NEW YORK – In the end, it was a boost of riboflavin, or vitamin B2, that halted the child's hearing loss and other progressive nerve problems — a treatment designed to overcome the riboflavin transporter defects she had inherited from both parents.
Without it, her symptoms almost certainly would have progressed, and the child would have experienced far worse in time: declining mobility, optic atrophy, and, eventually, inability to breathe without a ventilator, explained Livija Medne, a senior genetic counselor at Children's Hospital of Philadelphia (CHOP).
The young patient was not alone. Her younger brother also inherited two copies of the altered gene, and had already experienced mild hearing loss by the time his sister's genetic test results came in — symptoms that could also be stopped with riboflavin.
A more limited genetic test done years earlier had missed the mutation. But the family's healthcare team eventually found the faulty riboflavin transporter with exome sequencing at the Roberts Individualized Medical Genetics Center (RIMGC), a genomic medicine program named for the Philadelphia family behind Comcast.
"That was one of our first success stories, where the testing really saved the child from going downhill," noted Medne, who is codirector of RIMGC.
The center has its roots in a national genomic medicine research program that started nearly a decade ago but officially launched as a clinical venture at CHOP in 2014 with help from a Roberts family endowment. It has since become a hospital hub for everything from in-house exome sequencing to genetic and genomic test interpretation, counseling, and assistance with genetic test access, in house and beyond.
"We really were brought into existence to facilitate exome and genome sequencing, because of the complexity of the tests and the complexity of getting insurance authorization, but we do facilitate all genetic testing," said RIMGC Director Ian Krantz, pediatrics chair at CHOP who also directs the Center for Cornelia de Lange Syndrome and Related Diagnoses.
Medne, Krantz, and their colleagues detailed the approaches used at RIMGC — along with results from some of the 3,483 cases referred to the center during its first four years — for a paper published in the March issue of Pediatrics. From 2015 to 2018, for example, they received more than 800 referrals apiece from general genetics and ear, nose, and throat specialties, as well as 311 neurology cases and hundreds of referrals involving other kinds of conditions.
Through the center's administrative, clinical, educational, research, and rare diagnoses cores, clinicians, investigators, genetic counselors, administrative staff, and other experts administer and interpret genetic tests, seek insurance approvals, secure families' consent for testing, return results, educate physicians and families, collect and document well-phenotyped biobank samples, and more.
Patients referred to the program are being followed over time to see if, and how, testing affected their care. For more than a quarter of the 1,172 patients profiled by exome sequencing in the first years of RIMGC, the team secured diagnoses. Another 37 percent had potential, but less certain, diagnoses and 28 percent tested negative for mutations that might explain their conditions.
Demand for testing at the center is on the rise, Krantz noted, as clinicians from a growing set of clinical specialties seek genetic answers for their patients, including those who may not have as much experience traversing such complex genomic testing territory.
While cardiologists are very comfortable managing care for a patient with cardiomyopathy, for example, they may be somewhat less prepared to explain the specific gene changes behind that patient's condition or to recommend testing for other family members who might be affected. Consequently, cardiologists and other specialists at CHOP have been deferring to experts at RIMGC to return such test results and organize follow-up testing, if needed.
"You can imagine why [a] cardiologist wouldn't want to have to deal with a BRCA1 mutation that was found in their patient, and who else needs to be tested, and who do they need to be referred to for follow up," Krantz said.
Consequently, the RIMGC team sees a benefit to developing genomic medicine expertise at a centralized site within the institution, rather than having each medical division or program establish its own genetic testing programs, which would each require genetic counselors, administrators, and other genomic med experts.
"Having the centralized program, the RIMGC that we created, provides a resource for all of the clinicians in the hospital who want to undertake this testing to be able to provide the right tests for the families," Krantz explained, "and give meaningful results back, and then to manage those patients from a genetic perspective, not only from a clinical perspective."
Members of the team started building that know-how in exome sequencing while participating in a National Human Genome Research Institute-funded Clinical Sequencing Exploratory Research (CSER) consortium, which focused on genomic medicine implementation and integration.
"We were the main pediatric program that was looking at, 'How do we integrate genomic data into clinical care,'" Krantz recalled recently.
Under the CSER research program, which lasted for five years, the team focused on pediatric patients with hearing loss, heart conduction defects, mitochondrial disorders, and unexplained seizures, developing strategies to incorporate genomic findings into the clinical workflow for children with these conditions.
