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J Inherit Metab Dis. 2018 May;41(3):525-532. doi: 10.1007/s10545-017-0133-4. Epub 2018 Jan 25.

"Transcriptomics": molecular diagnosis of inborn errors of metabolism via RNA-sequencing.

Author information

1
Institute of Human Genetics, Technische Universität München, Trogerstrasse 32, 81675, Munich, Germany.
2
Institute of Human Genetics, Helmholtz Zentrum München, Munich, Germany.
3
Department of Pediatrics, Paracelsus Medical University Salzburg, Salzburg, Austria.
4
Institute of Human Genetics, Technische Universität München, Trogerstrasse 32, 81675, Munich, Germany. prokisch@helmholtz-muenchen.de.
5
Institute of Human Genetics, Helmholtz Zentrum München, Munich, Germany. prokisch@helmholtz-muenchen.de.

Abstract

Exome wide sequencing techniques have revolutionized molecular diagnostics in patients with suspected inborn errors of metabolism or neuromuscular disorders. However, the diagnostic yield of 25-60% still leaves a large fraction of individuals without a diagnosis. This indicates a causative role for non-exonic regulatory variants not covered by whole exome sequencing. Here we review how systematic RNA-sequencing analysis (RNA-seq, "transcriptomics") lead to a molecular diagnosis in 10-35% of patients in whom whole exome sequencing failed to do so. Importantly, RNA-sequencing based discoveries cannot only guide molecular diagnosis but might also unravel therapeutic intervention points such as antisense oligonucleotide treatment for splicing defects as recently reported for spinal muscular atrophy.

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