A Novel ATM Gene Variant (c.4940T>G; p.Leu1647Arg) in a Child with Ataxia–Telangiectasia: Clinical, Radiologic, and Genetic Correlation

A Novel ATM Gene Variant (c.4940T>G; p.Leu1647Arg) in a Child with Ataxia–Telangiectasia: Clinical, Radiologic, and Genetic Correlation | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report A Novel ATM Gene Variant (c.4940T>G; p.Leu1647Arg) in a Child with Ataxia–Telangiectasia: Clinical, Radiologic, and Genetic Correlation Zyad Al Frejat, Grace Hanna, Doaa Abo Hamza, Ghuroub Al Khayer This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8368178/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 Ataxia–telangiectasia (A-T) is a rare autosomal recessive disorder caused by mutations in the ATM gene, characterized by progressive cerebellar ataxia, telangiectasias, immunodeficiency, and increased cancer risk. Reporting novel ATM variants is essential to refine genotype–phenotype correlations. We report a 6-year-old boy presenting with progressive gait ataxia, recurrent respiratory infections, chronic otorrhea, and conjunctival telangiectasias. Laboratory studies revealed immunodeficiency with reduced IgG and IgA, and elevated IgM. Brain MRI showed mild cerebellar atrophy, while chest X-ray revealed bilateral interstitial infiltrates. Whole-exome sequencing identified a novel homozygous missense variant in ATM (c.4940T>G; p.Leu1647Arg), classified as a variant of uncertain significance but predicted deleterious by in silico tools. The patient improved with intravenous antibiotics and IVIG. Family genetic testing was recommended given parental consanguinity and an affected sibling. This case illustrates the classical phenotype of A-T with immunodeficiency and neurological dysfunction, combined with a novel ATM variant not previously reported in population databases. Such cases expand the known mutational spectrum and may guide diagnosis and counseling. Although the variant’s pathogenicity remains to be functionally validated, its clinical correlation supports disease relevance. Identification of novel ATM variants is crucial for advancing diagnostic precision, genetic counseling, and future therapeutic strategies in A-T. Medical Genetics Neurology Ataxia Telangiectasia Case Reports Genetics Mutation Figures Figure 1 Highlights • Ataxia–telangiectasia is a rare multisystem disorder caused by ATM mutations. • We report a 6-year-old boy with classical features of A-T and a novel homozygous ATM missense variant. • Genetic finding: c.4940T>G; p.Leu1647Arg, not previously reported in databases or literature. • This report adds to the mutational spectrum and informs genetic counseling. Introduction Ataxia-telangiectasia (A-T) is a rare, autosomal recessive multisystem disorder characterized by progressive cerebellar ataxia, oculocutaneous telangiectasias, immunodeficiency, radiosensitivity, and increased cancer predisposition [1]. The disease is caused by pathogenic variants in the ATM gene, which encodes a serine/threonine kinase central to the DNA damage response and cell-cycle control [2]. Loss of ATM function leads to genomic instability and contributes to the wide spectrum of clinical manifestations observed in affected individuals [3]. More than 1,000 variants in the ATM gene have been reported to date, including nonsense, frameshift, splice-site, and missense changes, with considerable heterogeneity in both genotype and phenotype [4]. While truncating variants typically result in the classic early-onset form of A-T, missense and leaky splice variants may be associated with atypical or milder presentations [5]. Continuous identification of novel ATM variants is therefore essential to improve understanding of the mutational spectrum, refine genotype–phenotype correlations, and support accurate genetic counseling. Here, we describe a patient with clinical features consistent with A-T who was found to carry a previously unreported homozygous missense variant in ATM (c.4940T>G; p.Leu1647Arg). To our knowledge, this variant has not been documented in population databases or the medical literature. We present the clinical and genetic findings and discuss their relevance in the context of existing knowledge about A-T. Case presentation A 6-year-old male was admitted to the hospital with a primary complaint of gait ataxia, accompanied by fever, non-productive cough, and purulent discharge from the right ear. Neurological symptoms had progressively worsened over recent weeks. The patient’s past medical history was notable for recurrent lower respiratory tract infections, intermittent abdominal pain, and chronic right sided otorrhea and ataxia noted approximately three years ago. Vital signs on admission: Temperature: 38°C Respiratory rate: 35 breaths/min Heart rate: 110 beats/min Blood pressure: 95/60 mmHg Physical examination revealed marked pallor and conjunctival telangiectasia. Neurological assessment demonstrated an ataxic gait, a positive finger-nose test (loss of coordination) suggestive of cerebellar