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Brain Malformations Associated With Knobloch Syndrome-Review of Literature, Expanding Clinical Spectrum, and Identification of Novel Mutations

dc.authorid Akgumus, Gozde/0000-0002-7410-8650
dc.authorid Caglar, Caner/0000-0002-5857-757X
dc.authorid Yasuno, Katsuhito/0000-0002-3606-532X
dc.authorid Demir, Nihat/0000-0003-3287-7221
dc.authorid Caglayan, Ahmet/0000-0002-2332-322X
dc.authorid Tuysuz, Beyhan/0000-0002-9620-5021
dc.authorid Kaymakcalan, Hande/0000-0001-7736-7634
dc.authorscopusid 16641940600
dc.authorscopusid 57216453016
dc.authorscopusid 35118690700
dc.authorscopusid 56428348600
dc.authorscopusid 7004016164
dc.authorscopusid 8943306800
dc.authorscopusid 7101974609
dc.authorwosid Bilguvar, Kaya/Kmy-5763-2024
dc.authorwosid Demi̇r, Ni̇hat/Gry-3625-2022
dc.authorwosid Kaymakcalan Celebiler, Hande/Afp-2191-2022
dc.authorwosid Caglayan, Ahmet/D-1066-2012
dc.authorwosid Guclu, Bulent/Itu-7284-2023
dc.authorwosid Caglar, Caner/Abe-5815-2021
dc.authorwosid Yasuno, Katsuhito/E-1960-2012
dc.contributor.author Caglayan, Ahmet Okay
dc.contributor.author Baranoski, Jacob E.
dc.contributor.author Aktar, Fesih
dc.contributor.author Han, Wengi
dc.contributor.author Tuysuz, Beyhan
dc.contributor.author Guzel, Asian
dc.contributor.author Gunel, Murat
dc.date.accessioned 2025-05-10T17:43:04Z
dc.date.available 2025-05-10T17:43:04Z
dc.date.issued 2014
dc.department T.C. Van Yüzüncü Yıl Üniversitesi en_US
dc.department-temp [Caglayan, Ahmet Okay; Baranoski, Jacob E.; Akgumus, Gozde Tugce; Murray, Phillip B.; Erson-Omay, Emine Z.; Caglar, Caner; Bakircioglu, Mehmet; Yasuno, Katsuhito; Gunel, Murat] Yale Univ, Sch Med, Dept Neurosurg, New Haven, CT 06510 USA; [Caglayan, Ahmet Okay; Baranoski, Jacob E.; Akgumus, Gozde Tugce; Murray, Phillip B.; Erson-Omay, Emine Z.; Caglar, Caner; Bakircioglu, Mehmet; Yasuno, Katsuhito; Gunel, Murat] Yale Univ, Sch Med, Dept Neurobiol, New Haven, CT 06510 USA; [Caglayan, Ahmet Okay; Baranoski, Jacob E.; Akgumus, Gozde Tugce; Murray, Phillip B.; Erson-Omay, Emine Z.; Caglar, Caner; Bakircioglu, Mehmet; Yasuno, Katsuhito; Bilguvar, Kaya; Gunel, Murat] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA; [Aktar, Fesih] Diyarbakir State Hosp, Dept Pediat, Diyarbakir, Turkey; [Han, Wengi; Sestan, Nenad] Yale Univ, Sch Med, Kavli Inst Neurosci, New Haven, CT 06510 USA; [Tuysuz, Beyhan] Istanbul Univ, Dept Pediat, Div Genet, Cerrahpasa Fac Med, Istanbul, Turkey; [Guzel, Asian] Bahcesehir Univ, Dept Neurosurg, Istanbul, Turkey; [Guzel, Asian] Med Pk Hosp, Dept Neurosurg, Gaziantep, Turkey; [Guclu, Bulent] Sevket Yilmaz Educ & Res Hosp, Dept Neurosurg, Bursa, Turkey; [Kaymakcalan, Hande] Bahcesehir Univ, Dept Genet & Bioinformat, Istanbul, Turkey; [Aktekin, Berrin] Akdeniz Univ, Fac Med, Dept Neurol, TR-07058 Antalya, Turkey; [Sakalar, Yildirim Bayezit] Dicle Univ, Fac Med, Dept Ophthalmol, Diyarbakir, Turkey; [Guzel, Ebru] Med Pk Hosp, Dept Radiol, Gaziantep, Turkey; [Demir, Nihat; Tuncer, Oguz] Yuzuncu Yil Univ, Dept Pediat, Van, Turkey; [Senturk, Senem] Istanbul Medeniyet Univ, Goztepe Educ & Res Hosp, Dept Radiol, Istanbul, Turkey; [Ekici, Saris] Istanbul Univ, Fac Med, Dept Pediat, Istanbul, Turkey; [Minja, Frank J.] Yale Univ, Sch Med, Dept Radiol, New Haven, CT 06510 USA; [Bilguvar, Kaya] Yale Ctr Genome Anal, Orange, CA USA; [Caksen, Huseyin] Necmettin Erbakan Univ, Meram Med Fac, Dept Pediat, Konya, Turkey en_US
dc.description Akgumus, Gozde/0000-0002-7410-8650; Caglar, Caner/0000-0002-5857-757X; Yasuno, Katsuhito/0000-0002-3606-532X; Demir, Nihat/0000-0003-3287-7221; Caglayan, Ahmet/0000-0002-2332-322X; Tuysuz, Beyhan/0000-0002-9620-5021; Kaymakcalan, Hande/0000-0001-7736-7634 en_US
