Comprehensive Analysis of Tissue-wide Gene Expression and Phenotype Data Reveals Tissues Affected in Rare Genetic Disorders

Linking putatively pathogenic variants to the tissues they affect is necessary for determining the correct diagnostic workup and therapeutic regime in undiagnosed patients. Here, we explored how gene expression across healthy tissues can be used to infer this link. We integrated 6,665 tissue-wide transcriptomes with genetic disorder knowledge bases covering 3,397 diseases. Receiver-operating characteristics (ROC) analysis using expression levels in each tissue and across tissues indicated significant but modest associations between elevated expression and phenotype for most tissues (maximum area under ROC curve = 0.69). At extreme elevation, associations were marked. Upregulation of disease genes in affected tissues was pronounced for genes associated with autosomal dominant over recessive disorders. Pathways enriched for genes expressed and associated with phenotypes highlighted tissue functionality, including lipid metabolism in spleen and DNA repair in adipose tissue. These results suggest features useful for evaluating the likelihood of particular tissue manifestations in genetic disorders. The web address of an interactive platform integrating these data is provided. [Display omitted] •Significant but modest associations link elevated expression to affected tissues•Disease genes upregulated in affected tissues mostly for dominant disorders•Genes expressed and associated with phenotypes highlight novel tissue functionality•Aid variant interpretation combining expression, inheritance mode, and pathways Tissue-wide transcriptome analysis of disease-associated genes in rare genetic disorders reveals significant but modest associations between elevated steady-state expression and affected tissues. By integrating disease and phenotype knowledge bases, we show that the strength of this association varies across tissues and modes of inheritance.