dysfunction. Chest auscultation revealed fine bilateral crackles. Laboratory investigations revealed: White blood cell count: 13,200/μL (60% neutrophils) Hemoglobin: 10.3 g/dL Platelet count: 319,000/μL Erythrocyte sedimentation rate (ESR): 28 mm/hr C-reactive protein (CRP): elevated (10× upper limit of normal) Renal function: within normal limits Immunoglobulin panel: IgG: 200 mg/dL (decreased) IgA: 50 mg/dL (decreased) IgM: 452 mg/dL (elevated) IgE: 20 IU/mL Radiological imaging showed: Chest X-ray: bilateral interstitial infiltrates Abdominal ultrasound: absence of the left kidney (suggestive of renal agenesis) Brain MRI revealed mild cerebellar atrophy with prominence of the folia and widening of cerebellar fissures, particularly in the vermis (Figure 1A and 1B). No supratentorial abnormalities were observed [Fig 1]. Whole-exome sequencing (CentoXome®, Centogene GmbH, Germany) identified a homozygous missense variant in ATM (NM_000051.4:c.4940T>G; p.Leu1647Arg). According to Centogene’s report, this variant has not been previously reported in public databases (gnomAD, 1000G, ESP) and was classified as a variant of uncertain significance (VUS) under ACMG/AMP guidelines. In silico analyses predicted a deleterious effect (PolyPhen: probably damaging; SIFT: deleterious; MutationTaster: disease-causing). The clinical correlation with the patient’s phenotype (ataxia, telangiectasia, immunodeficiency) supports the variant’s likely pathogenic role. Parental targeted testing was recommended to confirm homozygosity versus possible compound heterozygosity. The patient was treated with intravenous antibiotics targeting pneumonia and otitis media, along with intravenous immunoglobulin (IVIG), which led to significant The patient was treated with intravenous antibiotics targeting pneumonia and otitis media, along with intravenous immunoglobulin (IVIG), which led to significant improvement in infectious symptoms and neurological stability. He was discharged on oral antibiotic with close clinical follow-up planned. Genetic testing of family members was strongly recommended, given the positive history of cerebellar ataxia in a 4-year-old sibling and the presence of parental consanguinity. Discussion Ataxia Telangiectasia (AT) is an autosomal recessive multisystem disorder that commonly presents with ataxia, oculocutaneous telangiectasia, immunodeficiency, frequent pulmonary infections, and certain cancers[6] AT is caused by biallelic mutations in the ataxia telangiectasia mutated (ATM) gene which is located on chromosome 11q22.3. The ATM gene encodes a protein that belongs to the family of phosphoinositide-3-kinase like kinase. This protein (∼350 KDa) regulates a complex signaling cascade in response to DNA double strand breaks, oxidative stress and other genotoxic stress. When both copies of the ATM gene are inactivated, it leads to A-T. The prevalence of A-T in the US is 1:40,000-1:100,000 live births, but it varies with the degree of consanguinity in a country and the incidence is significantly higher in populations with highly consanguineous marriage rates than in the general population[7–9] The type and frequency of specific mutations in different localities can vary widely, with more than 1,000 clinically relevant variants in the ATM (1,485 classified as pathogenic) and with some regions having a specific founder mutation and more. [10–12] In this patient, genetic analysis through whole exome sequencing (WES) revealed a rare pathogenic variant in the ATM gene: c.4940T>G; p.(Leu1647Arg), which causes an amino acid change from Leucine to Arginine at position 1647 in exon(s) no. 33 (of 63). All in silico tools point toward a deleterious effect of the variant in the protein, in the presence of parental consanguinity and a positive history of cerebellar ataxia in a 4-year-old sibling. The novel variant is classified as variant of uncertain significance based on implementation of the ACMG/AMP/ClinGen SVI guidelines The data was analyzed focusing on variants affecting protein function (nonsense, frameshift, conserved splice site and missense with high pathogenicity predictions) in genes with supporting evidence on zygosity, segregation or functional importance of the gene. Available literature or experimental data on expression and/or animal models were considered. However, no such variants could be identified for the patient. Genetic testing of family members was strongly recommended. In order to obtain a more definable information on this variant, given the positive history of cerebellar ataxia in a 4-year-old sibling and the presence of parental consanguinity [11,12] Limitation based on misinterpretation of genetic results of results may occur if the provided genetic data or patient information is inaccurate and/or incomplete. In the classical form of AT, ataxia is the main neurological sign of the disease and is usually the first clinical manifestation that occurs in childhood. Truncal ataxia is usually seen in the first year of life. Cerebellar pathology