Identification of a new frameshift homozygous variant of PEX3 gene in a preterm infant with profound global developmental delay and bilateral ptosis: a case report and update literature review

Identification of a new frameshift homozygous variant of PEX3 gene in a preterm infant with profound global developmental delay and bilateral ptosis: a case report and update literature review | 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 Identification of a new frameshift homozygous variant of PEX3 gene in a preterm infant with profound global developmental delay and bilateral ptosis: a case report and update literature review Jinfeng Su, Yingbo Tao, Lian Zhang, Jun Luo This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4785114/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 06 Jan, 2026 Read the published version in BMC Pediatrics → Version 1 posted 14 You are reading this latest preprint version Abstract Background Loss-of-function mutations in PEX3 have been associated with Zellweger syndrome (ZS), a severe form of peroxisome biogenesis disorders (PBD, OMIM: 601539) characterized by significant global developmental delay, muscle weakness with bilateral ptosis, cholestasis, hypotonia, and seizures. ZS can be life-threatening if manifested in the neonatal period. Case presentation This study presents a unique case of a male infant with severe ZS whose condition deteriorated despite intensive supportive treatment. Through whole exome sequencing, an intronic variant NM 003630.2:c.288-10T>A, located 10 nucleotides before exon 4 of the PEX3 gene, was identified. Sanger sequencing revealed a homozygous variant in the infant and a heterozygous variant in both parents. Further analysis using reverse transcription-polymerase chain reaction (RT-PCR) and immunofluorescence confirmed the abnormal transcript of the PEX3 gene caused by a frameshift variant resulting from the PEX3 gene c.288-10T>A mutation. This modification led to a splicing error that deleted exon 4, causing a direct splicing of exons 3 and 5. This alteration produced a truncated protein comprising 32 incorrect amino acids. Conclusions We here report the first case of severe Zellweger spectrum disorders (ZSDs) due to the PEX3 [c.288-10T>A: p.F97Pfs*33] variant in China. This study broadens the known range of severe ZSDs due to PEX3 pathogenic variants. peroxisome biogenesis disorder PEX3 Zellweger syndrome newborn whole exome sequencing Full Text Additional Declarations No competing interests reported. Supplementary Files FiguresS1.pptx Supplementary Fig1. Frameshift mutation results in abnormal termination of PEX3. (A) Comparison of PEX3 protein sequences between a healthy individual and the patient, with consensus sequences highlighted in pink. (B) The absence of exon 4 led to a distinct amino acid sequence of PEX3 in the patient, with the red asterisk indicating the incorrect end of translation. FiguresS2.pptx Supplementary Fig2. The developmental delay in the proband is evident on the Fenton Preterm growth chart. FiguresS3.pptx Supplementary Fig 3. Alterations in hepatic and renal function of the proband within a 3-month period. DBIL findings in (A). (B) ALT results. (C) BUN results. (D) AFP results. FiguresS4.pptx Supplementary Fig 4. EEG characteristics. Sleep and wake EEGs showed middle- to high-amplitude sharp waves and sharp slow waves in the bilateral temporal regions. Interictal EEGs displayed two focal myoclonic seizures during sleep. (A-D) The arrow indicates the EEG waveform during the seizure. PEX3gelfulluncroppedGelsandBlotsimages.tif Cite Share Download PDF Status: Published Journal Publication published 06 Jan, 2026 Read the published version in BMC Pediatrics → Version 1 posted Editorial decision: Revision requested 30 Oct, 2025 Reviews received at journal 28 Oct, 2025 Reviews received at journal 22 Oct, 2025 Reviewers agreed at journal 12 Oct, 2025 Reviewers agreed at journal 10 Oct, 2025 Reviews received at journal 28 Aug, 2025 Reviewers agreed at journal 08 Aug, 2025 Reviews received at journal 12 Sep, 2024 Reviewers agreed at journal 05 Sep, 2024 Reviewers invited by journal 02 Sep, 2024 Editor invited by journal 31 Jul, 2024 Editor assigned by journal 30 Jul, 2024 Submission checks completed at journal 30 Jul, 2024 First submitted to journal 22 Jul, 2024 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-4785114","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":344774122,"identity":"48a76056-7677-4c68-bf2b-8af9bdd1035d","order_by":0,"name":"Jinfeng Su","email":"","orcid":"","institution":"Shenzhen Baoan Women’s and Children’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Jinfeng","middleName":"","lastName":"Su","suffix":""},{"id":344774123,"identity":"4f7d3e83-d2c3-42aa-9cf4-b820f0652ad7","order_by":1,"name":"Yingbo