Distinct genetic etiologies with overlapping neurodevelopmental phenotypes: a two-case series involving GNAI1 and CHAMP1 variants

Distinct genetic etiologies with overlapping neurodevelopmental phenotypes: a two-case series involving GNAI1 and CHAMP1 variants | 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 Distinct genetic etiologies with overlapping neurodevelopmental phenotypes: a two-case series involving GNAI1 and CHAMP1 variants MARCO ALBUQUERQUE This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8242970/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 Neurodevelopmental disorders (NDDs) comprise a genetically heterogeneous group of conditions characterized by global developmental delay, epilepsy and behavioral abnormalities. Advances in next-generation sequencing have expanded the number of genes implicated in NDDs, including GNAI1 and CHAMP1 , which act through distinct molecular pathways yet may produce overlapping phenotypes. Case Presentation: We describe two unrelated boys with severe developmental delay and hypotonia but without epilepsy. Case 1 involved a 4-year-old with marked axial hypotonia and distal hypertonia mimicking dystonic–spastic cerebral palsy. Whole-exome sequencing identified a de novo heterozygous GNAI1 variant (c.118G > C; p.Gly40Arg). Case 2 involved a 6-year-old with global hypotonia, autistic features, and mild dysmorphism who achieved independent walking. Exome analysis revealed a novel heterozygous nonsense CHAMP1 variant (c.736G > T; p.Glu246*), not previously reported in ClinVar or gnomAD. In both cases, speech was absent. Conclusions : Despite distinct molecular mechanisms—impaired G-protein signaling in GNAI1 and haploinsufficiency in CHAMP1 —both cases shared early hypotonia, developmental delay, and absent speech. These cases expand the clinical spectrum of GNAI1 - and CHAMP1 -related disorders and underscore the importance of early genomic investigation in children with unexplained developmental delay, even in the absence of epilepsy or structural brain abnormalities Medical Genetics Neurodevelopmental disorder GNAI1 CHAMP1 hypotonia developmental delay speech impairment whole-exome sequencing Introduction With advances in next-generation sequencing, the number of genes associated with neurodevelopmental disorders (NDDs) has expanded significantly ( 1 ). NDDs comprise a genetically heterogeneous group of disorders commonly presenting with developmental delay, intellectual disability, and autism spectrum disorder (ASD) ( 1 , 2 ). Pathogenic variants in GNAI1 and CHAMP1 have been associated with distinct but overlapping forms of NDD. GNAI1 encodes the G-protein α-subunit essential for intracellular signal transduction and neuronal differentiation, while CHAMP1 encodes a chromosomal alignment–maintaining phosphoprotein crucial for chromatin organization and neurogenesis. Patients with GNAI1 mutations typically exhibit severe developmental delay, axial hypotonia, impaired speech, and behavioral abnormalities, with early-onset seizures in about two-thirds of cases ( 3 ). Conversely, CHAMP1 variants are associated with severe developmental delay, hypotonia, intellectual disability, and profound speech loss, often accompanied by epilepsy ( 4 , 5 ). We report two unrelated patients with similar neurodevelopmental features—global delay, hypotonia, and absent speech—caused by variants in GNAI1 and CHAMP1 , respectively. The first patient presented dystonia and spasticity mimicking cerebral palsy, while the second demonstrated a predominantly autistic phenotype with improved motor function. In both cases, epilepsy was absent. This report underscores the importance of molecular testing in differentiating genetic causes of developmental disorders with overlapping phenotypes. Case 1 A 4-year-old boy, presented with severe global developmental delay and marked axial hypotonia. He was born prematurely wit 36 weeks. Head control was achieved only at 8 months of corrected age, and nowadays he could only sit briefly without support but is unable to stand or walk. Speech is completely absent. Neurological examination revealed reduced spontaneous movements, a frog-like posture, and distal spasticity associated with fluctuating hypertonia with contorted movements suggestive of dystonia. Muscle strength was grade IV in all limbs, and deep tendon reflexes were brisk. Brain MRI showed mild frontal CSF prominence and periventricular hyperintensities, while EEG and polysomnography were normal. A genetic panel for movement disorders