in A-T includes cerebellar atrophy of the frontal and posterior vermis and atrophy of both cerebellar hemispheres. Neurologically, this patient presented with typical ataxic gait and cerebellar dysfunction confirmed with brain MRI showing mild cerebellar atrophy with otherwise normal brain structures [13] Immunodeficiency is seen in two-thirds of the patients and pulmonary disease is relatively common in classical AT. This patient presented with clinical features of immunodeficiency, including recurrent otorrhea and lower respiratory tract infections. Radiological evaluation revealed bilateral interstitial infiltrates on chest X-ray. Most importantly, laboratory investigations demonstrated a markedly elevated C-reactive protein (CRP) level (10× upper limit of normal) and leukocytosis with a white blood cell count of 13,200/μL (60% neutrophils). Furthermore, the immunoglobulin panel showed an abnormal pattern: IgG 200 mg/dL (decreased), IgA 50 mg/dL (decreased), IgM 452 mg/dL (elevated), and IgE 20 IU/mL [14] Marked pallor and conjunctival telangiectasia were also detectable on physical examination. Our patient's clinical presentation was compatible with the classical form of AT except for the fact that there was no evidence for malignancy up to discharge, with subsequent follow up appointments and screening considered. These findings were clinically similar to the case of an eight years old Syrian girl, whose genetic sequencing showed a novel intronic mutation resulting in missplicing of mRNA and a nonsense mutation, in comparison with our case that showed a different variant and a missense mutation[15] Different studies worldwide showed that most ATM gene mutations involve frameshift or nonsense mutations located in the proximal, central, and distal regions of the ATM gene, meanwhile ATM missense mutations in A-T are less frequent and are commonly due to malfunction of kinase activity [16–18] Although there is currently no cure for A-T patients, identifying mutations in the ATM gene is vital for future cures and risk managements, especially with the rapid development of mutation-targeted therapeutic approaches.[19] In summary and based on our research of the relevant medical literature, this study is the first to report on the discovery of the c.4940T>G; p.(Leu1647Arg) disease variant, paving the way for future diagnosis of other AT patients or identifying carriers. Conclusion This case highlights the clinical and genetic complexity of ataxia–telangiectasia. Our patient exhibited classical neurological and immunological features along with a novel ATM variant (c.4940T > G; p.Leu1647Arg). Reporting such variants enhances understanding of disease heterogeneity and supports improved diagnosis and counseling, especially in populations with high consanguinity rates. Further functional studies are required to confirm the pathogenicity of this novel variant. Declarations Funding: None declared. Conflict of Interest: The authors declare no conflicts of interest. Informed Consent: Written informed consent was obtained from the patient’s legal guardian for publication of this case report and accompanying images. Ethical Approval: Ethical approval was not required for a single-patient case report according to institutional policy. Data Availability: All data supporting this report are included within the manuscript. Author Contributions: Zyad Al-Frejat contributed to data collection, manuscript drafting, and revision. Grace Hanna and Doaa Abo Hamza supervised and reviewed the manuscript. Ghuroub Al Khayer revised the manuscript and contributed to the academic writing. Acknowledgements: The authors thank Centogene GmbH for providing the genetic testing support and the patient’s family for their cooperation. References BODER E, SEDGWICK RP. Ataxia-telangiectasia; a familial syndrome of progressive cerebellar ataxia, oculocutaneous telangiectasia and frequent pulmonary infection. Pediatrics 1958;21:526–54. Shiloh Y, Ziv Y. The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nat Rev Mol Cell Biol 2013;14:197–210. https://doi.org/10.1038/NRM3546. Lavin MF. Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer. Nat Rev Mol Cell Biol 2008;9:759–69. https://doi.org/10.1038/NRM2514. Sandoval N, Platzer M, Rosenthal A, Dörk T, Bendix R, Skawran B, et al. Characterization of ATM gene mutations in 66 ataxia telangiectasia families. Hum Mol Genet 1999;8:69–79. https://doi.org/10.1093/HMG/8.1.69. Taylor AMR, Lam Z, Last JI, Byrd PJ. Ataxia telangiectasia: more variation at clinical and cellular levels. Clin Genet 2015;87:199–208. https://doi.org/10.1111/CGE.12453. Sirajwala AA, Khan S, Rathod VM, Gevariya VC, Jansari JR, Patel YM. Ataxia-Telangiectasia: A Case Report and a Brief Review. Cureus 2023;15. https://doi.org/10.7759/CUREUS.39346. Savitsky K, Bar-Shira A, Gilad S, Rotman G, Ziv Y, Vanagaite L, et al. