Scientists have discovered the underlying source of a rare, novel respiratory disorder. The report, which was published in the American Journal of Human Geonomics, describes how biallelic loss-of-function variants in the TMEM63B gene causes the severe lung disease.
According to researchers at Baylor College of Medicine and Texas Children’s Hospital in Houston, no previous studies had reported symptoms of the affected patients due to biallelic loss-of-function variants. They had seen studies where patients with gain-of-function (one copy) of the TMEM63B gene had led to neurologic symptoms, such as epilepsy. Their research findings are detailed in the report, “Biallelic loss-of-function variants in TMEM63B cause syndromic surfactant dysfunction disorder.”
The TMEM63B gene encrypts an ion channel found in epithelial cells of the lungs and nerves. When an individual is born with two abnormal copies of the same gene (one from each parent), they are missing this channel entirely.
“The brain has other channels that can pick up the slack. But in the lung, there is no ability to make up for the loss of that channel. This is probably why we see the differences in conditions impacting the brain and the lungs based on the type of variant,” said co-author Jill Rosenfeld, PhD, in a Baylor news release. Dr. Rosenfeld is an associate professor of molecular and human genetics at Baylor.
The first patient included in the new report enrolled in the Baylor and Texas Children’s site of the Undiagnosed Disease Network (UDN), where Dr. Rosenfeld is also a co-principal investigator. Four additional individuals with the same pulmonary symptoms and TMEM63B mutations were identified through the UDN website. All five patients demonstrated signs of lung abnormalities, early onset respiratory distress and developmental delay, but no epilepsy.
“Through patient matching initiatives and international collaboration, we have successfully identified a novel TMEM63B-associated condition responsible for severe childhood lung disease,” said first author Sock Hoai Chan, PhD, principal medical laboratory scientist at KK Women’s and Children’s Hospital in Singapore and Duke-NUS Medical School. “This discovery offers crucial answers to affected families and equips clinicians and diagnostic laboratories with new evidence for future diagnoses.”
The group of patients underwent functional evaluations to confirm the loss-of-function mechanism in the TMEM63B variants. Researchers also found the patients’ phenotypes matched previously studied TMEM63B-knockout mice with neonatal respiratory failure.
“Childhood interstitial lung disease may be caused by variants in genes that are important to the production and function of the surfactant, the material that helps our lungs to expand with breathing. Surfactant-related disorders can be life-threatening, requiring early diagnosis and appropriate management for best clinical outcome. Identifying variants in TMEM63B as a novel cause of this condition can significantly impact management of patients with this rare disorder,” said co-corresponding author Keren Machol, PhD, assistant professor of molecular and human genetics at Baylor and a clinical geneticist at Texas Children’s.
The Texas-based research team collaborated with institutions in Asia and Europe.
