PROJECT SUMMARY
Neurodevelopmental disorders (NDDs) affect >1% of the population and are comprised of multiple
phenotypes including autism, intellectual disability, and other developmental delays. Over the last
ten years, there has been considerable progress in understand the contribution of rare protein-
coding variants in NDDs. However, the role of rare noncoding variation has been less clear due
to the limited number of individuals with whole-genome sequencing (WGS) data previously
available. We were one of the first to identify aggregate enrichment for promoters and enhancers
in the first 516 families assessed by WGS; signals that have now been seen by multiple additional
groups. Currently, we have analyzed ~2,700 families with autism and identified enrichment in a
top enhancer. In Aim 1 of proposed studies we will expand this work to analyze 10,719 families
with NDDs to identify specific noncoding regions using statistical tests to identify enrichment
based on sequence context (fitDNM), enriched clustering of variants (GRUMP), and a
transmission-disequilibrium based test, respectively. We will perform massively parallel reporter
assays (MPRA) to follow up specific noncoding variants in the enriched elements and combine
this with deep phylogenetic assessment using existing and new reference genomes (ACES). Our
recent work suggests that dosage sensitivity is an important characteristic to consider when
testing specific promoters and enhancers for enrichment in NDDs. In Aim 2, we will build a copy
number map from 92,081 individuals, without NDDs, from the Centers for Common Disease
Genomics dataset. We will specifically assess 1,327,879 noncoding regulatory regions for
dosage-sensitivity in the human genome. As in Aim 1, we will follow up identified elements using
MPRA and our ACES phylogenetic workup. The primary goal of proposed studies is to improve
our understanding of noncoding variants in NDDs. We will do this by 1) identifying noncoding
regulatory regions with enrichment of variation in NDDs and 2) developing a dosage sensitivity
map of noncoding regulatory regions to inform studies of NDDs. This unique proposal, with its
mirrored aims, focuses on noncoding variation as opposed to the majority NDD focus on protein-
coding regions and it tests dosage in a large high-quality WGS dataset. This work will be integral
to the genetic understanding of NDDs and the consequences of noncoding variation. It will also
provide key insights into their role in the overall genetic architecture of NDDs.