returned negative result. Whole-exome sequencing identified a heterozygous de novo GNAI1 variant chr7:80,135,278 G > C (c.118G > C – ENST00000649796), located within the GTP-binding domain (CADD score 28.9), which promotes substitution of glycine at codon 40 for arginine. Case 2 A 6-year-old boy has been followed for global developmental delay, profound speech impairment, hypotonia, and behavioral features consistent with autism spectrum disorder (ASD). Early motor development was delayed, with marked hypotonia in infancy; however, independent walking was achieved at three years. He remains nonverbal and displays stereotyped movements, poor social interaction, and sensory hypersensitivity. Physical examination revealed mild dysmorphic features, including hypertelorism, a flattened nasal bridge with upturned nostrils and ankyloglossia. Brain MRI was normal, and no seizures were reported. Whole-exome sequencing identified a heterozygous nonsense variant c.736G > T in the CHAMP1 gene (exon 3), predicted to introduce a premature stop codon at position 246 (p.Glu246*). This alteration is expected to result in either a truncated or absent protein product. The variant is absent from population databases (dbSNP, gnomAD), has no previous reports in ClinVar or medical literature, and is classified as likely pathogenic according to ACMG criteria. This mutation leads to haploinsufficiency of CHAMP1, reducing protein expression below the level required for normal neurodevelopment, consistent with the diagnosis of intellectual developmental disorder type 40 (MIM #616579). Table 1 Discussion These cases illustrate how disruptions in distinct molecular pathways can result in overlapping neurodevelopmental phenotypes. The GNAI1 gene (NM_002069) encodes the G protein α-subunit, essential for intracellular signaling and neuronal differentiation. Pathogenic variants disrupt G-protein signaling, leading to widespread neurodevelopmental impairment ( 3 ). Conversely, CHAMP1 encodes a chromosome alignment–maintaining protein involved in chromatin organization and neuronal development. Haploinsufficiency of CHAMP1 reduces protein expression by approximately 50%, impairing normal neurogenesis and resulting in intellectual developmental disorder type 40 (MIM #616579) ( 4 , 5 ). Despite their distinct molecular origins, both conditions converge phenotypically in early hypotonia, global developmental delay, and profound speech impairment. This highlights how monogenic neurodevelopmental disorders may share common clinical hallmarks that obscure their underlying genetic heterogeneity. In the GNAI1 case, the presentation was dominated by axial hypotonia and distal hypertonia with spasticity and dystonia, but without behavioral abnormalities or epilepsy, thus mimicking a chronic non-progressive encephalopathy such as dystonic–spastic cerebral palsy. The absence of a clear perinatal insult and only mild neuroimaging abnormalities suggested a genetic etiology. Notably, the identified variant has been previously reported as pathogenic and associated with global developmental delay, though dystonia and spasticity, as observed here, have not been described. In contrast, the CHAMP1 case exhibited early hypotonia and mild motor delay, followed by social and communication deficits consistent with classic autism spectrum disorder, preserved ambulation, and no seizures. Our report expands the phenotypic spectrum of GNAI1 - and CHAMP1 -related neurodevelopmental disorders. Although both patients presented with early hypotonia and absent speech, their divergent motor and behavioral trajectories reflect distinct pathogenic mechanisms. Conclusion Whole-exome sequencing should be considered early in children with unexplained motor and speech delay, even in the absence of epilepsy or structural brain abnormalities, as it prevents misdiagnosis, guides prognosis, informs genetic counseling, and supports future gene-targeted therapeutic approaches. Declarations Conflicts of interests: The author declare that there is no conflict of interests regarding the publication of this article. Patient Consent: Written informed consent for publication of these cases report and any accompanying images was obtained from the patient’s legal guardians. Funding Declaration No funding was received for the preparation of this manuscript. Clinical Trial Number Clinical trial number: not applicable. Ethics and Consent to Participate Ethics and consent to participate declarations: not applicable. Written informed consent for publication of the