Clinical RNA sequencing for better diagnosis of genetic diseases

What is it about?

Advancements in next generation DNA sequencing has been revolutionary in accurate and faster diagnosis of genetic diseases overcoming the diagnostic "odyssey" that patients face. But with a meteoric rise in technology and vast data generation, we face a problem in classifying the genetic mutations of uncertain significance identified, whether disease-causing or benign. Moreover, complex disease and heterogeneous disorders such as neuromuscular disease still pose a problem in definitive diagnosis due to the complexities of their genetic etiologies. Functional assays downstream of DNA level, such as that of RNA or protein levels are needed to classify accurately the mutations and for better diagnosis of complex disease. We describe the newer technologies and trends of next generation or massively parallel RNA sequencing to interpret the effect of the mutations at the functional level (RNA) for classification which is starting to be used for better diagnosis of Mendelian and complex diseases.

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Why is it important?

In diagnostic clinics, approximately 70-80% of all mutations are of uncertain significance and remain unclassified. Patients remain undiagnosed due to this and due to complex diseases. For example, about 30-40% neuromuscular disease patients remain unclassified after undergoing next generation DNA sequencing test. Therefore, downstream functional level RNA sequencing important to consider in the clinical setting to classify mutations and better diagnosis.