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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要该提案的目标是利用 Joubert 识别隐性遗传条件下缺失的遗传力综合征（JS）作为一种模型，是一种遗传性隐性神经发育疾病。 1997 年，我们在确定孟德尔疾病的遗传原因方面取得了巨大的成功，同时也面临着挑战。 JS 特有的“臼齿征”在大脑成像中被识别出来，它看起来非常具体，以至于 JS 可能只有一个遗传原因；然而，前两个 JS 相关基因占 <10% 快进到 2018 年，我们很快意识到 JS 的基因是非常异质的。最近的靶向测序数据表明，双等位基因（或半合子）罕见、预测有害超过 35 个基因的编码变异（RDV）解释了约 70% 的家族的遗传原因。所有基因都编码在初级纤毛内及其周围发挥作用的蛋白质，初级纤毛是一种基于微管的投射大多数细胞充当解释细胞外信号的天线。 JS 的生物学机制导致了功能测定来验证候选遗传原因。该项目的前提是，没有遗传原因的剩余个体提供了独特的机会识别非编码 RDV、新型 JS 相关基因以及 JS 背后的非隐性遗传机制。为了确定这些遗传原因，我们将尖端基因组技术应用于超过 600 个家庭的队列受 JS 影响的人，尤其是原因不明的 30% 在目标 1 中，我们将确定神秘的“第二个”。在已知 JS 基因中具有单一 RDV 的个体中，很难确定变异的贡献通过下一代测序鉴定，例如结构和非编码变体、重复扩展、移动元素插入和潜在的新颖机制在目标 2 中，我们将识别与 JS 相关的新颖机制。在目标 3 中，我们将确定是否有任何已知 JS 基因中没有 RDV 的个体的基因。寡基因遗传和显性遗传等隐性机制在 Joubert 中发挥着重要作用作为该项目的结果，我们将确定绝大多数患有该综合征的个体的遗传原因。 JS 并揭示了典型隐性孟德尔疾病的遗传机制谱这些信息将直接转化为改进的测试策略、变体。为家庭提供口译和咨询，并为未来的工作提供信息，以确定精确目标疗法。