Genetic sequencing in Saudi patients with systemic lupus erythematosus

Genetic sequencing in Saudi patients with systemic lupus erythematosus | 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 Research Article Genetic sequencing in Saudi patients with systemic lupus erythematosus Ibrahim A. Al-Homood, Sarah Binhassan, Khalid AlMatham, Lena M. Hassen, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8515505/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 Objective: To perform Whole Exome Sequencing on a cohort of Saudi SLE patients to Identify rare pathogenic variants and investigated their distribution against 550 common variant loci from the NHGRI-EBI GWAS Catalogue. Methods: Whole Exome Sequencing was performed on the extracted genomic DNA for 29 patients with confirmed systemic lupus erythematosus. Descriptive analyses were used to summarize the patients’ characteristics. The genomic analysis was conducted using R software R version 4.4.2 and several specialised packages. Results: Our analysis revealed a "multi-hit" genetic landscape, with significant co-occurrence clusters involving the DNA damage response (ATM, BRCA1, RECQL4), membrane integrity (DYSF, USH2A), and signal transduction (GRK2, GRK4). Notably, NPFFR2 emerged as a major recurrently mutated gene, identified in 24% of the cohort. Phenotypic partitioning analysis demonstrated that NPFFR2 variants define a distinct neuro-musculoskeletal endotype, where 85.7% (6/7) of mutated patients exhibited musculoskeletal involvement alongside a marginal trend toward oral ulcers (P=0.093). Conversely, NPFFR2 mutation showed a strong trend toward mutual exclusivity with haematological involvement (P=0.066), suggesting a disease trajectory that bypasses traditional systemic complications. Furthermore, complex mutational profiles involving NPFFR2 and the spindle assembly checkpoint kinase BUB1 were associated with clinical drug resistance. These findings establish a novel neuro-immune hypothesis for SLE, where rare variants in the NPFFR2–HPA axis pathway act as phenotypic determinants, guiding disease expression toward specific organ systems. Conclusion: This study shifts the paradigm of SLE from a monolithic autoimmune condition to a collection of genetically defined endotypes, providing a roadmap for precision medicine and the early identification of treatment-refractory patients. Systemic Lupus Erythematosus (SLE) Whole Exome Sequencing (WES) NPFFR2 variant drug resistance Full Text Additional Declarations No competing interests reported. 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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8515505","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":583777784,"identity":"aa6fb1af-bc55-4d1b-a813-6125c630b6c3","order_by":0,"name":"Ibrahim A. 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Descriptive analyses were used to summarize the patients’ characteristics. The genomic analysis was conducted using R software R version 4.4.2 and several specialised packages.\u003c/p\u003e\n\u003cp\u003eResults: Our analysis revealed a \"multi-hit\" genetic landscape, with significant co-occurrence \u0026nbsp;clusters involving the DNA damage response (ATM, BRCA1, RECQL4), membrane integrity \u0026nbsp;(DYSF, USH2A), and signal transduction (GRK2, GRK4). Notably, NPFFR2 emerged as a major \u0026nbsp;recurrently mutated gene, identified in 24% of the cohort. Phenotypic partitioning analysis \u0026nbsp;demonstrated that NPFFR2 variants define a distinct neuro-musculoskeletal endotype, where \u0026nbsp;85.7% (6/7) of mutated patients exhibited musculoskeletal involvement alongside a marginal trend toward oral ulcers (P=0.093). Conversely, NPFFR2 mutation showed a strong trend toward mutual exclusivity with haematological involvement (P=0.066), suggesting a disease trajectory that bypasses traditional systemic complications. Furthermore, complex mutational profiles involving NPFFR2 and the spindle assembly checkpoint kinase BUB1 were associated with \u0026nbsp;clinical drug resistance. These findings establish a novel neuro-immune hypothesis for SLE, where rare variants in the NPFFR2–HPA axis pathway act as phenotypic determinants, guiding \u0026nbsp;disease expression toward specific organ systems.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConclusion: This study shifts the paradigm of SLE from a monolithic autoimmune condition to a \u0026nbsp;collection of genetically defined endotypes, providing a roadmap for precision medicine and the early identification of treatment-refractory patients.\u003c/p\u003e","manuscriptTitle":"Genetic sequencing in Saudi patients with systemic lupus erythematosus","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-02 08:36:22","doi":"10.21203/rs.3.rs-8515505/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":"c17caa51-b750-4099-accb-e52e42ad9bb0","owner":[],"postedDate":"February 2nd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-21T20:09:28+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-02 08:36:22","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8515505","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8515505","identity":"rs-8515505","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}