Tao","email":"","orcid":"","institution":"Shenzhen Baoan Women’s and Children’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yingbo","middleName":"","lastName":"Tao","suffix":""},{"id":344774124,"identity":"b9ea7aff-87b2-4c1c-bbe5-ae09bd708c06","order_by":2,"name":"Lian Zhang","email":"","orcid":"","institution":"Shenzhen Baoan Women’s and Children’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Lian","middleName":"","lastName":"Zhang","suffix":""},{"id":344774125,"identity":"8d1d2932-f6eb-4e13-ac9e-57cf4a8f501f","order_by":3,"name":"Jun Luo","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAwUlEQVRIiWNgGAWjYBACPiA2AOL6fvbGxocfiNHCBtXCOLPncLOxBLFaQIBxw430NgEeorRIJB8o5t3BwCw582EbgwSDnZxuA0EtaQnGvGcY2PilE9seFDAkG5sdIKglx8CYt+0/j+TsxHYDCYYDiduI1MIgYXDzYJsEDylaDAxuMBKrhedZguHcNoYEyZ5EYCAbEOEXfvbkYwZvgVr42Y8/fPihwk6OoBaQRQYItgFuZciA+QFx6kbBKBgFo2DEAgC4cDloYbmGPQAAAABJRU5ErkJggg==","orcid":"","institution":"Shenzhen Baoan Women’s and Children’s Hospital","correspondingAuthor":true,"prefix":"","firstName":"Jun","middleName":"","lastName":"Luo","suffix":""}],"badges":[],"createdAt":"2024-07-23 02:38:57","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4785114/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4785114/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12887-025-06472-0","type":"published","date":"2026-01-06T15:58:35+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":100069347,"identity":"aba6cfc7-b3c2-4c8a-92f1-efcb722eea33","added_by":"auto","created_at":"2026-01-12 16:13:07","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1380954,"visible":true,"origin":"","legend":"","description":"","filename":"PEX3manuscript7.30.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4785114/v1_covered_8a679435-9e5f-4aee-b462-84b43c6c776b.pdf"},{"id":63237092,"identity":"b7d59a48-a785-4dbe-9ccf-3a5093e715d0","added_by":"auto","created_at":"2024-08-26 03:24:28","extension":"pptx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":494084,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Fig1.\u003c/strong\u003e \u003cstrong\u003eFrameshift mutation results in abnormal termination of PEX3.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e(A) Comparison of PEX3 protein sequences between a healthy individual and the patient, with consensus sequences highlighted in pink.\u003c/p\u003e\n\u003cp\u003e(B) The absence of exon 4 led to a distinct amino acid sequence of PEX3 in the patient, with the red asterisk indicating the incorrect end of translation.\u003c/p\u003e","description":"","filename":"FiguresS1.pptx","url":"https://assets-eu.researchsquare.com/files/rs-4785114/v1/16b8b4ec8b18f07d009fdb13.pptx"},{"id":63237091,"identity":"b2c48eac-10dc-449c-a4cc-9ded554ccd90","added_by":"auto","created_at":"2024-08-26 03:24:28","extension":"pptx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":647705,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Fig2.\u003c/strong\u003e \u003cstrong\u003eThe developmental delay in the proband is evident on the Fenton Preterm growth chart.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"FiguresS2.pptx","url":"https://assets-eu.researchsquare.com/files/rs-4785114/v1/1c98ab8d9430be3dfafc0371.pptx"},{"id":63237089,"identity":"3f0ee406-f25c-4aa7-9f82-97ef31cd3ae1","added_by":"auto","created_at":"2024-08-26 03:24:28","extension":"pptx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":122753,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Fig 3.\u003c/strong\u003e \u003cstrong\u003eAlterations in hepatic and renal function of the proband within a 3-month period. \u003c/strong\u003eDBIL findings in (A). (B) ALT results. (C) BUN results. (D) AFP results.\u003c/p\u003e","description":"","filename":"FiguresS3.pptx","url":"https://assets-eu.researchsquare.com/files/rs-4785114/v1/6ea014b100d90358d563e473.pptx"},{"id":63237090,"identity":"cfaaf4ba-ac76-4a9d-9641-4aa6936fd6a9","added_by":"auto","created_at":"2024-08-26 03:24:28","extension":"pptx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":461722,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Fig 4.\u003c/strong\u003e \u003cstrong\u003eEEG characteristics.\u003c/strong\u003e Sleep and wake EEGs showed middle- to high-amplitude sharp waves and sharp slow waves in the bilateral temporal regions. Interictal EEGs displayed two focal myoclonic seizures during sleep. (A-D) The arrow indicates the EEG waveform during the seizure.