Genetic discovery could be 'tip of the iceberg' to better understand lung disease among Inuit

In his years as a pediatric respirologist at CHEO, Dr. Tom Kovesi had cared for many children with severe respiratory illnesses. But one patient stood out.

Kovesi, who is also an investigator with the CHEO Research Institute, had been following the Inuk girl from Nunavut since she was a baby. CHEO is the tertiary centre for children from Nunavut. She had struggled through recurring bouts of severe pneumonia and serious ear infections.

Her condition was so severe that it was consistent with the rare disease known as primary cilliary dyskinesia, or PCD, which Kovesi describes as a “cousin” of cystic fibrosis. But the belief had always been that Inuit populations, which have among of the highest rates of lung disease in the world, did not have PCD.

That belief was based on previous research using less advanced diagnostic techniques than are currently available. In search of more information about her illness, Kovesi used an electron microscope to determine whether she had PCD, but the results were normal. Not satisfied, he tried genetic testing and that is where he found an answer: a never-before-discovered gene variant that causes PCD. He repeated the test at a second lab to be certain.

Once she was given treatment for PCD, her condition began to stabilize. The girl from Nunavut became Patient Zero for a new discovery that could have profound implications for treatment and better understanding of lung disease among members of the Inuit populations in Canada and elsewhere.

Genetic testing on other Inuit patients found others with the genetic marker for PCD.

Meanwhile, Dr. Adam Shapiro, an investigator in the Child Health and Human Development Program at the research institute of McGill University and a pediatric respirologist at Montreal Children’s Hospital, also found the gene variant in some patients.

Kovesi and Shapiro are co-senior authors of a paper published in the journal Pediatric Pulmonology that reports on seven Inuit patients with PCD identified through genetic testing.

The findings, in a gene called DNAH11 in Inuit individuals from both Nunavik in northern Quebec and Nunavut, suggest that the disease may be “quite common among Inuit and may be an important cause of lung disease in this population,” said Kovesi.

The research should lead to routine testing for Inuit with recurrent pneumonia and/or chronic lung disease to determine whether they have PCD, the authors wrote. Kovesi also said routine newborn screening for PCD through genetic analysis should be considered in Inuit regions.

Diagnosing PCD is important, Kovesi said, because treatments — similar to therapies to treat cystic fibrosis — are available. Treatment includes daily airway clearance and the use of antibiotics to prevent infections, among other things.

Primary ciliary dyskinesia, or PCD, is a rare disease that affects the tiny, hair-like structures (cilia) that line the airways. Cilia move together in wavelike motions. That motion carries mucus toward the mouth or nose to be coughed or sneezed out of the body.

But in patients with PCD, cilia do not work the same way to move mucus out of the body, which can cause breathing problems and recurrent infections.

PCD affects about one in 20,000 Canadians, but in Inuit populations, that number is estimated to be closer to one in 1,400, although more research is needed, say the authors of the paper.

Inuit populations have high rates of lung disease, including the highest known rates of respiratory syncytial virus (RSV) for children in the first year of life and high rates of tuberculosis.

“We see so much lung disease in the Inuit and it is so severe, it is disproportionate,” said Shapiro.

The genetic findings do not explain all of the lung disease in the Inuit population, he said, “but it explains some of it.”

Other key factors contributing to lung disease in Inuit populations include crowded and poorly ventilated housing and poverty.

Shapiro noted that out of 40 children being followed at Montreal Children’s Hospital for severe chronic lung disease, the majority do not have PCD.

Both Shapiro and Kovesi said more work needs to be done, not only to treat patients, but to better understand the genetic causes of chronic lung disease.

“I think this is the tip of the iceberg,” said Shapiro. “It will open the floodgates for more genetic work.”

Kovesi said better understanding of the prevalence of PCD caused by genetic variants in the gene DNAH11 and possibly other genes in the Inuit population will require more research. The work, he said, is an important step “towards improved delivery of care to affected Inuit families.”

onlinelibrary.wiley.com/doi/10.1002/ppul.26414