Phenotype-tissue expression and exploration (PTEE) resource facilitates the choice of tissue for RNA-seq-based clinical genetics studies

Abstract

Background RNA-seq emerges as a valuable method for clinical genetics. The transcriptome is “dynamic” and tissue-specific, but typically the probed tissues to analyze (TA) are different from the tissue of interest (TI) based on pathophysiology. Results We developed Phenotype-Tissue Expression and Exploration (PTEE), a tool to facilitate the decision about the most suitable TA for RNA-seq. We integrated phenotype-annotated genes, used 54 tissues from GTEx to perform correlation analyses and identify expressed genes and transcripts between TAs and TIs. We identified skeletal muscle as the most appropriate TA to inquire for cardiac arrhythmia genes and skin as a good proxy to study neurodevelopmental disorders. We also explored RNA-seq limitations and show that on-off switching of gene expression during ontogenesis or circadian rhythm can cause blind spots for RNA-seq-based analyses. Conclusions PTEE aids the identification of tissues suitable for RNA-seq for a given pathology to increase the success rate of diagnosis and gene discovery. PTEE is freely available at https://bioinf.eva.mpg.de/PTEE/

Altered gene expression profiles impair the nervous system development in individuals with 15q13.3 microdeletion

“…This revealed that there are four genes with high expression in brain cortex (Supplementary Fig. S1 14 ): FAN1, MTMR10, KLF13, OTUD7A , all of which showed significant down-regulation in blood (Supplementary Table S1) of our subjects, as well as mouse brain cortex, confirming that a gene dosage effect of the microdeletion contributes to the transcriptional dysregulation. Other genes included in the typical deletion region: TRPM1, CHRNA7, MIR211, ARHGAP11B , display low expression levels in brain cortex and blood (Supplementary Fig.…”

“…S1). Four genes have an expression higher than 1.5 TPMs in brain cortex 14 ( FAN1, MTMR10, KLF13, OTUD7A ) of which MTMR10 and KLF13 are also highly expressed in blood (Supplementary Fig. S1).…”

“…Expression data of DEGs were obtained from PTEE (version 1.1) 14 for the adult brain cortex. Genes expressed at a low level in adult brain tissue may be expressed at a higher level in the developing brain and therefore, could still play a significant role in neurodevelopment.…”

“…A list of genes, which are known to play a role in NDDs, was obtained from PTEE 14 . DEGs of 15q13.2q13.3 microdeletion patients were compared to the list of NDD genes, to determine DEGs that could contribute to the neurological symptoms observed in those patients.…”

“…One major challenge of transcriptomics in a clinical setting is tissue-specific gene expression 14,15 and the fact that most of the times the only accessible tissue to probe is blood 16 . In our previous work we showed, however, that known genes for neurodevelopmental disorders are not necessarily expressed in the adult brain and that genes which are relevant during embryonic development of the central nervous system can be silenced at a later timepoint 14 . Thus, although not regarded as a representative tissue, blood transcriptomics has the potential to reveal aspects missed in other tissues or iPSCs.…”