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Gene Discovery Leads to New Diagnostic for Pulmonary Hypertension

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NEW YORK (GenomeWeb) – Intermountain Healthcare announced this month that it and its partner ARUP Laboratories have made a new gene mutation test available to help physicians diagnose patients who have a subset of pulmonary arterial hypertension (PAH) that may require different clinical management than other forms of the disease.

The test identifies alterations in the EIF2AK4 gene and has been incorporated into ARUP's larger PAH next-gen sequencing panel, and can also be analyzed on its own using Sanger sequencing if patients have already received another PAH panel test but physicians want to add EIF2AK testing after the fact.

Gregory Elliott, chairman of the department of medicine at Intermountain Medical Center and a leader of the team of researchers that discovered the link between EIF2AK and PAH, told GenomeWeb this week that prior to his team's discovery, there were already a number of other known genetic contributors to pulmonary hypertension, mainly within a subset of the disease called pulmonary arterial hypertension.

However, pathologists have long been aware of the existence of two rare subgroups — pulmonary veno-occlusive disease (PVOD) and pulmonary capillary haemangiomatosis (PCH) —  with different clinical and pathological features than other forms of PAH.

PCH is defined by uncontrolled growth of the capillaries in the lungs and occurs most commonly in adults aged 20 to 40 years old, but can affect people of all ages. PVOD is defined by the widespread obstruction of the pulmonary veins, which can lead to heart failure.

Picking out patients with these two specific forms of pulmonary hypertension is important, Elliott explained, because it has implications for patients' prognosis and can help treating physicians make the best decisions about how to treat them.

Patients with PVOD and PCH have the poorest prognoses among the overall population of pulmonary arterial hypertensives. There are no specific therapies for the two disorders, Elliott said, and actually, therapies that are effective in patients with other PAH types, like vasodilators, can be harmful in PVOD or PCH, causing pulmonary edema that fills the lungs with fluid.

Because of these risks, and the poor prognosis for patients with these subsets, the most recent practice guidelines for pulmonary hypertension — published last year in the European Heart Journal — recommend that clinicians list patients for transplantation at diagnosis of either PVOD or PCH, and that they not be treated with drug therapy except in centers with significant clinical expertise.

Importantly, and unfortunately, Elliott said, PVOD and PCH have traditionally been difficult to diagnose, often requiring pathological analysis of lung tissue which is rarely possible for patients because of the severity of their symptoms.

Because many patients can't be biopsied, clinicians can't confirm definitively that they have PVOD or PCHT until after patients receive a lung transplant or after they die, he said.

When Elliott and colleagues discovered several years ago that inherited alterations in EIF2AK4 were present in a large proportion of patients with these two disorders, it opened up for the first time the possibility of a non-invasive diagnosis that could help clinicians identify these patients much more readily, hopefully allowing them to better plan for transplantation, and to use appropriate caution with available drugs.

Since that discovery the Intermountain investigators have been working to develop a clinical test, and through their agreement with ARUP have now made this sequencing-based analysis available to patients and physicians.

The test, either performed as part of ARUP's larger PAH NGS panel, which involves targeted capture of all coding exons and intron/exon junctions in the gene, followed by massively parallel sequencing, or as a single-gene test via Sanger sequencing. The lab also performs deletion/duplication analysis using a custom-designed comparative genomic hybridization array.

ARUP's Hunter Best, who co-developed the new test with Elliott's team at Intermountain, said that the two centers share revenues from the testing performed by ARUP.

Best said that other labs can also develop and offer clinical sequencing assays for mutations in EIF2AK4, and ARUP actually has helped other groups validate their own assays or provided sequencing for patients of other labs before they were able to implement their own tests.

Baylor College of Medicine, for example, has also added EIF2AK4 to the genes covered by the PAH panel offered through its John Welsh Cardiovascular Diagnostic Laboratory.

EIF2AK4 is not a perfect predictor of PVOD or PCH.  Some patients develop these particular hypertension disorders without inheriting a mutation in the gene. However, Elliott said, while this has not yet been researched thoroughly, so far it appears that the penetrance is high. If a person does have a known pathogenic mutation, they almost always develop pulmonary hypertension at some point in their life.

Though PVOD and PCH are relatively rare, Elliott estimated that there are "easily 50-100 centers around the US evaluating patients with pulmonary arterial hypertension."

"A lot of patients are seen and evaluated, and in that population there are going to be these cases, and they are hard to recognize. That's the challenge, and that's where I think genetic testing will have its value," he said.

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