Italian research discovers cardiac risk modifier gene
A study conducted by Irccs Auxologico in Milan shows that the same variant can have opposite effects in two forms of sudden death syndrome among the leading causes of death among young people
They die swimming, running, from a fright or from the ringing of a bell that wakes them up at night. They are teenagers, children, and their death seems inexplicable until it is discovered that their heart hides a secret in their DNA. It is called Long QT syndrome, it affects one in every one thousand five hundred people and is the leading cause of sudden cardiac death in young people. Now, thanks to a study just published in the European Heart Journal, that disease is a little less mysterious and more controllable.
The work bears the signature of Professor Peter Schwartz, director of the Centre for Genetic Arrhythmias at the Irccs Istituto Auxologico Italiano in Milan, Italy, with colleagues from Sweden, America and Hong Kong, and his group with Professors Lia Crotti, Massimiliano Gnecchi and Dr. Luca Sala. The question that drove the research is twenty-five years old: why do two brothers with the exact same genetic mutation have such different fates? One dies suddenly, the other lives a completely normal life. Schwartz suspected that there were harmless genetic variants in healthy individuals but capable of modifying, for better or worse, the effects of the mutation-disease. He had begun to prove this by studying five hundred people from twenty-six South African families, all descended from a Dutch ancestor in 1690 and all affected by the syndrome: from that work the first 'modifier genes' for heart disease had emerged.
The breakthrough came in 2018 with a seemingly ordinary case: a boy with long QT type 1 who had suffered cardiac arrest, while his father and two uncles with the same mutation had never had any symptoms. Using pluripotent stem cells - which make it possible to reproduce the patient's heart cells in the laboratory - the team identified a variant of the MTMR4 gene present only in healthy family members. This variant, by interacting with another gene, was able to neutralise the effects of the mutation. This was the first time that the mechanism of action of a modifier gene had been clarified.
The most surprising finding came later. Analysing 1192 patients, the study demonstrated something that had never been hypothesised: the same variant that protects patients with type 1 long QT increases the risk of fatal arrhythmias in those with type 2. The same gene, in different molecular contexts, does opposite things. "The individual propensity for arrhythmias depends not only on the disease-causing mutation, but on the patient's entire genomic landscape," Schwartz explains. "We need to think more and more in terms of personalised medicine."
The practical benefits are already concrete. "For many months now, my centre has been the first in the world to check by routine screening whether patients are carriers of this variant on MTMR4," says the professor. "If they are LQT1 we can rest easier; if they are LQT2 we adopt a more aggressive prevention. This is really precision medicine'. And the screening is immediately extendable to other centres: just add MTMR4 to the panel of genes already analysed.
