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RNA-sequencing for diagnosing genetic disorders


An article published in Pediatric Investigation discussed the advantages of using RNA-sequencing when diagnosing human genetic disorders.

RNA-sequencing can be used to improve the accuracy of diagnosing human genetic disorders, according to a recent press release from Pediatric Investigation.

Diagnosing human genetic disorders has been simplified through the use of next-generation sequencing (NGS), with scientists capable of identifying diseases at the single gene level since the mapping of the human genome. However, DNA-sequencing is unable to record changes in non-coding regions of the genome, which have been identified as key components of certain disorders.

The sources behind many genetic disorders cannot be discovered through NGS techniques such as whole-exome sequencing (WES) and whole-genome sequencing (WGS), limiting the efficacy of NGS techniques in diagnosing genetic disorders. RNA-sequencing has been identified as a potential clinical tool for this purpose.

In RNA-sequencing, the limits of other methods are overcome using samples of fibroblasts, blood, and muscle biopsies. Scientists can discover details on certain RNA sequences’ structure, sequence, and quantity. The diagnostic improvement from RNA-sequences has been estimated to be almost 15% by investigators.

On March 5, 2022, investigators published an article in Pediatric Investigation on improving the diagnostic efficacy of NGS techniques through RNA-sequencing. The team was led by Holger Prokisch, PhD, from the Technical University of Munich.

"RNA-sequencing demonstrates success in prioritizing and detecting not only deleterious deep intronic variants but also coding variants affecting gene expression, which are often overlooked by WES and WGS,” Prokisch said.

The authors saw a 15% improvement in DNA-based sequency when RNA sequencing was used across 8 prior studies. One potential reason for abnormal RNA content in cells listed by the authors was a defect in the cell’s machinery during transcriptions caused by an “aberrant expression.”

Another reason for abnormal RNA content discussed by investigators was abnormal RNA profiles and silencing of 1 allele or gene copy caused by "mono-allelic expression.” The final reason discussed was poor processing of a newly formed RNA transcript, which is most common when a non-protein coding region is spliced.

These abnormal patterns can be easily discovered by RNA-sequencing. However, RNA-sequencing has limitations as well, with tissue-specific expression vital for this method. The clinical application of RNA-sequencing is still limited, making it important to incorporate additional NGS data such as proteomics.

"If we can identify and leverage these abnormal phenotypes, identifying rare genetic diseases and their causes may become easier and more fulfilling in clinical practice,” Prokisch concluded.


Pediatric investigation review throws light on improving diagnosis of genetic diseases with RNA sequencing. Pediatric Investigation. February 8, 2023. Accessed February 8, 2023. https://www.prnewswire.com/news-releases/pediatric-investigation-review-throws-light-on-improving-diagnosis-of-genetic-diseases-with-rna-sequencing-301740763.html

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