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 1995;268:1749–53. https://doi.org/10.1126/SCIENCE.7792600. Rothblum-Oviatt C, Wright J, Lefton-Greif MA, McGrath-Morrow SA, Crawford TO, Lederman HM. Ataxia telangiectasia: a review. Orphanet J Rare Dis 2016;11. https://doi.org/10.1186/S13023-016-0543-7. Swift M, Morrell D, Cromartie E, Chamberlin AR, Skolnick MH, Bishop DT. The incidence and gene frequency of ataxia-telangiectasia in the United States. Am J Hum Genet 1986;39:573–83. Amirifar P, Ranjouri MR, Lavin M, Abolhassani H, Yazdani R, Aghamohammadi A. Ataxia-telangiectasia: epidemiology, pathogenesis, clinical phenotype, diagnosis, prognosis and management. Expert Rev Clin Immunol 2020;16:859–71. https://doi.org/10.1080/1744666X.2020.1810570. Telatar M, Teraoka S, Wang Z, Chun HH, Liang T, Castellvi-Bel S, et al. Ataxia-telangiectasia: identification and detection of founder-effect mutations in the ATM gene in ethnic populations. Am J Hum Genet 1998;62:86–97. https://doi.org/10.1086/301673. Landrum MJ, Lee JM, Benson M, Brown GR, Chao C, Chitipiralla S, et al. ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res 2018;46:D1062–7. https://doi.org/10.1093/NAR/GKX1153. Sahama I, Sinclair K, Pannek K, Lavin M, Rose S. Radiological imaging in ataxia telangiectasia: a review. Cerebellum 2014;13:521–30. https://doi.org/10.1007/S12311-014-0557-4. Cavone F, Cappelli S, Bonuccelli A, D’Elios S, Costagliola G, Peroni D, et al. Ataxia Telangiectasia Arising as Immunodeficiency: The Intriguing Differential Diagnosis. Journal of Clinical Medicine 2023, Vol 12, Page 6041 2023;12:6041. https://doi.org/10.3390/JCM12186041. Arslan Ateş E, Türkyılmaz A, Eltan SB, Barış S, Güney AI. A Novel ATM Gene Mutation Affecting Splicing in an Ataxia-Telangiectasia Patient. Mol Syndromol 2022;13:80–4. https://doi.org/10.1159/000518629. Barone G, Groom A, Reiman A, Srinivasan V, Byrd PJ, Taylor AMR. Modeling ATM mutant proteins from missense changes confirms retained kinase activity. Hum Mutat 2009;30:1222–30. https://doi.org/10.1002/HUMU.21034. Jacquemin V, Rieunier G, Jacob S, Bellanger D, D’Enghien CD, Laugé A, et al. Underexpression and abnormal localization of ATM products in ataxia telangiectasia patients bearing ATM missense mutations. Eur J Hum Genet 2012;20:305–12. https://doi.org/10.1038/EJHG.2011.196. Amirifar P, Ranjouri MR, Pashangzadeh S, Lavin M, Yazdani R, Moeini Shad T, et al. The spectrum of ATM gene mutations in Iranian patients with ataxia-telangiectasia. Pediatr Allergy Immunol 2021;32:1316–26. https://doi.org/10.1111/PAI.13461. van Os NJH, Haaxma CA, van der Flier M, Merkus PJFM, van Deuren M, de Groot IJM, et al. Ataxia-telangiectasia: recommendations for multidisciplinary treatment. Dev Med Child Neurol 2017;59:680–9. https://doi.org/10.1111/DMCN.13424. Additional Declarations The authors declare no competing interests. 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. 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Sagittal T1-weighted MRI showing cerebellar volume loss with prominence of the folia. Figure 1B. Axial T2-weighted MRI demonstrating cerebellar vermis atrophy with widened cerebellar fissures\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-8368178/v1/09da23a2e926697291780fc1.jpg"},{"id":98445673,"identity":"3b78b338-878e-4f91-b891-11a4c08a70f4","added_by":"auto","created_at":"2025-12-17 17:20:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":400054,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8368178/v1/13ea4176-6895-4796-b997-60a9e5b62d9d.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003eA Novel ATM Gene Variant (c.4940T\u0026gt;G; p.Leu1647Arg) in a Child with Ataxia–Telangiectasia: Clinical, Radiologic, and Genetic Correlation\u003c/p\u003e","fulltext":[{"header":"Highlights","content":"\u003cp\u003e\u0026bull; Ataxia\u0026ndash;telangiectasia is a rare multisystem disorder caused by ATM mutations.\u003c/p\u003e\n\u003cp\u003e\u0026bull; We report a 6-year-old boy with classical features of A-T and a novel homozygous ATM missense variant.\u003c/p\u003e\n\u003cp\u003e\u0026bull; Genetic finding: c.4940T\u0026gt;G; p.Leu1647Arg, not previously reported in databases or literature.\u003c/p\u003e\n\u003cp\u003e\u0026bull; This report adds to the mutational spectrum and informs genetic counseling.\u003c/p\u003e"},{"header":"Introduction","content":"\u003cp\u003eAtaxia-telangiectasia (A-T) is a rare, autosomal recessive multisystem disorder characterized by progressive cerebellar ataxia, oculocutaneous telangiectasias, immunodeficiency, radiosensitivity, and increased cancer predisposition [1]. The disease is caused by pathogenic variants in the ATM gene, which encodes a serine/threonine kinase central to the DNA damage response and cell-cycle control [2]. Loss of ATM function leads to genomic instability and contributes to the wide spectrum of clinical manifestations observed in affected individuals [3].