dc.description.abstract Background: Knobloch syndrome is a rare, autosomal recessive, developmental disorder characterized by stereotyped ocular abnormalities with or without occipital skull deformities (encephalocele, bone defects, and cutis aplasia). Although there is clear heterogeneity in clinical presentation, central nervous system malformations, aside from the characteristic encephalocele, have not typically been considered a component of the disease phenotype. METHODS: Four patients originally presented for genetic evaluation of symptomatic structural brain malformations. Whole-genome genotyping, whole-exome sequencing, and confirmatory Sanger sequencing were performed. Using immunohistochemical analysis, we investigated the protein expression pattern of COL18A1 in the mid-fetal and adult human cerebral cortex and then analyzed the spatial and temporal changes in the expression pattern of COL18A1 during human cortical development using the Human Brain Transcriptome database. RESULTS: We identified two novel homozygous deleterious frame-shift mutations in the COL18A1 gene. On further investigation of these patients and their families, we found that many exhibited certain characteristics of Knobloch syndrome, including pronounced ocular defects. Our data strongly support an important role for COL18A1 in brain development, and this report contributes to an enhanced characterization of the brain malformations that can result from deficiencies of collagen XVIII. CONCLUSIONS: This case series highlights the diagnostic power and clinical utility of whole-exome sequencing technology allowing clinicians and physician scientists to better understand the pathophysiology and presentations of rare diseases. We suggest that patients who are clinically diagnosed with Knobloch syndrome and/or found to have COL18A1. mutations via genetic screening should be investigated for potential structural brain abnormalities even in the absence of an encephalocele. en_US
dc.description.sponsorship Yale Program on Neurogenetics and National Institutes of Health [RC2 NS070477, U01MH081896]; Yale Center for Mendelian Disorders [U54HG006504]; Howard Hughes Medical Institute; Gregory M. Kiez and Mehmet Kutman Foundation; Scientific and Technological Research Council of Turkey [2219] en_US
dc.description.sponsorship The authors thank the patients and their families for participating in this study. The authors thank Angeliki Louvi, PhD for her contribution in editing the manuscript. This work was supported by the Yale Program on Neurogenetics and National Institutes of Health grants (RC2 NS070477 to M.G., U01MH081896 to N.S.), the Yale Center for Mendelian Disorders (U54HG006504 to R.P. Lifton, KG., M. Gerstein, and S. Mane), the Howard Hughes Medical Institute (to W.H.), Gregory M. Kiez and Mehmet Kutman Foundation [to M.G.], and The Scientific and Technological Research Council of Turkey [2219 to A.O.C.]. en_US
dc.description.woscitationindex Science Citation Index Expanded
dc.identifier.doi 10.1016/j.pediatrneurol.2014.08.025
dc.identifier.endpage 813 en_US
dc.identifier.issn 0887-8994
dc.identifier.issn 1873-5150
dc.identifier.issue 6 en_US
dc.identifier.pmid 25456301
dc.identifier.scopus 2-s2.0-84912083992
dc.identifier.scopusquality Q2
dc.identifier.startpage 806 en_US
dc.identifier.uri https://doi.org/10.1016/j.pediatrneurol.2014.08.025
dc.identifier.uri https://hdl.handle.net/20.500.14720/15744
dc.identifier.volume 51 en_US
dc.identifier.wos WOS:000346113900010
dc.identifier.wosquality Q1
dc.language.iso en en_US
dc.publisher Elsevier Science inc en_US
dc.relation.publicationcategory Makale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı en_US
dc.rights info:eu-repo/semantics/openAccess en_US
dc.subject Knobloch Syndrome en_US
dc.subject Cortical Development en_US
dc.subject Col18A1 en_US
dc.subject Collagen Xviii en_US
dc.subject Whole-Exome Sequencing en_US
dc.title Brain Malformations Associated With Knobloch Syndrome-Review of Literature, Expanding Clinical Spectrum, and Identification of Novel Mutations en_US
dc.type Article en_US

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