What is RNA splicing and why does it matter?
To make a protein, the cell first copies a gene as RNA, a kind of rough draft. That draft is then cut and re-joined: some pieces are removed and others kept. This step is called splicing.
It is remarkably precise, but the mechanisms that let the cell choose the right cutting spots are not fully understood. A mutation, meaning a change in DNA, can shift a cut and produce a faulty message.
Splicing errors are a known cause of disease, but they were hard to spot when they came from discreet changes far from the obvious cutting sites.
How did the researchers go about it?
They designed a deep neural network, a program that learns on its own from examples, able to spot splice junctions accurately in any uncut RNA sequence.
They used it to spot mutations that cause hidden (cryptic) splicing: changes in non-coding regions, or that do not alter the protein, and that were often assumed to be harmless.
The strength of the approach is that it needs only the sequence: there is no need to measure each patient's RNA to get a first lead.
What did they find?
Mutations flagged as disrupting splicing were confirmed at a high rate when real cells' RNA was read by sequencing. They are also strongly harmful in the human population, meaning they are rarely passed on from one generation to the next.
In patients with autism or intellectual disability, new mutations that disturb splicing are more common than in healthy controls. In 28 of these patients, 21 were confirmed by RNA sequencing. Overall, the authors estimate that 9% to 11% of mutations behind rare genetic disorders belong to this previously underappreciated class.
This work suggests we may have been looking in the wrong place for a long time: mutations judged harmless could in fact matter in brain development disorders, including autism and intellectual disability.
Key figures
- 21 of 28patients whose flagged mutation was confirmed in their RNA
- 9% to 11%estimated share of pathogenic mutations in rare genetic disorders due to this class
What could this change for patients?
For a family searching for the origin of a rare genetic condition without finding it, this means some causes may hide in mutations that had been set aside. Better spotting could, in time, help reach more diagnoses.
For now it is a research tool for understanding genetics, not a test anyone can ask for today.
What are the limits?
The result in patients rests on a small group: 28 people for the laboratory check. A mutation that disturbs splicing is not always the cause of the disease, and the link still has to be shown case by case.
The 9% to 11% figure is the authors' estimate, to be refined by other studies.
A rare condition with no cause found: preparing your questions
This laboratory research helps spot mutations whose effect used to go unnoticed. It is not a hospital test, but for a family without a diagnosis it may one day reopen leads.
If your family has been searching for a cause for a long time, Mima keeps track of appointments, tests and the answers you received. She helps you prepare the question: "Could my genetic file be looked at again with the latest methods?" She also explains difficult words.
Frequently asked questions
What is splicing?
It is the step where the cell cuts a draft of a gene (RNA) and re-joins some of the pieces before making a protein. If a cut is misplaced, the message is wrong.
What is a cryptic mutation?
It is a DNA change that looks harmless, for example because it does not alter the protein, but in fact shifts a cut in the RNA.
Does this program mean a new genetic test?
The study does not offer one. It is a research tool that helps understand which mutations can cause disease.
Does this concern autism?
The study found these mutations more often in patients with autism or intellectual disability than in healthy controls. That does not mean they explain every case.
The original study
Jaganathan K, Kyriazopoulou Panagiotopoulou S, McRae JF, et al. “Predicting Splicing from Primary Sequence with Deep Learning.” Cell, 17 January 2019. DOI : 10.1016/j.cell.2018.12.015
Read the full study in CellThis article summarises a scientific study and is not medical advice.