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Pediatr Neurol. 2014 Dec;51(6):806-813.e8. doi: 10.1016/j.pediatrneurol.2014.08.025. Epub 2014 Sep 4.

Brain malformations associated with Knobloch syndrome--review of literature, expanding clinical spectrum, and identification of novel mutations.

Author information

1
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.
2
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.
3
Department of Pediatrics, Diyarbakir State Hospital, Diyarbakir, Turkey.
4
Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, Connecticut.
5
Division of Genetics, Department of Pediatrics, Istanbul University, Cerrahpasa Faculty of Medicine, Istanbul, Turkey.
6
Department of Neurosurgery, Bahcesehir University, Istanbul, Turkey; Department of Neurosurgery, Medical Park Hospital, Gaziantep, Turkey.
7
Department of Neurosurgery, Sevket Yilmaz Education and Research Hospital, Bursa, Turkey.
8
Department of Genetics and Bioinformatics, Bahcesehir University, Istanbul, Turkey.
9
Department of Neurology, Akdeniz University Medical Faculty, Antalya, Turkey.
10
Department of Ophthalmology, Faculty of Medicine, Dicle University, Diyarbakir, Turkey.
11
Department of Radiology, Medical Park Hospital, Gaziantep, Turkey.
12
Department of Pediatrics, Yuzuncu Yil University, Van, Turkey.
13
Department of Radiology, Istanbul Medeniyet University Göztepe Education and Research Hospital, Istanbul, Turkey.
14
Department of Pediatrics, Istanbul University, Istanbul Medical Faculty, Istanbul, Turkey.
15
Department of Radiology, Yale School of Medicine, New Haven, Connecticut.
16
Department of Genetics, Yale School of Medicine, New Haven, Connecticut; Yale Center for Genome Analysis, Orange, Connecticut.
17
Department of Pediatrics, Necmettin Erbakan University, Meram Medical Faculty, Konya, Turkey.

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.

KEYWORDS:

COL18A1; Knobloch syndrome; collagen XVIII; cortical development; whole-exome sequencing

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