Gene networks underlying convergent and pleiotropic phenotypes in a large and systematically-phenotyped cohort with heterogeneous developmental disorders

PLoS Genetics
Tallulah AndrewsCaleb Webber

Abstract

Readily-accessible and standardised capture of genotypic variation has revolutionised our understanding of the genetic contribution to disease. Unfortunately, the corresponding systematic capture of patient phenotypic variation needed to fully interpret the impact of genetic variation has lagged far behind. Exploiting deep and systematic phenotyping of a cohort of 197 patients presenting with heterogeneous developmental disorders and whose genomes harbour de novo CNVs, we systematically applied a range of commonly-used functional genomics approaches to identify the underlying molecular perturbations and their phenotypic impact. Grouping patients into 408 non-exclusive patient-phenotype groups, we identified a functional association amongst the genes disrupted in 209 (51%) groups. We find evidence for a significant number of molecular interactions amongst the association-contributing genes, including a single highly-interconnected network disrupted in 20% of patients with intellectual disability, and show using microcephaly how these molecular networks can be used as baits to identify additional members whose genes are variant in other patients with the same phenotype. Exploiting the systematic phenotyping of this cohort, we obs...Continue Reading

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Citations

Mar 8, 2017·Trends in Genetics : TIG·Caleb Webber
Feb 14, 2020·PLoS Genetics·Mayanglambam Dhruba SinghSanthosh Girirajan
Aug 3, 2019·Nature Communications·Stephan C CollinsBinnaz Yalcin

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Methods Mentioned

BETA
genotyping
RNAseq

Software Mentioned

Ensembl
GTEx
BrainSpan
DECIPHER
Dapple
DECIPHER DatabasE
bedTools
Ensembl Resources

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