Genomic basis of phenotypic variability of genomic disorders

Project Summary / Abstract Genomic basis of phenotypic variability of complex disorders Extensive phenotypic variability has complicated our understanding of complex disorders. We study the 520- kbp deletion on chromosome 16p12.1 as a paradigm to dissect the genetic basis of complex disorders. Originally identified in children manifesting developmental delay, the deletion is inherited in >95% of cases from a parent with mild neuropsychiatric features, conferring differential susceptibilities to disease among carriers in the same family. We found that carrier children were more likely to carry another large CNV or rare deleterious mutation (“second-hit”) elsewhere in the genome compared to their carrier parents, indicating that the deletion sensitizes the genome for a range of neurodevelopmental outcomes, and the ultimate phenotype is determined by variants in the genetic background. Our long-term goal is to understand how specific combinations of second-hit variants, in concert with the 16p12.1 deletion, lead to distinct clinical outcomes. In the previous funding period, we analyzed the genomes and quantitative phenotypes of 150 families with the 16p12.1 deletion, and tested individual as well as 214 pairwise interactions of homologs of 16p12.1 genes in Drosophila melanogaster and Xenopus laevis models. We found that patterns of rare variants correlated with the severity of clinical features, which were contingent upon family history of neuropsychiatric disease and assortative mating profiles of parents. Furthermore, knockdown of individual 16p12.1 homologs in Drosophila and X. laevis resulted in distinct developmental defects and these homologs interacted synergistically with patient-specific second-hits to modulate neuronal and cellular defects. Here, we propose to fine-map genetic and familial factors in larger cohorts, assess deeper cell type-specific effects, and identify generalizable principles for phenotypic variability of complex disorders, through the following Specific Aims: Aim 1: Perform whole genome sequencing and detailed phenotyping on an additional 250 families carrying the 16p12.1 deletion, and leverage the increased sample size to identify effects of single and combinations of genes and variant classes as well as polygenic risks towards variability in families, including anticipation across generations; Aim 2: Assess patterns of second-hits across different proband phenotypic profiles, family histories, disease ascertainments, and unselected populations of 1,281 unrelated 16p12.1 deletion carriers, and compare results with 2,200 individuals with other rare CNVs, such as 16p11.2 and 15q13.3 deletions, to identify patterns of second-hits that are common or unique to different CNVs and ascertainments; Aim 3: Perform functional studies to assess interactions of 16p12.1 genes with second-hits within neuronal cell types in Drosophila and quantitative neurological assays in Danio rerio models. Ultimately, our study will improve strategies for genetic diagnosis, counseling, and development of therapeutic strategies for complex disorders.