Genomic duplications in anophthalmia, microphthalmia and coloboma

无眼症、小眼症和缺损的基因组重复

• 批准号: 10538727
• 负责人: Elena V Semina
• 金额: $ 38万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10538727
• 关键词: 3q29; Advanced Development; Affect; Animal Model; Anophthalmos; BCL2L1 gene; Bilateral; Collection; Coloboma; Complex; Copy Number Polymorphism; DLG1 gene; DNA; Data; Detection; Development; Disease; Dissection; Enrollment; Exhibits; Eye; Eye Development; Family; Future; Genes; Genetic study; Genomic Segment; Genomics; Health; Human; Individual; Inherited; Literature; Live Birth; Microphthalmos; Modeling; Orthologous Gene; Pathway interactions; Patients; Penetrance; Phenotype; Recurrence; Reporting; Role; Sampling; Structure; Syndrome; Testing; Time; Variant; Zebrafish; base; cohort; de novo mutation; defined contribution; dosage; genetic disorder diagnosis; human disease; novel; proband; success

PROJECT SUMMARY Microphthalmia, anophthalmia and coloboma (MAC) is a group of severe ocular phenotypes characterized by a reduction in size or absence of the eye or a gap (hole) involving various ocular structures. The success rate for identifying a genetic diagnosis for MAC spectrum remains incomplete, making the discovery of novel mechanisms an important priority. Copy number variations (CNVs) are deletions or duplications of genomic segments that can be inherited or occur as dominant de novo variants. There is a growing list of developmental phenotypes associated with CNVs, indicating that dosage imbalance represents an important factor in human disease. Within this group, the contribution of dosage gain variants remains underappreciated due to many factors including the involvement of multiple genes necessitating complex functional studies. In this proposal, we will combine our expertise in MAC and the zebrafish model to reveal novel mechanisms of these debilitating human phenotypes. We present evidence for the association of dosage gain at two different genomic regions, 20q11 and 3q29, with isolated and syndromic MAC, with multiple affected families identified in our cohort for both loci. We will utilize our extensive collection of DNA samples from individuals affected with MAC to further define the contribution of these and other candidate regions to human disease, as well as to discover novel disease-causing dosage-sensitive loci. Specifically, we will: 1) identify the driver gene(s) and pathway(s) involved in phenotypes associated with 20q11 dosage variation by generating and studying dosage gain/loss models for the zebrafish id1, bcl2l1 and tpx2 genes, identified as top candidates within the region; 2) reveal driver gene(s) and pathway(s) involved in phenotypes associated with 3q29 dosage variation by exploring dosage gain/loss models for zebrafish rubcn, dlg1 and/or bdh1 genes, located in the affected human region; and 3) uncover critical dosage-sensitive regions involved in human MAC spectrum by additional mapping of previously identified CNVs as well as exploring a large cohort (760 samples from affected individuals and their relatives) of extensively tested but unexplained MAC families, followed by dissection of novel candidate regions in zebrafish. The successful completion of this project will identify novel factors in human ocular development, both genomic regions/genes and affected pathways, and generate robust animal models of these complex human phenotypes.

项目摘要 微观恐惧症，性心含量和古罗巴马（MAC）是一组以A为特征的严重眼表型 减少涉及各种眼部结构的眼睛的大小或缺失或间隙（孔）。成功率 确定MAC光谱的遗传诊断仍然不完整，从而发现新颖 机制是重要的优先级。拷贝数变化（CNV）是基因组的缺失或重复 可以继承或作为主要de从头变体而出现的段。发育越来越多的清单 与CNV相关的表型，表明剂量不平衡是人类的重要因素 疾病。在该组中，由于许多 包括需要复杂功能研究的多个基因参与的因素。在此提案中， 我们将在Mac和斑马鱼模型中结合我们的专业知识，以揭示这些新型机制 使人类表型衰弱。我们提供了两个不同的剂量增益关联的证据 基因组区域，20q11和3Q29，具有孤立和综合症的MAC，并确定了多个受影响的家族 在我们的两个基因座的队列中。我们将利用受影响的个体的大量DNA样品集 Mac进一步定义了这些和其他候选地区对人类疾病的贡献，以及 发现新型致病剂量敏感的基因座。具体来说，我们将：1）确定驱动器基因和 通过产生和研究剂量，参与与20q11剂量变化相关的表型的途径 斑马鱼ID1，BCL2L1和TPX2基因的增益/损失模型，被确定为该地区的顶级候选者； 2） 揭示了与3q29剂量变化相关的表型的驱动基因和途径 探索位于受影响人类 地区; 3）通过额外 先前识别的CNV和探索大型队列的映射（760个样本 经过广泛测试但无法解释的MAC家庭的个人及其亲戚，然后解剖 斑马鱼的新型候选地区。该项目的成功完成将确定新的因素 人眼发育，基因组区域/基因和影响途径，并产生健壮的动物 这些复杂的人类表型的模型。