PDF(Pubmed)
Abstract：
Ocular malformations (OMs) arise from early defects during embryonic eye development. Despite the identification of over 100 genes linked to this heterogeneous group of disorders, the genetic cause remains unknown for half of the individuals following Whole-Exome Sequencing. Diagnosis procedures are further hampered by the difficulty of studying samples from clinically relevant tissue, which is one of the main obstacles in OMs. Whole-Genome Sequencing (WGS) to screen for non-coding regions and structural variants may unveil new diagnoses for OM individuals. In this study, we report a patient exhibiting a syndromic OM with a de novo 3.15 Mb inversion in the 6p25 region identified by WGS. This balanced structural variant was located 100 kb away from the FOXC1 gene, previously associated with ocular defects in the literature. We hypothesized that the inversion disrupts the topologically associating domain of FOXC1 and impairs the expression of the gene. Using a new type of samples to study transcripts, we were able to show that the patient presented monoallelic expression of FOXC1 in conjunctival cells, consistent with the abolition of the expression of the inverted allele. This report underscores the importance of investigating structural variants, even in non-coding regions, in individuals affected by ocular malformations.
摘要：
眼部畸形（OMs）是由胚胎眼部发育过程中的早期缺陷引起的。尽管已经鉴定出超过100个与这一异质性疾病相关的基因,全外显子组测序后，一半个体的遗传原因仍然未知。诊断程序进一步受到难以研究来自临床相关组织的样本的阻碍。全基因组测序（WGS）筛选非编码区和结构变异可能为OM个体揭示新的诊断。在这项研究中,我们报告了1例表现为综合征型OM的患者,WGS鉴定的6p25区域从头3.15Mb倒置.这种平衡的结构变体位于距离FOXC1基因100kb的地方，以前与文献中的眼部缺陷有关。我们假设倒置会破坏FOXC1的拓扑关联域并损害基因的表达。使用一种新型样本来研究成绩单，我们能够显示患者在结膜细胞中呈现FOXC1的单等位基因表达，与消除反向等位基因的表达一致。这份报告强调了研究结构变体的重要性，即使在非编码区域，受眼畸形影响的个体。