\u003c/p\u003e\n\u003cp\u003eMore than 1,000 variants in the ATM gene have been reported to date, including nonsense, frameshift, splice-site, and missense changes, with considerable heterogeneity in both genotype and phenotype [4]. While truncating variants typically result in the classic early-onset form of A-T, missense and leaky splice variants may be associated with atypical or milder presentations [5]. Continuous identification of novel ATM variants is therefore essential to improve understanding of the mutational spectrum, refine genotype–phenotype correlations, and support accurate genetic counseling.\u003c/p\u003e\n\u003cp\u003eHere, we describe a patient with clinical features consistent with A-T who was found to carry a previously unreported homozygous missense variant in ATM (c.4940T\u0026gt;G; p.Leu1647Arg). To our knowledge, this variant has not been documented in population databases or the medical literature. We present the clinical and genetic findings and discuss their relevance in the context of existing knowledge about A-T.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eA 6-year-old male was admitted to the hospital with a primary complaint of gait ataxia, accompanied by fever, non-productive cough, and purulent discharge from the right ear. Neurological symptoms had progressively worsened over recent weeks.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe patient’s past medical history was notable for recurrent lower respiratory tract infections, intermittent abdominal pain, and chronic right sided otorrhea and ataxia noted approximately three years ago.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eVital signs on admission:\u003c/p\u003e\n\u003cp\u003eTemperature: 38°C\u003c/p\u003e\n\u003cp\u003eRespiratory rate: 35 breaths/min\u003c/p\u003e\n\u003cp\u003eHeart rate: 110 beats/min\u003c/p\u003e\n\u003cp\u003eBlood pressure: 95/60 mmHg\u003c/p\u003e\n\u003cp\u003ePhysical examination revealed marked pallor and conjunctival telangiectasia. Neurological assessment demonstrated an ataxic gait, a positive finger-nose test (loss of coordination) \u0026nbsp;suggestive of cerebellar dysfunction. Chest auscultation revealed fine bilateral crackles.\u003c/p\u003e\n\u003cp\u003eLaboratory investigations revealed:\u003c/p\u003e\n\u003cp\u003eWhite blood cell count: 13,200/μL (60% neutrophils)\u003c/p\u003e\n\u003cp\u003eHemoglobin: 10.3 g/dL\u003c/p\u003e\n\u003cp\u003ePlatelet count: 319,000/μL\u003c/p\u003e\n\u003cp\u003eErythrocyte sedimentation rate (ESR): 28 mm/hr\u003c/p\u003e\n\u003cp\u003eC-reactive protein (CRP): elevated (10× upper limit of normal)\u003c/p\u003e\n\u003cp\u003eRenal function: within normal limits\u003c/p\u003e\n\u003cp\u003eImmunoglobulin panel:\u003c/p\u003e\n\u003cp\u003eIgG: 200 mg/dL (decreased)\u003c/p\u003e\n\u003cp\u003eIgA: 50 mg/dL (decreased)\u003c/p\u003e\n\u003cp\u003eIgM: 452 mg/dL (elevated)\u003c/p\u003e\n\u003cp\u003eIgE: 20 IU/mL\u003c/p\u003e\n\u003cp\u003eRadiological imaging showed:\u003c/p\u003e\n\u003cp\u003eChest X-ray: bilateral interstitial infiltrates\u003c/p\u003e\n\u003cp\u003eAbdominal ultrasound: absence of the left kidney (suggestive of renal agenesis)\u003c/p\u003e\n\u003cp\u003eBrain MRI revealed mild cerebellar atrophy with prominence of the folia and widening of cerebellar fissures, particularly in the vermis (Figure 1A and 1B). No supratentorial abnormalities were observed [Fig 1].\u003c/p\u003e\n\u003cp\u003eWhole-exome sequencing (CentoXome®, Centogene GmbH, Germany) identified a homozygous missense variant in ATM (NM_000051.4:c.4940T\u0026gt;G; p.Leu1647Arg). According to Centogene’s report, this variant has not been previously reported in public databases (gnomAD, 1000G, ESP) and was classified as a variant of uncertain significance (VUS) under ACMG/AMP guidelines. In silico analyses predicted a deleterious effect (PolyPhen: probably damaging; SIFT: deleterious; MutationTaster: disease-causing). The clinical correlation with the patient’s phenotype (ataxia, telangiectasia, immunodeficiency) supports the variant’s likely pathogenic role. Parental targeted testing was recommended to confirm homozygosity versus possible compound heterozygosity.\u003c/p\u003e\n\u003cp\u003eThe patient was treated with intravenous antibiotics targeting pneumonia and otitis media, along with intravenous immunoglobulin (IVIG), which led to significant The patient was treated with intravenous antibiotics targeting pneumonia and otitis media, along with intravenous immunoglobulin (IVIG), which led to significant improvement in infectious symptoms and neurological stability. He was discharged on oral antibiotic with close clinical follow-up planned.\u003c/p\u003e\n\u003cp\u003eGenetic testing of family members was strongly recommended, given the positive history of cerebellar ataxia in a 4-year-old sibling and the presence of parental\u0026nbsp;consanguinity.