Beyond Genomics: How Multiomics Can Improve Rare Disease Diagnostics
Transcriptomics, proteomics and other technologies could provide additional diagnostic power to help solve medical mysteries.
In a review published in the journal Pediatric Research, scientists at the University of Miami Miller School of Medicine explored how several technologies can help diagnose rare diseases. In addition to genomics, which can identify the faulty genes that underlie many conditions, transcriptomics, proteomics, epigenomics and metabolomics could provide important diagnostic information to help solve profound medical mysteries.
“We are improving the diagnostic capabilities of genomics, but sometimes genomics is not enough,” said Pankaj Agrawal, M.D., chief of the Division of Neonatology at the Miller School and Jackson Health System and senior author on the paper. “By bringing these other technologies into the mix, we can improve our ability to diagnose rare diseases and get answers for these families.”
Genomics and Beyond
In the review, Dr. Agrawal, also professor of pediatrics and genetics at the Miller School, and co-authors Sara Ali, M.D., a neonatal/perinatal fellow, and Qifei Li, Ph.D., a research assistant professor in the Miller School’s Department of Pediatrics, discuss how molecular diagnostics are rapidly evolving. Prior to next-generation sequencing (NGS), many families went through years-long diagnostic odysseys to figure out what was causing their child’s disease.
Over the past 20 years, NGS has revolutionized how medical teams diagnose rare childhood diseases. By pinpointing the exact genetic variations driving the disease, these tests can provide definitive diagnoses and, in some cases, offer patients access to effective treatments and clinical trials.
However, NGS does not always provide definitive answers. In some cases, these tests produce no results or identify variants of unknown significance (VUS): mutations that might – or might not – be causing the child’s disease.
To solve this problem, researchers and clinicians have been developing molecular tests that can, in some instances, provide actionable information.
Multiomics is a viable path forward to help diagnose these kids and get them the care they need. We need to take advantage of every tool we have.
Dr. Pankaj Agrawal
“In select cases, we need to look beyond genomics and embrace multiomics,” said Dr. Agrawal. “These technologies are becoming more clinically available, and the literature shows they can improve our ability to diagnose these challenging cases.”
A Suite of Diagnostic Tools
Cells go through a templated series of steps to get work done. DNA is transcribed into messenger RNA (mRNA), which transfers the genetic code out of the cell’s nucleus. The mRNA is then translated into proteins, which implement the instructions encoded in the DNA. Each of these elements can go awry, so measuring them has become increasingly important.
Transcriptomics identifies mRNA levels, and its quality, in a sample. Sometimes there is not enough (or too much) mRNA for a specific gene, and that can cause problems. In addition, certain DNA changes can affect RNA splicing, which can be only identified by transcriptomic analysis.
Proteomics catalogues the proteins in a sample, which can help determine if these molecules are being produced at the appropriate levels or are being modified in pathogenic ways. Metabolomics measures metabolites, which are produced by chemical reactions in cells and can flag potential issues. Epigenetics helps identify whether specific genes are turned on or off. In some cases, the issue isn’t a mutation but rather how that gene is being regulated.
These technologies have been used in research labs for years and are now moving into the clinic. The same technologies that sequence DNA can also read RNA. In addition, clinical labs are springing up to provide epigenomic, proteomic and metabolomic insights for hospitals.
“It’s important that we leave no stones unturned for these patients,” said Dr. Agrawal. “If the genomic test is inconclusive, we have other technologies available to help get answers. There is significant research showing that multiomics is a viable path forward to help diagnose these kids and get them the care they need. We need to take advantage of every tool we have.”
Tags: Department of Pediatrics, Dr. Pankaj Agrawal, epigenetic strategy, gene editing, Gene sequencing, genomics, pediatrics, rare diseases