The Role of RNA-Sequencing as a New Genetic Diagnosis Tool

Curry, Philippa D. K.; Broda, Krystyna L.; Carroll, Christopher J.

doi:10.1007/s40142-021-00199-x

Cited by 16 publications

(13 citation statements)

References 53 publications

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“…Chromatin packing, histone modification, transcription initiation, RNA polyadenylation, splicing, and translation initiation all tightly regulate gene expression. Genetic variation, both coding and noncoding, is well known to impact these processes 12 . Low expression level of a disease gene often translates into low protein level and indicates a genetic disorder.…”

Section: Definition Of the Transcriptomementioning

confidence: 99%

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RNA sequencing role and application in clinical diagnostic

Peymani

Farzeen

Prokisch

2022

Pediatric Investigation

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Although whole‐exome sequencing and whole‐genome sequencing has tremendously improved our understanding of the genetic etiology of human disorders, about half of the patients still do not receive a molecular diagnosis. The high fraction of variants with uncertain significance and the challenges of interpretation of noncoding variants have urged scientists to implement RNA sequencing (RNA‐seq) in the diagnostic approach as a high throughput assay to complement genomic data with functional evidence. RNA‐seq data can be used to identify aberrantly spliced genes, detect allele‐specific expression, and identify gene expression outliers. Amongst eight studies utilizing RNA‐seq, a mean diagnostic uplift of 15% has been reported. Here, we provide an overview of how RNA‐seq has been implemented to aid in identifying the causal variants of Mendelian disorders.

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Section: Definition Of the Transcriptomementioning

confidence: 99%

“…Genetic variation, both coding and noncoding, is well known to impact these processes. 12 Low expression level of a disease gene often translates into low protein level and indicates a genetic disorder.…”

Section: Definition Of the Transcriptomementioning

confidence: 99%

RNA sequencing role and application in clinical diagnostic

Peymani

Farzeen

Prokisch

2022

Pediatric Investigation

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“…In some cases, targeting an affected but not causal gene results in worse patient outcomes [ 23 ]. Since diagnostic yield from exome sequencing remains well under 50%, the accessibility of immune cells for genomic profiling of peripheral blood samples obtained by standard phlebotomy raises prospects of RNA-based analyses, specifically RNAseq, that might identify aberrant molecular events such as altered splicing or gene expression [ 5 , 35 , 36 , 37 , 38 , 39 ]. The relevant mutations might not be observable in exome sequences, or may be of uncertain significance.…”

Section: Introductionmentioning

confidence: 99%

“…RNAseq complements WES and WGS by providing evidence of mRNA effects (or lack thereof) for specific variants as well as identifying alterations in splicing or other structural changes that DNA sequencing methods cannot see [ 37 ]. In large cohorts, transcript abundance can also be used to analyze downstream effects of some pathogenic variants and characterize pathways involved in disease [ 48 , 49 ].…”

Section: Introductionmentioning

confidence: 99%

Targeted RNAseq Improves Clinical Diagnosis of Very Early-Onset Pediatric Immune Dysregulation

Berger

Arafat

Chandrakasan

et al. 2022

JPM

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Despite increased use of whole exome sequencing (WES) for the clinical analysis of rare disease, overall diagnostic yield for most disorders hovers around 30%. Previous studies of mRNA have succeeded in increasing diagnoses for clearly defined disorders of monogenic inheritance. We asked if targeted RNA sequencing could provide similar benefits for primary immunodeficiencies (PIDs) and very early-onset inflammatory bowel disease (VEOIBD), both of which are difficult to diagnose due to high heterogeneity and variable severity. We performed targeted RNA sequencing of a panel of 260 immune-related genes for a cohort of 13 patients (seven suspected PID cases and six VEOIBD) and analyzed variants, splicing, and exon usage. Exonic variants were identified in seven cases, some of which had been previously prioritized by exome sequencing. For four cases, allele specific expression or lack thereof provided additional insights into possible disease mechanisms. In addition, we identified five instances of aberrant splicing associated with four variants. Three of these variants had been previously classified as benign in ClinVar based on population frequency. Digenic or oligogenic inheritance is suggested for at least two patients. In addition to validating the use of targeted RNA sequencing, our results show that rare disease research will benefit from incorporating contributing genetic factors into the diagnostic approach.

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“…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 .…”

Section: Introductionmentioning

confidence: 99%

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

Körner

Velluva

Bundalian

et al. 2022

Preprint

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Background: The 15q13.3 microdeletion has pleiotropic effects ranging from apparently healthy to severely affected individuals. The underlying basis of the variable phenotype remains elusive. Methods: We analyzed gene expression using blood from 3 individuals with 15q13.3 microdeletion and brain cortex tissue from 10 mice Df[h15q13]/+. We assessed differentially expressed genes (DEGs), protein-protein interaction (PPI) functional modules, and gene expression in brain developmental stages. Results: The deleted genes' haploinsufficiency was not transcriptionally compensated, suggesting a dosage effect may contribute to the pathomechanism. DEGs shared between tested individuals and a corresponding mouse model show a significant overlap including genes involved in monogenic neurodevelopmental disorders. Yet, network-wide dysregulatory effects suggest the phenotype is not caused by a singular critical gene. A significant proportion of blood DEGs, silenced in adult brain, have maximum expression during the prenatal brain development. Based on DEGs and their PPI partners we identified altered functional modules related to developmental processes, including nervous system development. Conclusions: We show that the 15q13.3 microdeletion has a ubiquitous impact on the transcriptome pattern, especially dysregulation of genes involved in brain development. The high phenotypic variability seen in 15q13.3 microdeletion could stem from an increased vulnerability during brain development, instead of a specific pathomechanism.

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The Role of RNA-Sequencing as a New Genetic Diagnosis Tool

Cited by 16 publications

References 53 publications

RNA sequencing role and application in clinical diagnostic

RNA sequencing role and application in clinical diagnostic

Targeted RNAseq Improves Clinical Diagnosis of Very Early-Onset Pediatric Immune Dysregulation

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

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