Based on the cases evaluated during those first years, it quickly became clear that the genomic medicine program had promise for improving diagnoses and care for patients with still other conditions, prompting Krantz and his colleagues to move forward with the clinical program.
"We built the framework through the research grant and transitioned it to a clinical program that was half in pediatrics and half in pathology, and served to bring genomic diagnostics across the entire institution," Krantz explained.
That transition was possible, in part, because of technological advances that have taken place in the years since CHOP made its first foray into genomic medicine for CSER, including a steep decline in sequencing cost and increased sequencing speed.
While analytics remain more labor intensive and time consuming than sequencing itself, the field as a whole has made significant progress in understanding how various genes — and the variants within and between them — can influence disease since the early days of clinical sequencing.
"When we started, there was so much gray zone. There were so many things that we were unsure about," Krantz said. "There's still significant uncertainty in the [exome] test, but there's so much more that we are comfortable with and know about, and so many more disease-gene associations."
These days, variants at RIMGC are typically classified bioinformatically with an algorithm trained with databases such as ClinVar. From there, specialists at RIMGC review the variants to find those with potential clinical relevance based on the available databases, literature, reports at meetings, and so on.
In many cases, a diagnosis alone marks a meaningful step forward, making it possible to manage a patient's care appropriately and providing insights that may impact other members of the family, Krantz noted. But such diagnoses are even more significant when they point to potential targeted treatment options for children, which is increasingly the case.
Part of RIMGC's purview is to help patients and their families access the most appropriate form of genetic testing — whether it is exome, panel, or single-gene testing at the center itself or genetic testing done externally at commercial labs or elsewhere.
"Most of the testing is done here in house, but we send out a significant number that go out — for tests that aren't offered here or when insurance doesn't cover the cost of the test here," Krantz said.
The team also works to secure insurance coverage for the test selected, whenever possible, Medne explained, since most insurance companies require pre-authorization for out-patient exome sequencing tests.
In their paper, the investigators noted that insurers declined coverage for roughly 30 percent of genetic tests requested over RIMGC's first few years, though that is slowly changing.
"It is a big part of why we exist, is to navigate [the system]," she explained. "And we have developed good approaches to convince insurance companies that this is not experimental, this is not research. Even though we don't know what every one of the 20,000 genes does, this is true clinical care, and it's really meant to guide the clinical care for the child."
To that end, experts at RIMGC routinely write individualized letters of medical necessity for payers, outlining how a genetic test may influence management or care based on details in a patient's chart.
In cases tested with exome sequencing, the team typically reanalyzes unresolved cases after one or two years, taking into account any changes that have occurred in a patient's clinical features — and any new variant interpretations that have been documented — in the interim.
"Our approach, generally, is to bring the families back in and see them, see if there's a change in their clinical picture, which often helps for reanalysis," Krantz noted.
The center currently sees around 1,000 patients per year, though roughly 250 more patients who are referred to the program annually do not proceed with testing, for one reason or another. Even so, RIMGC is looking ahead to even greater growth in test requests, as more conditions are considered for testing.
"We've been overwhelmed with the volume, so we've grown dramatically in four or five years," Krantz said, noting that there are "new populations that we're being asked to see: isolated autism, for example, patients that sometimes are more likely to have susceptibility genes than pure Mendelian inherited genes."
He and his colleagues are considering ways to continue improving the ways that exome sequence and other genetic data gets used for patient care and management in the longer term as well, including efforts to incorporate this data into electronic health records in a way that is searchable and can be transferred between health systems — an area of active research in the field of genomic medicine more broadly.
They are also continuing to refine the clinical reports used to document and return a patient's test results, iteratively updating the reports every couple of years to make them as useful and integrated with EHRs as possible. That may involve the development of "care assistant modules" based on the genetic data, so that each patient can receive appropriate care over time, depending on the genetic changes they carry, Krantz explained.
Finally, the investigators are starting to prepare for a future where clinical exome or genome sequencing expands to include healthy individuals, perhaps starting in infancy.
"I don't think we're quite there yet," Krantz cautioned. "There's still enough gray zone and uncertainly in the genome. But I don't think we're too far off from pretty much everybody having their genome sequenced as part of their routine healthcare, and maybe doing that as almost a newborn screening test."