Caglayan Ahmet Okay, Baranoski Jacob F, Aktar Fesih, Han Wengi, Tuysuz Beyhan, Guzel Aslan, Guclu Bulent, Kaymakcalan Hande, Aktekin Berrin, Akgumus Gozde Tugce, Murray Phillip B, Erson-Omay Emine Z, Caglar Caner, Bakircioglu Mehmet, Sakalar Yildirim Bayezit, Guzel Ebru, Demir Nihat, Tuncer Oguz, Senturk Senem, Ekici Baris, Minja Frank J, Šestan Nenad, Yasuno Katsuhito, Bilguvar Kaya, Caksen Huseyin, Gunel Murat
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.
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.
Pediatr Neurol. 2014 Dec;51(6):806-813.e8. doi: 10.1016/j.pediatrneurol.2014.08.025. Epub 2014 Sep 4.
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.
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.
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.
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.
诺布罗赫综合征是一种罕见的常染色体隐性发育障碍，其特征为典型的眼部异常，伴有或不伴有枕骨颅骨畸形（脑膨出、骨缺损和皮肤发育不全）。尽管临床表现存在明显的异质性，但除了特征性的脑膨出外，中枢神经系统畸形通常不被视为疾病表型的一部分。
4例患者最初因有症状的结构性脑畸形进行基因评估。进行了全基因组基因分型、全外显子组测序和验证性桑格测序。我们使用免疫组织化学分析研究了COL18A1在胎儿中期和成人人类大脑皮层中的蛋白表达模式，然后利用人类大脑转录组数据库分析了COL18A1在人类皮层发育过程中表达模式的时空变化。
我们在COL18A1基因中鉴定出两个新的纯合有害移码突变。在对这些患者及其家族进行进一步研究时，我们发现许多人表现出诺布罗赫综合征的某些特征，包括明显的眼部缺陷。我们的数据有力地支持了COL18A1在大脑发育中的重要作用，本报告有助于更全面地描述由ⅩⅧ型胶原蛋白缺乏导致的脑畸形。
该病例系列突出了全外显子组测序技术的诊断能力和临床实用性，使临床医生和医学科学家能够更好地理解罕见疾病的病理生理学和表现。我们建议，即使没有脑膨出，对于临床诊断为诺布罗赫综合征和/或通过基因筛查发现有COL18A1突变的患者，也应检查是否存在潜在的结构性脑异常。
