title: Brain malformations associated with Knobloch syndrome--review of literature, expanding clinical spectrum, and identification of novel mutations.
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.
authors.affiliation: Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut; Department of Neurobiology, Yale School of Medicine, New Haven, Connecticut; Department of Genetics, Yale School of Medicine, New Haven, Connecticut. Electronic address: ahmet.caglayan@yale.edu.
authors.forename: Ahmet Okay
authors.initials: AO
authors.lastname: Caglayan
authors.affiliation: Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut; Department of Neurobiology, Yale School of Medicine, New Haven, Connecticut; Department of Genetics, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Jacob F
authors.initials: JF
authors.lastname: Baranoski
authors.affiliation: Department of Pediatrics, Diyarbakir State Hospital, Diyarbakir, Turkey.
authors.forename: Fesih
authors.initials: F
authors.lastname: Aktar
authors.affiliation: Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Wengi
authors.initials: W
authors.lastname: Han
authors.affiliation: Division of Genetics, Department of Pediatrics, Istanbul University, Cerrahpasa Faculty of Medicine, Istanbul, Turkey.
authors.forename: Beyhan
authors.initials: B
authors.lastname: Tuysuz
authors.affiliation: Department of Neurosurgery, Bahcesehir University, Istanbul, Turkey; Department of Neurosurgery, Medical Park Hospital, Gaziantep, Turkey.
authors.forename: Aslan
authors.initials: A
authors.lastname: Guzel
authors.affiliation: Department of Neurosurgery, Sevket Yilmaz Education and Research Hospital, Bursa, Turkey.
authors.forename: Bulent
authors.initials: B
authors.lastname: Guclu
authors.affiliation: Department of Genetics and Bioinformatics, Bahcesehir University, Istanbul, Turkey.
authors.forename: Hande
authors.initials: H
authors.lastname: Kaymakcalan
authors.affiliation: Department of Neurology, Akdeniz University Medical Faculty, Antalya, Turkey.
authors.forename: Berrin
authors.initials: B
authors.lastname: Aktekin
authors.affiliation: Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut; Department of Neurobiology, Yale School of Medicine, New Haven, Connecticut; Department of Genetics, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Gozde Tugce
authors.initials: GT
authors.lastname: Akgumus
authors.affiliation: Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut; Department of Neurobiology, Yale School of Medicine, New Haven, Connecticut; Department of Genetics, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Phillip B
authors.initials: PB
authors.lastname: Murray
authors.affiliation: Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut; Department of Neurobiology, Yale School of Medicine, New Haven, Connecticut; Department of Genetics, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Emine Z
authors.initials: EZ
authors.lastname: Erson-Omay
authors.affiliation: Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut; Department of Neurobiology, Yale School of Medicine, New Haven, Connecticut; Department of Genetics, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Caner
authors.initials: C
authors.lastname: Caglar
authors.affiliation: Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut; Department of Neurobiology, Yale School of Medicine, New Haven, Connecticut; Department of Genetics, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Mehmet
authors.initials: M
authors.lastname: Bakircioglu
authors.affiliation: Department of Ophthalmology, Faculty of Medicine, Dicle University, Diyarbakir, Turkey.
authors.forename: Yildirim Bayezit
authors.initials: YB
authors.lastname: Sakalar
authors.affiliation: Department of Radiology, Medical Park Hospital, Gaziantep, Turkey.
authors.forename: Ebru
authors.initials: E
authors.lastname: Guzel
authors.affiliation: Department of Pediatrics, Yuzuncu Yil University, Van, Turkey.
authors.forename: Nihat
authors.initials: N
authors.lastname: Demir
authors.affiliation: Department of Pediatrics, Yuzuncu Yil University, Van, Turkey.
authors.forename: Oguz
authors.initials: O
authors.lastname: Tuncer
authors.affiliation: Department of Radiology, Istanbul Medeniyet University Göztepe Education and Research Hospital, Istanbul, Turkey.
authors.forename: Senem
authors.initials: S
authors.lastname: Senturk
authors.affiliation: Department of Pediatrics, Istanbul University, Istanbul Medical Faculty, Istanbul, Turkey.
authors.forename: Baris
authors.initials: B
authors.lastname: Ekici
authors.affiliation: Department of Radiology, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Minja
authors.affiliation: Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, Connecticut.
authors.forename: Nenad
authors.initials: N
authors.lastname: Šestan
authors.affiliation: Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut; Department of Neurobiology, Yale School of Medicine, New Haven, Connecticut; Department of Genetics, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Katsuhito
authors.initials: K
authors.lastname: Yasuno
authors.affiliation: Department of Genetics, Yale School of Medicine, New Haven, Connecticut; Yale Center for Genome Analysis, Orange, Connecticut.
authors.forename: Kaya
authors.initials: K
authors.lastname: Bilguvar
authors.affiliation: Department of Pediatrics, Necmettin Erbakan University, Meram Medical Faculty, Konya, Turkey.
authors.forename: Huseyin
authors.initials: H
authors.lastname: Caksen
authors.affiliation: Department of Neurosurgery, Yale School of Medicine, New Haven, Connecticut; Department of Neurobiology, Yale School of Medicine, New Haven, Connecticut; Department of Genetics, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Murat
authors.initials: M
authors.lastname: Gunel
mesh_terms: D000293:Adolescent; D000328:Adult; D002540:Cerebral Cortex / Q000196:embryology / Q000254:growth & development / Q000378:metabolism*; D043170:Collagen Type XVIII / Q000235:genetics*; D003241:Consanguinity; D004677:Encephalocele / Q000235:genetics* / Q000473:pathology*; D059472:Exome / Q000235:genetics*; D005260:Female; D005333:Fetus; D006801:Humans; D008297:Male; D009154:Mutation; D012162:Retinal Degeneration; D012163:Retinal Detachment / Q000151:congenital* / Q000235:genetics / Q000473:pathology; D055815:Young Adult
chemical_list: D043170:Collagen Type XVIII
keywords: COL18A1; Knobloch syndrome; collagen XVIII; cortical development; whole-exome sequencing