clinical details was obtained from the patients’ legal guardians. References Need AC, Shashi V, Hitomi Y et al (2012) Clinical application of exome sequencing in undiagnosed genetic conditions. J Med Genet 49(6):353–361 Deciphering Developmental Disorders Study (2017) Prevalence and architecture of de novo mutations in developmental disorders. Nature 542(7642):433–438 Muir AM, Gardner JF, van Jaarsveld RH et al (2021) Variants in GNAI1 cause a syndrome associated with variable features including developmental delay, seizures, and hypotonia. Genet Med 23(5):881–887 Jansen S et al (2021) Clinical delineation of CHAMP1 -associated intellectual disability and insights into pathogenic mechanisms. Am J Med Genet A 185(11):3384–3394 Popoola DO et al (2022) CHAMP1 -related neurodevelopmental disorder: clinical spectrum and molecular insights. Eur J Med Genet 65(6):104538 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. 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. 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NDDs comprise a genetically heterogeneous group of disorders commonly presenting with developmental delay, intellectual disability, and autism spectrum disorder (ASD) (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003ePathogenic variants in \u003cem\u003eGNAI1\u003c/em\u003e and \u003cem\u003eCHAMP1\u003c/em\u003e have been associated with distinct but overlapping forms of NDD. \u003cem\u003eGNAI1\u003c/em\u003e encodes the G-protein α-subunit essential for intracellular signal transduction and neuronal differentiation, while \u003cem\u003eCHAMP1\u003c/em\u003e encodes a chromosomal alignment\u0026ndash;maintaining phosphoprotein crucial for chromatin organization and neurogenesis. Patients with \u003cem\u003eGNAI1\u003c/em\u003e mutations typically exhibit severe developmental delay, axial hypotonia, impaired speech, and behavioral abnormalities, with early-onset seizures in about two-thirds of cases (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Conversely, \u003cem\u003eCHAMP1\u003c/em\u003e variants are associated with severe developmental delay, hypotonia, intellectual disability, and profound speech loss, often accompanied by epilepsy (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eWe report two unrelated patients with similar neurodevelopmental features\u0026mdash;global delay, hypotonia, and absent speech\u0026mdash;caused by variants in \u003cem\u003eGNAI1\u003c/em\u003e and \u003cem\u003eCHAMP1\u003c/em\u003e, respectively. The first patient presented dystonia and spasticity mimicking cerebral palsy, while the second demonstrated a predominantly autistic phenotype with improved motor function. In both cases, epilepsy was absent.\u003c/p\u003e\u003cp\u003eThis report underscores the importance of molecular testing in differentiating genetic causes of developmental disorders with overlapping phenotypes.\u003c/p\u003e"},{"header":"Case 1","content":"\u003cp\u003eA 4-year-old boy, presented with severe global developmental delay and marked axial hypotonia. He was born prematurely wit 36 weeks. Head control was achieved only at 8 months of corrected age, and nowadays he could only sit briefly without support but is unable to stand or walk. Speech is completely absent. Neurological examination revealed reduced spontaneous movements, a frog-like posture, and distal spasticity associated with fluctuating hypertonia with contorted movements suggestive of dystonia. Muscle strength was grade IV in all limbs, and deep tendon reflexes were brisk. Brain MRI showed mild frontal CSF prominence and periventricular hyperintensities, while EEG and polysomnography were normal. A genetic panel for movement disorders returned negative result. Whole-exome sequencing identified a heterozygous de novo GNAI1 variant chr7:80,135,278 G \u0026gt; C (c.118G \u0026gt; C – ENST00000649796), located within the GTP-binding domain (CADD score 28.9), which promotes substitution of glycine at codon 40 for arginine.\u003c/p\u003e"},{"header":"Case 2","content":"\u003cp\u003eA 6-year-old boy has been followed for global developmental delay, profound speech impairment, hypotonia, and behavioral features consistent with autism spectrum disorder (ASD). Early motor development was delayed, with marked hypotonia in infancy; however, independent walking was achieved at three years. He remains nonverbal and displays stereotyped movements, poor social interaction, and sensory hypersensitivity. Physical examination revealed mild dysmorphic features, including hypertelorism, a flattened nasal bridge with upturned nostrils and ankyloglossia. Brain MRI was normal, and no seizures were reported.