Thread by @thatdnaguy

#ASHG20 EM
Personalized regulatory genomics: Identifying gene dysregulation to solve undiagnosed rare disease cases.
Evonne McArthur.

#ASHG20 EM Most patients with a rare genetic disease have no diagnosis. The undiagnosed disease network (UDN) helps to solve some of these cases. About 35% solved.

#ASHG20 EM Commonly think that coding changes lead to alterations in protein structure. But how to you identify and interpret variants that are not coding? Gene regulatory mutations are harder. May have tissue and time-specific effect. Can you skip some of these challenges?

#ASHG20 EM Think might be able to use whole genome sequencing (WGS) to predict a gene regulation defect. Need to build a model that links genotype to expression. Like making a weighted model of all the genes / variants contributing to a gene's expression.

#ASHG20 EM Models only consider common variation with minor allele > 5% and cis-variants within 1 MB of the gene body [ i.e. this isn't going to work for rare vars from the sound of it ].

#ASHG20 EM Plot the proband, mother, and father onto a reference distribution. If the model puts predicted expression at an extreme you can get a prioritized list of up and down-regulated genes. Look at gene predictions and see if relevant to phenotype.

#ASHG20 EM Example - 4 yo male w/ cataracts, optic myopathy, short stature, delay, seizures, and cortical atrophy. Model predicted decreased expression of WFS1. What does gene do? Mutations in WFS1 associated w/ variable expressivity incl isolated cataract and deafness.

#ASHG20 EM Think it has other uses. To identify how non-coding variation contributes to disease. Ex - patient with multiple symptoms in different organ systems. Had ATXN7 expansion. But model predicted down-regulation of PIGN, which could explain some non-ATXN7 phenotypes.

#ASHG20 EM [ This is really interesting model taking into account common variant epistasis. Needs some validation to give it some teeth, but could be really useful. ]

#ASHG20 EM Developing a transmission disequilibrium test that uses predicted dysregulation. Will test for over-transmission of predicted tissue dysregulation to quantify effect size on rare disease.