Identifying the missing heritability in recessive disorders using Joubert syndrome as a model

使用 Joubert 综合征作为模型来识别隐性遗传性疾病中缺失的遗传力

• 批准号: 10668289
• 负责人: DANIEL DOHERTY
• 金额: $ 48.32万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-08 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10668289
• 关键词: Affect; Alleles; Biological; Biological Assay; Brain imaging; Candidate Disease Gene; Cell Line; Cells; Chromosomes; Cilia; Code; Copy Number Polymorphism; Counseling; Cues; DNA Insertion Elements; Data; Disease; Engineering; Enrollment; Epigenetic Process; Family; Fibroblasts; Future; Genes; Genetic; Genetic Diseases; Genome; Genomics; Goals; Heritability; Heterogeneity; Heterozygote; Human Genetics; Immunofluorescence Immunologic; Individual; Joubert syndrome; Knowledge; Length; Maps; Medical; Mendelian disorder; Methods; Microtubules; Modeling; Molar tooth; Monitor; Mosaicism; Neurodevelopmental Disorder; Oligogenic Traits; Pathogenicity; Patient Care; Patients; Phenotype; Play; Precision therapeutics; Proteins; RNA Splicing; Recessive Genetic Conditions; Research; Role; Sampling; Source; System; Techniques; Testing; Transcript; Translating; Untranslated RNA; Validation; Variant; Western Blotting; Work; candidate identification; candidate validation; cohort; extracellular; gene discovery; genetic element; genome sequencing; human disease; improved; insight; lymphoblastoid cell line; next generation sequencing; novel; precision medicine; protein function; rare variant; recruit; research clinical testing; smoothened signaling pathway; success; targeted sequencing; transcriptome sequencing; whole genome

Project Summary/Abstract The goal of this proposal is to identify the missing heritability in genetically recessive conditions using Joubert syndrome (JS) as a model. JS is a genetically recessive neurodevelopmental condition that embodies the great successes and challenges posed by identifying the genetic causes of Mendelian disorders. In 1997 when the pathognomonic “molar tooth sign” for JS was identified on brain imaging, it seemed so specific that JS might have only one genetic cause; however, after the first two JS-associated genes accounted for <10% of families, we quickly realized that JS would be very genetically heterogeneous. Fast forward to 2018, and our most recent targeted sequencing data indicate that biallelic (or hemizygous) rare, predicted-deleterious variants (RDVs) in the coding regions of >35 genes explain the genetic cause in ~70% of families. Remarkably, all of the genes encode proteins that function in and around the primary cilium, a microtubule-based projection from most cells that serves as an antenna to interpret extracellular cues. This new understanding of the biological mechanisms underlying JS has led to functional assays to validate candidate genetic causes. The premise of this project is that the remaining individuals without genetic causes provide a unique opportunity to identify non-coding RDVs, novel JS-associated genes, and non-recessive genetic mechanisms underlying JS. To identify these genetic causes, we will apply cutting-edge genomic techniques to our cohort of >600 families affected by JS, particularly the 30% in whom the cause is unknown. In Aim 1, we will identify cryptic “second hits” in individuals with single RDVs in known JS genes, determining the contribution of variants not easily identified by next generation sequencing, such as structural and non-coding variants, repeat expansions, mobile element insertions, and potentially novel mechanisms. In Aim 2, we will identify novel JS associated genes in individuals without RDVs in any of the known JS genes. In Aim 3, we will determine whether non- recessive mechanisms such as oligogenic and dominant inheritance play a significant role in Joubert syndrome. As a result of this project, we will define the genetic causes in the vast majority of individuals with JS and reveal the spectrum of genetic mechanisms underlying a prototypical recessive Mendelian disorder with extreme heterogeneity. This information will translate directly into improved testing strategies, variant interpretation, and counseling for families, as well as inform future work to identify targets for precision therapies.

项目摘要/摘要 该提议的目的是使用乔伯特确定一般隐性条件下缺失的遗传力 综合征（JS）作为模型。 JS是一种遗传性隐性神经发育状况，体现了 通过确定孟德尔疾病的遗传原因而带来的巨大成功和挑战。 1997年 在脑成像上鉴定了JS的病理学“摩尔牙齿标志”，它似乎是如此具体，以至于JS 可能只有一个遗传原因；但是，在前两个JS相关基因占<10％的基因之后 家庭，我们很快意识到JS在遗传上是非常异质的。快进到2018年，我们的 最新的针对测序数据表明，双质（或半合子）稀有，预测的 > 35个基因的编码区域中的变体（RDV）解释了约70％的家族的遗传原因。值得注意的是 所有基因编码在原发性纤毛中和周围起作用的蛋白质，这是一种基于微管的投影 来自大多数用作天线的细胞来解释细胞外提示。对 JS的生物学机制已导致功能测定，以验证候选遗传原因。 这个项目的前提是，没有遗传原因的其余个人为 识别非编码RDV，新型JS相关基因和JS的非衰退遗传机制。 为了识别这些遗传原因，我们将在我们的> 600个家庭的队列中应用尖端的基因组技术 受JS的影响，尤其是该原因未知的30％。在AIM 1中，我们将确定加密“第二 在已知JS基因中具有单个RDV的个体中的命中”，确定变体的贡献不容易 通过下一代测序（例如结构和非编码变体）确定，重复扩展， 移动元件插入和潜在的新型机制。在AIM 2中，我们将确定新颖的JS相关 在任何已知JS基因中没有RDV的个体中的基因。在AIM 3中，我们将确定是否非 隐性机制（例如氧和占主导地位）在乔伯特（Joubert）起着重要作用 综合征。由于这个项目，我们将定义绝大多数患有的遗传原因 JS并揭示了原型隐性孟德尔疾病的遗传机制的范围 具有极端异质性。该信息将直接转化为改进的测试策略，变体 解释和为家庭提供咨询，并为未来的工作提供信息，以确定目标的准确性 疗法。