\u003c/p\u003e\u003cp\u003eWhole-exome sequencing identified a heterozygous nonsense variant c.736G \u0026gt; T in the \u003cem\u003eCHAMP1\u003c/em\u003e gene (exon 3), predicted to introduce a premature stop codon at position 246 (p.Glu246*). This alteration is expected to result in either a truncated or absent protein product. The variant is absent from population databases (dbSNP, gnomAD), has no previous reports in ClinVar or medical literature, and is classified as likely pathogenic according to ACMG criteria. This mutation leads to haploinsufficiency of CHAMP1, reducing protein expression below the level required for normal neurodevelopment, consistent with the diagnosis of intellectual developmental disorder type 40 (MIM #616579). Table\u0026nbsp;1\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThese cases illustrate how disruptions in distinct molecular pathways can result in overlapping neurodevelopmental phenotypes. The \u003cem\u003eGNAI1\u003c/em\u003e gene (NM_002069) encodes the G protein α-subunit, essential for intracellular signaling and neuronal differentiation. Pathogenic variants disrupt G-protein signaling, leading to widespread neurodevelopmental impairment (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Conversely, \u003cem\u003eCHAMP1\u003c/em\u003e encodes a chromosome alignment\u0026ndash;maintaining protein involved in chromatin organization and neuronal development. Haploinsufficiency of \u003cem\u003eCHAMP1\u003c/em\u003e reduces protein expression by approximately 50%, impairing normal neurogenesis and resulting in intellectual developmental disorder type 40 (MIM #616579) (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eDespite their distinct molecular origins, both conditions converge phenotypically in early hypotonia, global developmental delay, and profound speech impairment. This highlights how monogenic neurodevelopmental disorders may share common clinical hallmarks that obscure their underlying genetic heterogeneity.\u003c/p\u003e\u003cp\u003eIn the \u003cem\u003eGNAI1\u003c/em\u003e case, the presentation was dominated by axial hypotonia and distal hypertonia with spasticity and dystonia, but without behavioral abnormalities or epilepsy, thus mimicking a chronic non-progressive encephalopathy such as dystonic\u0026ndash;spastic cerebral palsy. The absence of a clear perinatal insult and only mild neuroimaging abnormalities suggested a genetic etiology. Notably, the identified variant has been previously reported as pathogenic and associated with global developmental delay, though dystonia and spasticity, as observed here, have not been described.\u003c/p\u003e\u003cp\u003eIn contrast, the \u003cem\u003eCHAMP1\u003c/em\u003e case exhibited early hypotonia and mild motor delay, followed by social and communication deficits consistent with classic autism spectrum disorder, preserved ambulation, and no seizures.\u003c/p\u003e\u003cp\u003eOur report expands the phenotypic spectrum of \u003cem\u003eGNAI1\u003c/em\u003e- and \u003cem\u003eCHAMP1\u003c/em\u003e-related neurodevelopmental disorders. Although both patients presented with early hypotonia and absent speech, their divergent motor and behavioral trajectories reflect distinct pathogenic mechanisms.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eWhole-exome sequencing should be considered early in children with unexplained motor and speech delay, even in the absence of epilepsy or structural brain abnormalities, as it prevents misdiagnosis, guides prognosis, informs genetic counseling, and supports future gene-targeted therapeutic approaches.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflicts of interests:\u003c/strong\u003e The author declare that there is no conflict of interests regarding the publication of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatient Consent:\u003c/strong\u003e Written informed consent for publication of these cases report and any accompanying images was obtained from the patient\u0026rsquo;s legal guardians.\u0026nbsp;\u003c/p\u003e\n\u003ch3\u003e\u003cstrong\u003eFunding Declaration\u003c/strong\u003e\u003c/h3\u003e\n\u003cp\u003eNo funding was received for the preparation of this manuscript.\u003c/p\u003e\n\u003ch3\u003e\u003cstrong\u003eClinical Trial Number\u003c/strong\u003e\u003c/h3\u003e\n\u003cp\u003eClinical trial number: not applicable.