Over the past 20 years, more than 100 genes have been found that cause specific lung diseases, most of which can be tested for by DNA sequencing. However, interpreting and acting upon genetic test results can be a challenging task for any physician not trained in genetics.  The Pulmonary Genetics Center at Brigham and Women’s Hospital is bridging the gap by providing this expertise to patients and referring physicians and assisting them in navigating this complex new field.

“There are individuals all over the world who have particular expertise in one genetic form of lung disease – be it cystic fibrosis, alpha-1 antitrypsin deficiency, or other rare diseases,” said Benjamin Raby, MD, MPH, Director of the Pulmonary Genetics Center at the Brigham’s Lung Center. “But there really is no other place with expertise in genetics writ large, in an integrated multi-disciplinary, multi-specialty center to evaluate these patients comfortably.”

“We provide these services to help clarify and demystify genetic testing for patients with pulmonary disease and to help educate the physicians who consult us – so that they become more empowered to think about testing moving forward,” Raby said.

The idea for the Pulmonary Genetics Center emerged at a retreat for the hospital’s Division of Pulmonary Care and Critical Medicine about eight years ago, when colleagues turned to Dr. Raby, a clinician and researcher in the genetics of asthma, with an observation: “What we really need is the clinical capacity to evaluate these patients genetically.”

The timing was right. Raby had been working with the Laboratory for Molecular Medicine at Partners Healthcare to devise what became the PulmoGene Panel test for 64 genes, the first to evaluate multiple genes simultaneously across a wide spectrum of pulmonary diseases. As the Panel was nearing completion, Raby moved forward to offer genetic testing services at the Brigham. This early work set a cornerstone.

“Although the technologies are rapidly evolving in this field,” said Raby, “we have put in place this expertise and culture at Brigham and Women’s so that we are now in a position to implement the most appropriate applications for each patient.”

An Evaluative and Supportive Service for Patients and Referring Physicians

Today at the Pulmonary Genetics Center, patients may be tested with either the PulmoGene Panel or other whole-genome tests depending on their needs. Patients and their physicians typically seek out the Pulmonary Genetics Center to explore a range of scenarios:

• a lung condition for which the referring physician suspects a genetic cause, such as familial pulmonary fibrosis, idiopathic bronchiectasis, familial pneumothorax or lung disease with very early onset or other atypical features.
• a confirmed diagnosis for which a pulmonologist seeks guidance in how to care for a rare disorder, such as primary ciliary dyskinesia (PCD). The Brigham is the only PCD Foundation Center of Excellence for adults in New England.
• a strong family history or an incidental finding from other genetic testing.

Each new patient first is evaluated by Raby or another pulmonologist with expertise in genetics and meets with a genetic counselor to learn the potential implications of testing.

After a patient is tested and a diagnosis made, the referring physician receives a comprehensive overview of the results and a suggested management plan. Physicians of the Pulmonary Genetics Center are available for further consultation on long-term management.

“I view us as an evaluation and supportive service,” said Raby.  “We don’t manage the cases long-term or take over the care of these patients, unless specifically requested to do so. Rather, we want to see physicians becoming more comfortable with genetics.”

The Center’s mission also includes training the next generation of clinicians. Brigham fellows in pulmonary medicine regularly attend the clinic, as do Harvard Medical School’s medical genetics fellows. The program also hosts genetic counselors in training to familiarize them with lung disease.

Creating a resource and expertise in pulmonary genetic medicine is increasingly important as more genetic variants are identified and lines blur between monogenic and polygenic causes of lung disease. “Interpreting reports is complicated when you are looking at one or two genes — let alone the whole genome,” said Raby. “Most physicians have not received the training to do this.”

When the Diagnostic Journey Ends, Focus Switches to Care

Dr. Raby has seen how a genetic diagnosis can reassure patients and influence how they approach treatment. “The attitude of patients afterward is totally different when they realize this isn’t something they did to themselves and they are not to blame,” he said. “I explain, ‘We now understand one of the variants that is driving your health issues. And now we can confront it head on.’”

Testing often brings an end to the diagnostic odyssey. Then, the patient and physician can focus on care. Due largely to advances that did not exist just a few years ago, genetic diagnosis can now lead to very specific changes in a care plan, including:

• new medications now available for cystic fibrosis variants
• aggressive management of patients with short telomere syndrome, including early consideration for lung transplantation and screening for extrapulmonary complications in the bone marrow and liver
• use of biologics in patients with immune-dysregulation syndromes caused by genetic mutation

Conditions like these eventually may be amenable to more direct therapies like RNA-inhibition or CRISPR-Cas9 gene editing. “We’re seeing just the tip of the iceberg of being able to treat these patients,” Raby said.

Genetic screening also opens the door to early identification and therapy for family members who may share the genetic mutation but do not yet show symptoms of disease. In a NIH-funded study, Dr Raby and collaborators Ivan Rosas, MD and Gary Hunninghake, MD are studying the role of genetic testing in screening at-risk relatives of patients with idiopathic pulmonary fibrosis (IPF). Once a diagnosis of IPF is made, eligible first-degree family members are invited to undergo a free evaluation that includes genetic screening, assessment of lung function and lung imaging studies.

The study is still ongoing, but an interim analysis suggests a detection rate of interstitial lung disease in these relatives that is much higher than previously expected. Several of these family members in the study are now receiving medical care for fibrosis that was discovered through this study.

Raby recently became Division Chief for Pulmonary Medicine at Boston Children’s Hospital, while he continues to lead the Pulmonary Genetics Program at nearby Brigham and Women’s Hospital.

“One goal is to bridge the generations in pulmonary medicine,” he said. “We want to create comprehensive care across the family.”