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Invitae Aims to Aid 'Diagnostic Odyssey' With New Neurodevelopmental Genetic Test Suite


This article has been updated to include more information on the NGS panel used in Invitae's NDD package.

NEW YORK – Invitae aims to shorten the time to diagnoses for neurodevelopmental disorders (NDD) through a suite of genetic tests aimed at detecting developmental delays, intellectual disabilities, and autism spectrum disorders (ASD).

The suite consists of a chromosomal microarray, a panel for fragile X and related disorders, and a next-generation sequencing panel of 241 genes with variants associated with various NDD.

Although currently available only in the US as a laboratory-developed test, Invitae is seeking regulatory approval in Europe and elsewhere.

Genetic testing is becoming more commonplace in diagnosing NDD, with professional organizations such as the American Academy of Pediatrics and the American College of Medical Genetics and Genomics including it in treatment guidelines and calling for genetic testing to be done early in the patient evaluation process.

"Neurodevelopmental disorders have many causes, and it's really very difficult for even the most highly specialized physicians to be able to make a specific diagnosis based on clinical information alone," Robert Nussbaum, Invitae's chief medical officer, said in an interview.

Invitae's test suite, which is covered by Medicaid and several private insurers, targets specific disorders, such as fragile X, as well as specific kinds of genetic lesions in an effort to efficiently catch as many disorders as possible.

These include cases where no specific treatment is indicated as a result of testing.

"We think that there are disease-specific treatments for somewhere around 6 percent of the positive results," Nussbaum said.

Specific actionable results are not the only kind of information that genetic testing provides, Nussbaum explained, nor should that form the bar for justification of genetic testing.

In many cases, genetic results may lead to specialist referral, which makes a different set of treatment options available to patients.

A molecular diagnosis, Nussbaum explained, might bring attention to other potential problems that didn't appear in earlier examinations, such as a need for better audiometry and retinal exams, or a closer look at one's kidneys.

Results can also affect family planning.

"Reproductive decision making is a huge part of this," Nussbaum said. "Not just the knowledge of [knowing] why this happened, but could it happen again and is there anything we could do to intervene to prevent it from happening again?"

Invitae's NDD panel is openly advertised online but typically requires a physician's prescription to order.

"We do have pathways where the patient can initiate the testing and then it gets reviewed by a physician, and the decision is made about whether this is somebody who needs further evaluation by a physician," Nussbaum said.

The patient-initiated pathway is aimed at individuals on a "diagnostic odyssey," who experience difficulties in obtaining a diagnosis and have taken a more active role in seeking one.

Bringing self-obtained genetic results into a doctor's office does not necessarily ensure better care, however.

"That initial [interaction] is going to be like, 'I didn't order this, I don't know why it was done, so how am I supposed to interpret it?'" Kate Thewes, a family practitioner with a private practice in Columbus, Ohio, said in an interview.

Because interpreting and using genetic test results does often require some specialized learning, Invitae has established a support system for physicians, consisting of both written educational material and a network of genetic counselors who are available by phone within the US.

The company has also contracted with genetic management company Genome Medical to provide expert recommendations, care, and referrals.

While Invitae's internal clinical support is provided free of charge, Genome Medical does charge a separate fee for its services.

Thewes suggested that such a clinical support network could be key to the service's overall success. The way that medical training is done, she explained, can lead physicians to feel uncomfortable admitting that they don't know something related to patient care, thereby erecting barriers to seeking out information on one's own.

This could be accentuated, she said, in cases of rare genetic issues that someone may have never seen in their career.

Although some practitioners have voiced concerns for the risk of unnecessary testing in cases where tests are marketed directly to consumers, Thewes saw little concern in this case. By the time someone is seeking a genetic test, she explained, they more than likely have something going on that they need looked at in greater detail.

"You don't have a totally normal person go do a genetic test," she said, especially in the case of rare diseases.

While the NDD panel is only offered in the US, it is available to anyone in the world from whom Invitae can accept samples, and other components are available as individual assays. The chromosomal array and fragile X components are currently only available within the US.

Invitae is currently going through Europe's IVDR approval process for the test suite and expects it to become available in the near future.

Other companies offer similar gene panels to Invitae, such as Ambry in the US, with a panel examining over 1,450 genes, and CeGaT in Germany, which offers a 393-gene NDD panel. Ambry's panel also accompanies a suite of other neurodevelopmental tests, which include CMA and fragile X-associated disorders, as well as tests for Rett and Angelman syndromes, PTEN-related disorders, several ASD-targeted tests, and a panel specific for syndromic and non-syndromic intellectual disability.

Dee McKnight, Invitae's medical affairs director, pointed out that the company's own neurodevelopmental package tests for the same disorders as Ambry, including Rett and Angelman syndromes.

One key difference between the 241-gene Invitae panel and those with larger numbers of genes is the type of next-generation sequencing used, McKnight said.

"The tests with large numbers of genes are built on an exome backbone which is great at casting a wide net and including many genes; however the sequencing coverage of these genes is often incomplete, and the deletion/duplications sensitivity is reduced," she said.

Invitae uses a capture-based NGS similar to most standard exomes. The assay used for its panels focuses on a curated list of "highest clinical utility genes," McKnight said, with resolution down to a single exon, rather than covering the whole exome. This, she explained, increases the assay’s coverage, relative to tests built on an exome backbone, which cover the whole exome.

“Most exomes have coverage around 150X – our panel has higher and more balanced coverage (around 350X) which allows for that higher sensitivity of calling single exon deletions.”

McKnight also explained that Invitae's panel focuses on a curated list of "highest clinical utility genes," with resolution down to a single exon.

"Looking at early data around the clinical utility of our NDD panel,” she said, “we found that 12 percent of positive cases had one or two exon deletions that would likely have been missed on an exome or a panel run on an exome backbone."

Furthermore, turnaround times for exome tests generally run between six and eight weeks, compared to between 10 and 21 days for Invitae's NDD package.

"If there's an answer to be obtained, you can get the answer the vast majority of the time with this package," Nussbaum said. "It's faster, it's less expensive, and it's easier for providers to use."