According to Alfred George, Jr., MD, chief of the Division of Genetic Medicine at Vanderbilt, over 25 genes that can mutate and increase your risk for cardiac arrhythmias have been identified in the last 20 years, but ‘despite all this information, there are still cases that have no genetic diagnosis – they don’t have mutations in any of the known genes.’
Two such cases, of an Italian infant and another infant in Chicago, came to George’s attention. Both infants’ heart health suffered from early and repeated cardiac arrests which required resuscitation, medications, and eventually, implantable defibrillators, even though neither had a family history of heart rhythm disorders or parents with symptoms.
George and his colleagues realised that these children may have had a de novo or spontaneous and non-inherited mutation in a previously unknown arrhythmia susceptibility gene, and used these cases as a point of discovery. They scanned the protein-coding regions across the genome (exome sequencing) in the parent-child trios, which allowed them to zero in on the mutation causing the life-threatening disease.
George explained, ‘One of the biggest challenges in exome sequencing is sorting through the hundreds of thousands of gene variants to determine which one likely causes the disease. In these cases, in which we suspected de novo mutations, we eliminated more than 90% of all the variants we found because they were transmitted from a parent.’
The team discovered de novo mutations in two of the three genes coding for calmodulin, which is a calcium-binding protein that your body needs for cells to send signals to one another in multiple tissues, including those of the heart. George said he hopes that by fully understanding the ‘pathways and networks of genes that cause early-onset severe arrhythmias’, scientists may soon be able to develop new therapeutic approaches.