Researchers linked loss-of-function variants in the TMEM63B gene to a novel disorder causing interstitial lung disease in some pediatric patients.
RT’s Three Key Takeaways:
- Genetic Discovery: Researchers identified a novel disorder caused by biallelic loss-of-function variants in the TMEM63B gene, which results in severe lung disease.
- Clinical Presentation: Unlike gain-of-function variants linked to epilepsy, these loss-of-function mutations present as early onset respiratory distress and developmental delay without seizures.
- Diagnostic Impact: Identifying TMEM63B as a cause of pediatric interstitial lung disease (ILD) provides clinicians with a new target for diagnosing surfactant-related disorders.
Researchers at Baylor College of Medicine, Texas Children’s Hospital, and collaborating international institutions have identified a novel pediatric disorder caused by biallelic loss-of-function variants in the TMEM63B gene, which leads to severe lung disease.
The study, published in the American Journal of Human Genetics, describes how the disorder presented in five children from four unrelated families, according to Baylor College of Medicine. While previous studies linked gain-of-function variants in one copy of the TMEM63B gene to neurological symptoms like epilepsy and developmental delays, this report is the first to describe the symptoms of patients with biallelic loss-of-function variants.
The TMEM63B gene encodes an ion channel found in epithelial cells within the lungs and nerves:
- In gain-of-function cases, the ion channel remains open when it should be closed, which researchers believe triggers epilepsy.
- In loss-of-function cases, the individual inherits two abnormal copies of the gene, and the channel is missing 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 Jill Rosenfeld, associate professor of molecular and human genetics at Baylor and co-principal investigator of the Baylor Undiagnosed Diseases Network (UDN) site.
The first patient was identified through the UDN, a National Institutes of Health (NIH) research program. By posting the association of pulmonary symptoms and TMEM63B variants on the UDN website, researchers located four additional individuals with similar symptoms, including early onset respiratory distress, lung abnormalities, and developmental delay.
“Childhood interstitial lung disease may be caused by variants in genes that are important to the production and function of 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 Keren Machol, assistant professor of molecular and human genetics at Baylor and a clinical geneticist at Texas Children’s.
Functional evaluations of the variants showed a loss-of-function mechanism, and patient phenotypes paralleled previously studied Tmem63b-knockout mice that experienced neonatal respiratory failure.
“Through patient matching initiatives and international collaboration, we have successfully identified a novel TMEM63B-associated condition responsible for severe childhood lung disease. This discovery offers crucial answers to affected families and equips clinicians and diagnostic laboratories with new evidence for future diagnoses,” said Sock Hoai Chan, principal medical laboratory scientist at KK Women’s and Children’s Hospital and Duke-NUS Medical School.