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAtaxia Telangiectasia (AT) is an autosomal recessive multisystem disorder that commonly presents with ataxia, oculocutaneous telangiectasia, immunodeficiency, frequent pulmonary infections, and certain cancers[6]\u003c/p\u003e\n\u003cp\u003eAT is caused by biallelic mutations in the ataxia telangiectasia mutated (ATM) gene which is located on chromosome 11q22.3. The ATM gene encodes a protein that belongs to the family of phosphoinositide-3-kinase like kinase. This protein (∼350 KDa) regulates a complex signaling cascade in response to DNA double strand breaks, oxidative stress and other genotoxic stress. When both copies of the\u0026nbsp;ATM\u0026nbsp;gene are inactivated, it leads to A-T.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;The prevalence of A-T in the US is 1:40,000-1:100,000 live births, but it varies with the degree of consanguinity in a country and the incidence is significantly higher in populations with highly consanguineous marriage rates than in the general population[7–9]\u003c/p\u003e\n\u003cp\u003eThe type and frequency of specific mutations in different localities can vary widely, with more than 1,000 clinically relevant variants in the ATM (1,485 classified as pathogenic) and with some regions having a specific founder mutation and more. [10–12]\u003c/p\u003e\n\u003cp\u003eIn this patient, genetic analysis through whole exome sequencing (WES) revealed a rare pathogenic variant in the ATM gene: c.4940T\u0026gt;G; p.(Leu1647Arg), which causes an amino acid change from Leucine to Arginine at position 1647 in exon(s) no. 33 (of 63). All in silico tools point toward a deleterious effect of the variant in the protein, in the presence of parental consanguinity and a positive history of cerebellar ataxia in a 4-year-old sibling. \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe novel variant is classified as variant of uncertain significance based on implementation of the ACMG/AMP/ClinGen SVI guidelines\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe data was analyzed focusing on variants affecting protein function (nonsense, frameshift, conserved splice site and missense with high pathogenicity predictions) in genes with supporting evidence on zygosity, segregation or functional importance of the gene.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Available literature or experimental data on expression and/or animal models were considered. However, no such variants could be identified for the patient.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Genetic testing of family members was strongly recommended. In order to obtain a more definable information on this variant, given the positive history of cerebellar ataxia in a 4-year-old sibling and the presence of parental consanguinity [11,12]\u003c/p\u003e\n\u003cp\u003eLimitation based on misinterpretation of genetic results of results may occur if the provided genetic data or patient information is inaccurate and/or incomplete.\u003c/p\u003e\n\u003cp\u003eIn the classical form of AT, ataxia is the main neurological sign of the disease and is usually the first clinical manifestation that occurs in childhood.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Truncal ataxia is usually seen in the first year of life. Cerebellar pathology in A-T includes cerebellar atrophy of the frontal and posterior vermis and atrophy of both cerebellar hemispheres. Neurologically, this patient presented with typical ataxic gait and cerebellar dysfunction confirmed with brain MRI showing mild cerebellar atrophy with otherwise normal brain structures [13]\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Immunodeficiency is seen in two-thirds of the patients and pulmonary disease is relatively common in classical AT.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis patient presented with clinical features of immunodeficiency, including recurrent otorrhea and lower respiratory tract infections. Radiological evaluation revealed bilateral interstitial infiltrates on chest X-ray. Most importantly, laboratory investigations demonstrated a markedly elevated C-reactive protein (CRP) level (10× upper limit of normal) and leukocytosis with a white blood cell count of 13,200/μL (60% neutrophils). Furthermore, the immunoglobulin panel showed an abnormal pattern: IgG 200 mg/dL (decreased), IgA 50 mg/dL (decreased), IgM 452 mg/dL (elevated), and IgE 20 IU/mL [14]\u003c/p\u003e\n\u003cp\u003eMarked pallor and conjunctival telangiectasia were also detectable on physical examination.\u003c/p\u003e\n\u003cp\u003eOur patient's clinical presentation was compatible with the classical form of AT except for the fact that there was no evidence for malignancy up to discharge, with subsequent follow up appointments and screening considered.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThese findings were clinically similar to the case of an eight years old Syrian girl, whose genetic sequencing showed a novel intronic mutation resulting in missplicing of mRNA and a nonsense mutation, in comparison with our case that showed a different variant and a missense mutation[15]\u003c/p\u003e\n\u003cp\u003eDifferent studies worldwide showed that most ATM gene mutations involve frameshift or nonsense mutations located in the proximal, central, and distal regions of the ATM gene, meanwhile ATM missense mutations in A-T are less frequent and are commonly due to malfunction of kinase activity [16–18]\u003c/p\u003e\n\u003cp\u003eAlthough there is currently no cure for A-T patients, identifying mutations in the ATM gene is vital for future cures and risk managements, especially with the rapid development of mutation-targeted therapeutic approaches.