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.

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

Figure 1

MRI findings for our 4 patients and schematic representation of the COL18A1 gene and the mutation locations were given. For each mutation, representative chromatographs obtained via Sanger sequencing analysis of COL18A1 patients. A) Panels left and right – Axial T1- and T2-weighted images respectively, of patient NG133-1 demonstrating polymicrogyria of the bilateral frontal lobes and evidence of vitreo-retinal degeneration in the left eye globe with phthisis bulbi in the right eye globe, respectively. B) Panels left and right – Axial T1-weighted and coronal T2-weighted images respectively, of patient NG1348-1 demonstrating polymicrogyria involving the bilateral frontal and parietal lobes. C) Panels left and right – Axial T1-weighted images of patient NG1426-1 indicating polymicrogyria in the bilateral frontal lobes. D) Panels left and right – Axial and sagittal T1-weighted images respectively, of NG159-2 illustrating a Dandy-Walker Malformation (cerebellar vermian atrophy). There is also an occipital bony defect present without any visible herniation of the meninges or brain parenchyma. E) Schematic representation of the COL18A1 gene and the mutations identified in the described patients.

Figure 2

In the mid-fetal (A) and adult (B) human cerebral cortex, COL18A1 protein is expressed in the pia (arrow heads) as well as the blood vessels (arrows). In the mouse embryo (C), mouse Col1Ba1 mRNA is also highly expressed in the pia and blood vessels within the cerebral cortex. Mouse images were obtained from the publicly available Allen Developing Mouse Brain Atlas (http://developingmouse.brain-map.org/). PCW, postconception weeks; E, embryonic day. Rectangles represent area displayed in magnified panels. (The color version of this figure is available in the online edition.)