Thread by @thatdnaguy

#ASHG21 EP: Evin Padhi.
Computational and functional characterization of the hs737 enhancer in autism

#ASHG21 EP: Noncoding de novo variants are enriched in individuals with autism. How does that work? hs737 enhancer reaches significance in discovery and replication cohorts.

#ASHG21 EP: Individuals with de novo in hs737 have autism but also motor issues / hypotonia. All variants affect enhancer activity in luciferase activity in mouse neuronal cell line.

#ASHG21 EP: hs737 is enriched in CNVs in individuals with neurodevelopmental disorders (NDDs).

#ASHG21 EP: Evolutionary analysis of the element. Perfectly conserved across human / mouse. Used ACES (analysis of conservation using expanding species) shows high degree conservation.
github.com/TNTurnerLab/AC…

#ASHG21 EP: Looks like hs737 is a brain-specific and also developmental-specific enhancer. Forms a loop with EBF3. EBF3 is involved in neurodevelopmental processes and diseases. Known to be involved in HADD syndrome.

#ASHG21 EP: Looked at RNA-Seq from BrainSpan. Positively correlated with genes involved with chromatin and [others I missed]

#ASHG21 EP: EBF3 de novo variants are more severe than the de novo variants in hs737. Significantly associated with intellectual disability and delay.

#ASHG21 EP: EBF3 widely expressed. But hs737 brain-specific. Think hs737 controls expression in the brain.

#ASHG21 EP:
[ so it sounds like the hypothesis is that hs737 may be causing effects through dysregulation of EBF3 in the brain during development ]