[19]\u003c/p\u003e\n\u003cp\u003eIn summary and based on our research of the relevant medical literature, this study is the first to report on the discovery of the c.4940T\u0026gt;G; p.(Leu1647Arg) disease variant, paving the way for future diagnosis of other AT patients or identifying carriers.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis case highlights the clinical and genetic complexity of ataxia\u0026ndash;telangiectasia. Our patient exhibited classical neurological and immunological features along with a novel ATM variant (c.4940T\u0026thinsp;\u0026gt;\u0026thinsp;G; p.Leu1647Arg). Reporting such variants enhances understanding of disease heterogeneity and supports improved diagnosis and counseling, especially in populations with high consanguinity rates. Further functional studies are required to confirm the pathogenicity of this novel variant.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e None declared.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest:\u0026nbsp;\u003c/strong\u003eThe authors declare no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed Consent:\u0026nbsp;\u003c/strong\u003eWritten informed consent was obtained from the patient\u0026rsquo;s legal guardian for publication of this case report and accompanying images.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Approval:\u0026nbsp;\u003c/strong\u003eEthical approval was not required for a single-patient case report according to institutional policy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability:\u003c/strong\u003e All data supporting this report are included within the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u003c/strong\u003e Zyad Al-Frejat contributed to data collection, manuscript drafting, and revision. Grace Hanna and Doaa Abo Hamza supervised and reviewed the manuscript. Ghuroub Al Khayer revised the manuscript and contributed to the academic writing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u0026nbsp;\u003c/strong\u003eThe authors thank Centogene GmbH for providing the genetic testing support and the patient\u0026rsquo;s family for their cooperation.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eBODER E, SEDGWICK RP. Ataxia-telangiectasia; a familial syndrome of progressive cerebellar ataxia, oculocutaneous telangiectasia and frequent pulmonary infection. Pediatrics 1958;21:526\u0026ndash;54.\u003c/li\u003e\n\u003cli\u003eShiloh Y, Ziv Y. The ATM protein kinase: regulating the cellular response to genotoxic stress, and more. Nat Rev Mol Cell Biol 2013;14:197\u0026ndash;210. https://doi.org/10.1038/NRM3546.\u003c/li\u003e\n\u003cli\u003eLavin MF. Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer. Nat Rev Mol Cell Biol 2008;9:759\u0026ndash;69. https://doi.org/10.1038/NRM2514.\u003c/li\u003e\n\u003cli\u003eSandoval N, Platzer M, Rosenthal A, D\u0026ouml;rk T, Bendix R, Skawran B, et al. Characterization of ATM gene mutations in 66 ataxia telangiectasia families. Hum Mol Genet 1999;8:69\u0026ndash;79. https://doi.org/10.1093/HMG/8.1.69.\u003c/li\u003e\n\u003cli\u003eTaylor AMR, Lam Z, Last JI, Byrd PJ. Ataxia telangiectasia: more variation at clinical and cellular levels. Clin Genet 2015;87:199\u0026ndash;208. https://doi.org/10.1111/CGE.12453.\u003c/li\u003e\n\u003cli\u003eSirajwala AA, Khan S, Rathod VM, Gevariya VC, Jansari JR, Patel YM. Ataxia-Telangiectasia: A Case Report and a Brief Review. Cureus 2023;15. https://doi.org/10.7759/CUREUS.39346.\u003c/li\u003e\n\u003cli\u003eSavitsky K, Bar-Shira A, Gilad S, Rotman G, Ziv Y, Vanagaite L, et al. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 1995;268:1749\u0026ndash;53. https://doi.org/10.1126/SCIENCE.7792600.\u003c/li\u003e\n\u003cli\u003eRothblum-Oviatt C, Wright J, Lefton-Greif MA, McGrath-Morrow SA, Crawford TO, Lederman HM. Ataxia telangiectasia: a review. Orphanet J Rare Dis 2016;11. https://doi.org/10.1186/S13023-016-0543-7.\u003c/li\u003e\n\u003cli\u003eSwift M, Morrell D, Cromartie E, Chamberlin AR, Skolnick MH, Bishop DT. The incidence and gene frequency of ataxia-telangiectasia in the United States. Am J Hum Genet 1986;39:573\u0026ndash;83.\u003c/li\u003e\n\u003cli\u003eAmirifar P, Ranjouri MR, Lavin M, Abolhassani H, Yazdani R, Aghamohammadi A. Ataxia-telangiectasia: epidemiology, pathogenesis, clinical phenotype, diagnosis, prognosis and management. Expert Rev Clin Immunol 2020;16:859\u0026ndash;71. https://doi.org/10.1080/1744666X.2020.1810570.\u003c/li\u003e\n\u003cli\u003eTelatar M, Teraoka S, Wang Z, Chun HH, Liang T, Castellvi-Bel S, et al. Ataxia-telangiectasia: identification and detection of founder-effect mutations in the ATM gene in ethnic populations. Am J Hum Genet 1998;62:86\u0026ndash;97. https://doi.org/10.1086/301673.