This article has been updated to correct the number of confirmed diagnoses made in IDIOM.
NEW YORK (GenomeWeb) – A team from the Scripps Research Institute-led Idiopathic Diseases of Man (IDIOM) project has published data from the study's first three years of operation, during which researchers sequenced the whole genomes of patients with a presumed unique or unexplained disorder in an effort to find a genetic cause for their symptoms.
In the study, published in Genetics in Medicine this week, the IDIOM researchers reported that they achieved a confirmed diagnosis for three of 17 enrolled cases during these first three years. Ali Torkamani, the project's leader, told GenomeWeb this week that since submitting the paper, the study has updated that with five additional diagnoses among 21 total sequenced patients.
The researchers noted that the effort has also determined what the group deems a "plausible" genetic explanation for a full 60 percent of the sequenced cohort.
Unlike other rare disease sequencing efforts, clinical sequencing programs at academic medical centers, or even the National Institutes of Health Undiagnosed Diseases Program, IDIOM is focused exclusively on novel or mystery cases. Patients must fail to fit any previously described phenotype, or all possible causes of a known phenotype must have already been ruled out.
"If they have a clinical diagnosis, a named syndrome, then the known causes of that syndrome need to be excluded by a clinical test before we'll take the case," Torakamani said.
According to Torkamani and his coauthors, out of a total of 121 cases referred to the program's initial review in its first three years, only 59 made it through to a second-tier review and only 17 patients and their family members were finally enrolled and sequenced.
"No one was excluded for monetary reasons or anything like that," Torkamani said. "But there's no limit in terms of how old individuals can be, so some of the excluded cases we thought could be age related. And then you also get strange cases that are perhaps psychological, or don't appear to be genetic for other reasons."
Among the 17 patients and families who made the cut, whole genome sequencing identified what the IDIOM team deemed a plausible molecular diagnosis for 60 percent, and a confirmed molecular diagnosis for approximately 18 percent, or three of the subjects.
According to the authors, this diagnosis rate is encouraging, given the program's exclusive focus on novel diseases and disease-gene relationships. In fact, it runs quite close to the rate of confirmed genetic diagnoses — about 20 to 25 percent — reported by other programs in the field with less narrow entrance criteria, the team wrote.
For IDIOM, a plausible molecular diagnosis is one that identifies a variant that appears to segregate in the family and population at large in a way that is consistent with the rate of incidence of the disorder, and that influences the coding or splicing of a protein-coding gene and can be connected in some way to the presenting phenotype.
Of the 60 percent of cases meeting these criteria, the IDIOM team was able to complete functional confirmation of a novel gene-disease relationship for two patients and their families. For one other patient, sequencing uncovered a previously identified pathogenic variant.
Importantly, for all three cases where the researchers achieved a confirmed diagnosis, a new pharmacologic management strategy was initiated based on the findings. The researchers are currently closely monitoring these patients' response to the therapy and ultimate outcomes, they reported.
In one of these cases, a patient with a complex movement disorder, IDIOM found the cause to be a gain-of-function de novo mutation in ADCY5. The patient was started on a series of various medications in an n-of-1 style trial, which revealed that diazepam was effective in resolving the subject's nighttime myoclonic jerks.
The second confirmed diagnosis was of a patient presenting with a complex seizure disorder with drop attacks, which the team confirmed was due to a de novo mutation in the potassium channel KCNB1. The patient was placed on a specialized diet. "An anecdotal reduction in drop attacks has been noted by the treating physician, although longer follow-up is required to confirm a sustained benefit," the authors wrote.
Finally, in the third case, the researchers found that the symptoms of hypertrichotic osteochondrodysplasia (excess hair growth on the scalp, forehead, and face) were due to a known pathogenic de novo ABCC9 mutation. According to the authors, treatment modifications have been initiated, but again, long-term follow up is required to confirm a sustained benefit.
For the remaining patients with plausible but unconfirmed genetic diagnoses, there remains a possibility and a hope that as more and more subjects are sequenced by IDIOM and by other groups, the necessary functional data and the ability to identify additional affected individuals will emerge.
"We suspect that we have the right answer. But because it's novel, we don't have enough evidence to say for sure … We are now working on trying to convert the rest of that 60 percent over to a more proven gene-disease relationship," Torkamani said.
In fact, after publishing on the study's initial gene-disease relationships for two of the three confirmed cases, the IDIOM group said it has been contacted by other outside patients for whom the data has provided the first evidence to confirm a variant that was initially considered of unknown significance.
For example, the group received inquiries from two individuals with negative clinical exome results who had the same de novo ADCY5 mutation as the IDIOM team found in its first confirmed subject, the authors wrote.
Torkamani also discussed IDIOM's early results at the Scripps Future of Genomic Medicine Conference earlier this month. During the same session, the Medical College of Wisconsin's Liz Worthey described similar results MCW has experienced using whole genome sequencing to diagnose rare and novel diseases.
According to Worthey, MCW has been able to return clinical findings to its pediatric rare disease patients about 35 percent of the time. These individuals, she said, reflect some of the hardest cases, similar to the target population for IDIOM — children who have been in the system for years without an answer to the cause of their symptoms after less comprehensive testing.
Torkamani said that since the study period described in the paper, the Scripps IDIOM team has increased the number of sequenced patients to 21, and added another five confirmed diagnoses, a success rate of about 30 percent.
"The 60 percent rate for plausible diagnoses in these particular individuals is exciting as it suggests a potential rate of clinical and diagnostic utility that greatly exceeds what is reported in a traditional clinical sequencing setting. This potential is underscored by the 30% confirmed diagnosis rate we were able to achieve in individuals who have received prior negative results in available clinical tests," he added in an email.
According to Torkamani, IDIOM doesn't have a set endpoint or target number of subjects. "The more we can do the better, as long as we have money to pay for it," he said.