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

项目摘要/摘要 这项建议的目标是利用Joubert来确定遗传隐性条件下缺失的遗传力 证候(JS)作为模型。JS是一种遗传隐性神经发育疾病，体现了 在确定孟德尔病症的遗传原因方面取得的巨大成功和带来的挑战。1997年，当时 在脑部影像上发现了JS的病原学“磨牙征”，它似乎如此特异。 可能只有一个遗传原因；然而，在前两个与JS相关的基因占10%之后 我们很快意识到，JS在基因上是非常不同的。快进到2018年，我们的 最新的靶向测序数据表明，双等位基因(或半等位基因)罕见，预测有害 ~gt；35基因编码区的变异(RDVS)解释了约70%的家庭的遗传原因。值得注意的是， 所有基因编码的蛋白质都在初级纤毛内和周围发挥作用，初级纤毛是一种基于微管的投射。 作为解释细胞外信号的天线的大多数细胞。这就是对 JS背后的生物学机制导致了功能分析来验证候选遗传原因。这个 这个项目的前提是，剩下的没有遗传原因的个体提供了一个独特的机会 确定非编码RDVS、新的JS相关基因和JS的非隐性遗传机制。 为了确定这些遗传原因，我们将把尖端基因组技术应用到我们的600个家族中。 受JS影响，特别是原因不明的30%。在目标1中，我们将确定神秘的“秒” 在已知JS基因中存在单一RDVS的个体中的HITS，确定变异的贡献并非易事 由下一代测序识别，例如结构和非编码变体、重复扩展、 移动元件插入，以及潜在的新机制。在目标2中，我们将确定与之相关的新JS 在任何已知的JS基因中没有RDVS的个体的基因。在目标3中，我们将确定非 在Joubert病中，诸如少基因遗传和显性遗传等隐性机制起着重要作用 综合症。作为这个项目的结果，我们将确定绝大多数患有 并揭示了一种典型的隐性孟德尔遗传病的遗传机制 具有极端的异质性。这些信息将直接转化为改进的测试策略 为家庭提供口译和咨询，并为今后的工作提供信息，以确定准确的目标 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.