I'm in the Computational Methods... session on the final day of #ASHG20 The first speaker is Vincente Yepez, who will talk about "The added value of RNA sequencing over WES for variant interpretation and diagnosis of patient with rare genetic disorders"
50-75% of patients with rare diseases remain undiagnosed after WES. WGS gives all the variants, but not interpretable. VY will talk about using RNAseq to help diagnose. Focusses particularly on mitochondrial disorders #ASHG20
RNAseq can be used to resolve diagnoses in 10-15% of individuals with WES-undiagnosed mitochondrial disorders. Use a method called OUTRIDER to identify outlying gene expression signatures. Outliers are enriched for genes with rare LoF and aberrant splicing variants #ASHG20
Use FRASER to detect aberrant splicing of genes. Splicing outliers are enriched in rare splice, intronic and coding variants #ASHG20
Also examine monoallelic expression of the alternative allele. Show this is more frequent (in rare variants) on the reference allele. Combining all three methods gives an approach to obtaining a genetic diagnosis. Particularly effective in 5' and 3'UTRs #ASHG20
E.g. showed a homozygous synonymous variant that activated a splice site. E.g. 2, an intronic variant in NDUFAF5 creates a cryptic exon E.g. 3 - showed that homozyg splice acceptor variant in BUB1 did NOT result in a pathological spliced isoform #ASHG20
Overall, built all these methods into a suite called DROP (available here: github.com/gagneurlab/drop) #ASHG20
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