\u003c/li\u003e\n\u003cli\u003eLandrum MJ, Lee JM, Benson M, Brown GR, Chao C, Chitipiralla S, et al. ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res 2018;46:D1062\u0026ndash;7. https://doi.org/10.1093/NAR/GKX1153.\u003c/li\u003e\n\u003cli\u003eSahama I, Sinclair K, Pannek K, Lavin M, Rose S. Radiological imaging in ataxia telangiectasia: a review. Cerebellum 2014;13:521\u0026ndash;30. https://doi.org/10.1007/S12311-014-0557-4.\u003c/li\u003e\n\u003cli\u003eCavone F, Cappelli S, Bonuccelli A, D\u0026rsquo;Elios S, Costagliola G, Peroni D, et al. Ataxia Telangiectasia Arising as Immunodeficiency: The Intriguing Differential Diagnosis. Journal of Clinical Medicine 2023, Vol 12, Page 6041 2023;12:6041. https://doi.org/10.3390/JCM12186041.\u003c/li\u003e\n\u003cli\u003eArslan Ateş E, T\u0026uuml;rkyılmaz A, Eltan SB, Barış S, G\u0026uuml;ney AI. A Novel ATM Gene Mutation Affecting Splicing in an Ataxia-Telangiectasia Patient. Mol Syndromol 2022;13:80\u0026ndash;4. https://doi.org/10.1159/000518629.\u003c/li\u003e\n\u003cli\u003eBarone G, Groom A, Reiman A, Srinivasan V, Byrd PJ, Taylor AMR. Modeling ATM mutant proteins from missense changes confirms retained kinase activity. Hum Mutat 2009;30:1222\u0026ndash;30. https://doi.org/10.1002/HUMU.21034.\u003c/li\u003e\n\u003cli\u003eJacquemin V, Rieunier G, Jacob S, Bellanger D, D\u0026rsquo;Enghien CD, Laug\u0026eacute; A, et al. Underexpression and abnormal localization of ATM products in ataxia telangiectasia patients bearing ATM missense mutations. Eur J Hum Genet 2012;20:305\u0026ndash;12. https://doi.org/10.1038/EJHG.2011.196.\u003c/li\u003e\n\u003cli\u003eAmirifar P, Ranjouri MR, Pashangzadeh S, Lavin M, Yazdani R, Moeini Shad T, et al. The spectrum of ATM gene mutations in Iranian patients with ataxia-telangiectasia. Pediatr Allergy Immunol 2021;32:1316\u0026ndash;26. https://doi.org/10.1111/PAI.13461.\u003c/li\u003e\n\u003cli\u003evan Os NJH, Haaxma CA, van der Flier M, Merkus PJFM, van Deuren M, de Groot IJM, et al. Ataxia-telangiectasia: recommendations for multidisciplinary treatment. Dev Med Child Neurol 2017;59:680\u0026ndash;9. https://doi.org/10.1111/DMCN.13424.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Damascus University","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":"Ataxia Telangiectasia, Case Reports, Genetics, Mutation","lastPublishedDoi":"10.21203/rs.3.rs-8368178/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8368178/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eAtaxia–telangiectasia (A-T) is a rare autosomal recessive disorder caused by mutations in the ATM gene, characterized by progressive cerebellar ataxia, telangiectasias, immunodeficiency, and increased cancer risk. Reporting novel ATM variants is essential to refine genotype–phenotype correlations.\u003cbr\u003e\nWe report a 6-year-old boy presenting with progressive gait ataxia, recurrent respiratory infections, chronic otorrhea, and conjunctival telangiectasias. Laboratory studies revealed immunodeficiency with reduced IgG and IgA, and elevated IgM. Brain MRI showed mild cerebellar atrophy, while chest X-ray revealed bilateral interstitial infiltrates. Whole-exome sequencing identified a novel homozygous missense variant in ATM (c.4940T\u0026gt;G; p.Leu1647Arg), classified as a variant of uncertain significance but predicted deleterious by in silico tools. The patient improved with intravenous antibiotics and IVIG. Family genetic testing was recommended given parental consanguinity and an affected sibling.\u003cbr\u003e\nThis case illustrates the classical phenotype of A-T with immunodeficiency and neurological dysfunction, combined with a novel ATM variant not previously reported in population databases. Such cases expand the known mutational spectrum and may guide diagnosis and counseling. Although the variant’s pathogenicity remains to be functionally validated, its clinical correlation supports disease relevance.\u003cbr\u003e\nIdentification of novel ATM variants is crucial for advancing diagnostic precision, genetic counseling, and future therapeutic strategies in A-T.\u003c/p\u003e","manuscriptTitle":"A Novel ATM Gene Variant (c.4940T\u0026gt;G; p.Leu1647Arg) in a Child with Ataxia–Telangiectasia: Clinical, Radiologic, and Genetic Correlation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-16 14:18:48","doi":"10.21203/rs.3.rs-8368178/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":"df904634-91b0-4df0-bbfa-1a953fad717d","owner":[],"postedDate":"December 16th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":59692186,"name":"Medical Genetics"},{"id":59692187,"name":"Neurology"}],"tags":[],"updatedAt":"2026-01-23T19:08:26+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-16 14:18:48","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8368178","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8368178","identity":"rs-8368178","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}