\u003c/p\u003e\n\u003ch3\u003e\u003cstrong\u003eEthics and Consent to Participate\u003c/strong\u003e\u003c/h3\u003e\n\u003cp\u003eEthics and consent to participate declarations: not applicable.\u003c/p\u003e\n\u003cp\u003eWritten informed consent for publication of the clinical details was obtained from the patients\u0026rsquo; legal guardians.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eNeed AC, Shashi V, Hitomi Y et al (2012) Clinical application of exome sequencing in undiagnosed genetic conditions. J Med Genet 49(6):353\u0026ndash;361\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDeciphering Developmental Disorders Study (2017) Prevalence and architecture of de novo mutations in developmental disorders. Nature 542(7642):433\u0026ndash;438\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMuir AM, Gardner JF, van Jaarsveld RH et al (2021) Variants in \u003cem\u003eGNAI1\u003c/em\u003e cause a syndrome associated with variable features including developmental delay, seizures, and hypotonia. Genet Med 23(5):881\u0026ndash;887\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJansen S et al (2021) Clinical delineation of \u003cem\u003eCHAMP1\u003c/em\u003e-associated intellectual disability and insights into pathogenic mechanisms. Am J Med Genet A 185(11):3384\u0026ndash;3394\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePopoola DO et al (2022) \u003cem\u003eCHAMP1\u003c/em\u003e-related neurodevelopmental disorder: clinical spectrum and molecular insights. Eur J Med Genet 65(6):104538\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo","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":"Neurodevelopmental disorder, GNAI1, CHAMP1, hypotonia, developmental delay, speech impairment, whole-exome sequencing","lastPublishedDoi":"10.21203/rs.3.rs-8242970/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8242970/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\u003eNeurodevelopmental disorders (NDDs) comprise a genetically heterogeneous group of conditions characterized by global developmental delay, epilepsy and behavioral abnormalities. Advances in next-generation sequencing have expanded the number of genes implicated in NDDs, including \u003cem\u003eGNAI1\u003c/em\u003e and \u003cem\u003eCHAMP1\u003c/em\u003e, which act through distinct molecular pathways yet may produce overlapping phenotypes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase Presentation:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe describe two unrelated boys with severe developmental delay and hypotonia but without epilepsy. Case 1 involved a 4-year-old with marked axial hypotonia and distal hypertonia mimicking dystonic–spastic cerebral palsy. Whole-exome sequencing identified a de novo heterozygous \u003cem\u003eGNAI1\u003c/em\u003e variant (c.118G \u0026gt; C; p.Gly40Arg). Case 2 involved a 6-year-old with global hypotonia, autistic features, and mild dysmorphism who achieved independent walking. Exome analysis revealed a novel heterozygous nonsense \u003cem\u003eCHAMP1\u003c/em\u003e variant (c.736G \u0026gt; T; p.Glu246*), not previously reported in ClinVar or gnomAD. In both cases, speech was absent. \u003cstrong\u003eConclusions\u003c/strong\u003e: Despite distinct molecular mechanisms—impaired G-protein signaling in \u003cem\u003eGNAI1\u003c/em\u003e and haploinsufficiency in \u003cem\u003eCHAMP1\u003c/em\u003e—both cases shared early hypotonia, developmental delay, and absent speech. These cases expand the clinical spectrum of \u003cem\u003eGNAI1\u003c/em\u003e- and \u003cem\u003eCHAMP1\u003c/em\u003e-related disorders and underscore the importance of early genomic investigation in children with unexplained developmental delay, even in the absence of epilepsy or structural brain abnormalities\u003c/p\u003e","manuscriptTitle":"Distinct genetic etiologies with overlapping neurodevelopmental phenotypes: a two-case series involving GNAI1 and CHAMP1 variants","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-02 12:15:41","doi":"10.21203/rs.3.rs-8242970/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":"0ae6a595-707e-4deb-90a0-cd497fc844a1","owner":[],"postedDate":"December 2nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":58842725,"name":"Medical Genetics"}],"tags":[],"updatedAt":"2025-12-02T12:15:42+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-02 12:15:41","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8242970","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8242970","identity":"rs-8242970","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}