\u003c/p\u003e","description":"","filename":"FiguresS4.pptx","url":"https://assets-eu.researchsquare.com/files/rs-4785114/v1/1a8c18c24ac2f0e044e21b3d.pptx"},{"id":63237094,"identity":"927989fe-ddbd-47ba-9705-d9050ad1e561","added_by":"auto","created_at":"2024-08-26 03:24:28","extension":"tif","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":2901992,"visible":true,"origin":"","legend":"","description":"","filename":"PEX3gelfulluncroppedGelsandBlotsimages.tif","url":"https://assets-eu.researchsquare.com/files/rs-4785114/v1/2af75c22e5acc94fa25d5e5e.tif"}],"financialInterests":"No competing interests reported.","formattedTitle":"Identification of a new frameshift homozygous variant of PEX3 gene in a preterm infant with profound global developmental delay and bilateral ptosis: a case report and update literature review","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"peroxisome biogenesis disorder, PEX3, Zellweger syndrome, newborn, whole exome sequencing","lastPublishedDoi":"10.21203/rs.3.rs-4785114/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4785114/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground \u003c/strong\u003eLoss-of-function mutations in \u003cem\u003ePEX3\u003c/em\u003e have been associated with Zellweger syndrome (ZS), a severe form of peroxisome biogenesis disorders (PBD, OMIM: 601539) characterized by significant global developmental delay, muscle weakness with bilateral ptosis, cholestasis, hypotonia, and seizures. ZS can be life-threatening if manifested in the neonatal period.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase presentation\u003c/strong\u003e This study presents a unique case of a male infant with severe ZS whose condition deteriorated despite intensive supportive treatment. Through whole exome sequencing, an intronic variant NM 003630.2:c.288-10T\u0026gt;A, located 10 nucleotides before exon 4 of the \u003cem\u003ePEX3\u003c/em\u003e gene, was identified. Sanger sequencing revealed a homozygous variant in the infant and a heterozygous variant in both parents. Further analysis using reverse transcription-polymerase chain reaction (RT-PCR) and immunofluorescence confirmed the abnormal transcript of the \u003cem\u003ePEX3\u003c/em\u003egene caused by a frameshift variant resulting from the \u003cem\u003ePEX3\u003c/em\u003e gene c.288-10T\u0026gt;A mutation. This modification led to a splicing error that deleted exon 4, causing a direct splicing of exons 3 and 5. This alteration produced a truncated protein comprising 32 incorrect amino acids.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e We here report the first case of severe Zellweger spectrum disorders (ZSDs) due to the \u003cem\u003ePEX3\u003c/em\u003e [c.288-10T\u0026gt;A: p.F97Pfs*33] variant in China. This study broadens the known range of severe ZSDs due to \u003cem\u003ePEX3\u003c/em\u003e pathogenic variants.\u003c/p\u003e","manuscriptTitle":"Identification of a new frameshift homozygous variant of PEX3 gene in a preterm infant with profound global developmental delay and bilateral ptosis: a case report and update literature review","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-26 03:24:23","doi":"10.21203/rs.3.rs-4785114/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-10-30T19:46:09+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-28T14:25:03+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-22T19:08:30+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"59130499805874178559447790688760359810","date":"2025-10-12T14:28:30+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"149401222211831530800475082347210072686","date":"2025-10-10T13:32:16+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-28T09:03:55+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"53425615964627765689108810169204249974","date":"2025-08-08T08:21:26+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-09-12T12:09:17+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"47784693581623570946231480507071568615","date":"2024-09-05T06:05:29+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-09-02T17:58:34+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-07-31T05:14:34+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-07-30T11:36:56+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-07-30T11:36:45+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pediatrics","date":"2024-07-23T02:37:34+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"38cdae5e-4b05-4752-b8ff-177aaa23cbf4","owner":[],"postedDate":"August 26th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-01-12T16:04:49+00:00","versionOfRecord":{"articleIdentity":"rs-4785114","link":"https://doi.org/10.1186/s12887-025-06472-0","journal":{"identity":"bmc-pediatrics","isVorOnly":false,"title":"BMC Pediatrics"},"publishedOn":"2026-01-06 15:58:35","publishedOnDateReadable":"January 6th, 2026"},"versionCreatedAt":"2024-08-26 03:24:23","video":"","vorDoi":"10.1186/s12887-025-06472-0","vorDoiUrl":"https://doi.org/10.1186/s12887-025-06472-0","workflowStages":[]},"version":"v1","identity":"rs-4785114","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4785114","identity":"rs-4785114","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}