003c/em\u003e, \u003cem\u003eMECOM\u003c/em\u003e, \u003cem\u003eLYST\u003c/em\u003e, \u003cem\u003eRECQL4, G6PD\u003c/em\u003e appeared in more than one case. Mutations in \u003cem\u003eVPS13B\u003c/em\u003e was the most frequent finding, and in one case a homozygous missense variant in \u003cem\u003eVPS13B\u003c/em\u003e (NM_017890.4:c.9405\u0026thinsp;+\u0026thinsp;2T\u0026thinsp;\u0026gt;\u0026thinsp;C, Splice donor) was identified as likely pathogenic although this particular variant has not been previously reported in Cohen syndrome.\u003c/p\u003e\u003cp\u003eIdentifying genetic causes of neutropenia helps with treatment selection and follow-up planning in patients with inherited or congenital neutropenia\u003csup\u003e24, 25\u003c/sup\u003e. For example, most patients with MECOM-associated syndrome experience progressive bone marrow failure and require allogeneic hematopoietic bone marrow transplant\u003csup\u003e26, 27\u003c/sup\u003e. Early detection of pathogenic \u003cem\u003eMECOM\u003c/em\u003e mutation would warrant closer follow-up and theoretically improve the outcome of the patient. Also, genetic diagnostics may have an immediate clinical utility in neonatal testing to determine at-risk neonates, adding room for future research in prevention and management.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study underscores the genetic complexity of childhood neutropenia, with two-thirds of patients exhibiting rare variants in genes implicated in phagocyte function and bone marrow failure. Although most variants were classified as of uncertain significance, their low population frequencies and recurrence across multiple cases suggest a potential pathogenic role. Our findings emphasize the need for expanded genomic databases, functional validation studies, and collaborative efforts between clinical and research institutions to better define the role of these variants in disease pathogenesis.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflict Interest Statement:\u0026nbsp;\u003c/strong\u003eAll authors declare no conflict of interest\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData-sharing statement:\u0026nbsp;\u003c/strong\u003eAvailable upon request\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eNone\u003c/p\u003e\n\u003cp\u003eThis research was approved by the IRB of Maimonides Medical Center and consent was not required for publication.\u003c/p\u003e\n\u003cp\u003eAll available data will be anonymized and made available upon request\u003c/p\u003e\n\u003cp\u003eAuthors declare there are no competing interest associated with this research\u003c/p\u003e\n\u003cp\u003eAuthor’s contributions:\u003c/p\u003e\n\u003cp\u003eChen Chen: Data analysis and interpretation, writing of manuscript\u003c/p\u003e\n\u003cp\u003eFaith Ferguson: Collection, analysis, and interpretation of data\u003c/p\u003e\n\u003cp\u003eLori Tsang: Collection, analysis, and interpretation of data\u003c/p\u003e\n\u003cp\u003eMahmut Çeliker: Study design, supervision of data collection and analysis, interpretation\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003e1. 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Am J Hum Genet. 2015;97(6):848\u0026ndash;854.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003e20. Certain S, Barrat F, Pastural E, et al. Protein truncation test of LYST reveals heterogenous mutations in patients with Chediak-Higashi syndrome. Blood. 2000;95(3):979\u0026ndash;983.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003e21. Nagai K, Ochi F, Terui K, et al. Clinical characteristics and outcomes of chediak-Higashi syndrome: a nationwide survey of Japan. Pediatr Blood Cancer. 2013;60(10):1582\u0026ndash;1586.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003e22. Van Maldergem L, Siitonen HA, Jalkh N, et al. Revisiting the craniosynostosis-radial ray hypoplasia association: Baller-Gerold syndrome caused by mutations in the RECQL4 gene. J Med Genet. 2006;43(2):148\u0026ndash;152.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003e23. Siitonen HA, Sotkasiira J, Biervliet M, et al. The mutation spectrum in RECQL4 diseases. Eur J Hum Genet. 2009;17(2):151\u0026ndash;158.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003e24. Newburger PE, Dale DC. Evaluation and management of patients with isolated neutropenia. Semin Hematol. 2013;50(3):198\u0026ndash;206.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003e25. Connelly JA, Walkovich K. Diagnosis and therapeutic decision-making for the neutropenic patient. Hematology Am Soc Hematol Educ Program. 2021;2021(1):492\u0026ndash;503.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003e26. Germeshausen M, Ancliff P, Estrada J, et al. MECOM-associated syndrome: a heterogeneous inherited bone marrow failure syndrome with amegakaryocytic thrombocytopenia. Blood Adv. 2018;2(6):586\u0026ndash;596.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003e27. Lozano Chinga MM, Bertuch AA, Afify Z, et al. Expanded phenotypic and hematologic abnormalities beyond bone marrow failure in MECOM-associated syndromes. Am J Med Genet A. 2023;191(7):1826\u0026ndash;1835.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Neutropenia, inherited neutropenia, pediatric, genetic","lastPublishedDoi":"10.21203/rs.3.rs-7762296/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7762296/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNeutropenia in children presents with diverse etiologies, including genetic causes that remain incompletely understood. This study investigates the prevalence and clinical relevance of genetic variants in pediatric neutropenia.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGenetic testing was performed on 29 children diagnosed with neutropenia using commercial clinical sequencing panels. Variants were assessed for pathogenicity using ACMG guidelines and population frequency data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGenetic alterations were identified in 19 patients (66%), with most variants classified as variants of uncertain significance (VUS). Despite inconclusive pathogenicity, the majority of these variants had population frequencies below 0.1%, suggesting a plausible association with neutropenia. Recurrent mutations were observed in VPS13B, MECOM, LYST, RECQL4, and G6PD, with VPS13B being the most frequently affected gene.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe findings highlight the genetic heterogeneity of childhood neutropenia and the potential clinical utility of early genetic screening. Identification of high-risk mutations, such as those in MECOM, may inform treatment decisions and long-term management. Further research is needed to validate the pathogenicity of rare variants and improve diagnostic precision through expanded genomic databases and collaborative studies.\u003c/p\u003e","manuscriptTitle":"Uncovering the Genetic Landscape of Pediatric Neutropenia: Insights from a Case Series","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-28 12:08:27","doi":"10.21203/rs.3.rs-7762296/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9aa2e9f0-80c2-40e6-8547-c5d230e9ab6f","owner":[],"postedDate":"October 28th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-11-24T07:41:12+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-28 12:08:27","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7762296","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7762296","identity":"rs-7762296","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}