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

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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.