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

项目总结/摘要 这个建议的目的是确定失踪的遗传隐性条件下使用Joubert 综合征（JS）作为模型。JS是一种遗传隐性神经发育状况， 在确定孟德尔遗传疾病的遗传原因方面取得了巨大的成功，也面临着挑战。1997年 JS的特异性“臼齿征”在脑成像中被识别出来，它似乎是如此特异， 可能只有一个遗传原因;然而，在前两个JS相关基因占<10%之后， 家庭，我们很快意识到JS将是非常遗传异质性。快进到2018年，我们 最新的靶向测序数据表明，双等位基因（或半合子）罕见的，预测有害的， >35个基因编码区的RDV可以解释约70%家族的遗传原因。值得注意的是， 所有这些基因编码的蛋白质都在初级纤毛（一种基于微管的突起）内部和周围发挥作用 作为天线来解读细胞外信号。这种新的理解 JS潜在的生物学机制已经导致功能测定以验证候选遗传原因。的 该项目的前提是，没有遗传原因的剩余个体提供了一个独特的机会， 鉴定非编码RDV、新的JS相关基因和JS潜在的非隐性遗传机制。 为了确定这些遗传原因，我们将应用尖端的基因组技术，我们的队列>600个家庭 受JS影响，特别是30%的原因不明。在目标1中，我们将确定神秘的“第二 在已知JS基因中具有单个RDV的个体中，“命中”，不容易确定变体的贡献 通过下一代测序鉴定，如结构和非编码变体，重复扩增， 移动的元件插入和潜在的新颖机制。在目标2中，我们将确定与 在任何已知的JS基因中没有RDV的个体中的基因。在目标3中，我们将确定非 隐性遗传机制如寡基因遗传和显性遗传在Joubert中起重要作用 综合征作为这个项目的结果，我们将确定绝大多数个体的遗传原因， JS和揭示遗传机制的频谱潜在的一个原型隐性孟德尔疾病 具有极强的异质性。这些信息将直接转化为改进的测试策略， 翻译和家庭咨询，以及为未来的工作提供信息，以确定精确的目标 治疗

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.