Novel TMEM63B Biallelic Loss-of-Function Variants Cause Severe Childhood Interstitial Lung Disease
Key Insights
Researchers identified a novel genetic disorder caused by biallelic loss-of-function variants in the TMEM63B (search) gene, presenting as severe childhood interstitial lung disease (search) in five individuals from four unrelated families.
Unlike heterozygous gain-of-function TMEM63B (search) variants linked to epilepsy and developmental delays, biallelic loss-of-function variants result in early-onset respiratory distress and lung abnormalities without epilepsy.
Functional studies confirmed a loss-of-function mechanism, with patient phenotypes mirroring Tmem63b (search)-knockout mice that exhibit neonatal respiratory failure.
A new study published in the American Journal of Human Genetics has identified a novel genetic disorder caused by biallelic loss-of-function variants in the TMEM63B (search) gene, resulting in severe childhood interstitial lung disease (search). The international research effort, led by Baylor College of Medicine and Texas Children's Hospital with collaborating institutions across Asia and Europe, characterized the condition in five individuals from four unrelated families.
The discovery marks the first time that biallelic loss-of-function TMEM63B (search) variants have been linked to human disease. Previously, heterozygous gain-of-function variants in the same gene were associated with neurological symptoms including developmental delays and epilepsy. The newly described disorder presents with a distinct clinical picture: early-onset respiratory distress, lung abnormalities, and developmental delay, but notably without epilepsy.
From an Undiagnosed Case to a Global Collaboration
The first patient was enrolled at the Baylor and Texas Children's site of the Undiagnosed Diseases Network (UDN), a research program funded by the National Institutes of Health. When the association between pulmonary symptoms and loss-of-function TMEM63B (search) variants was posted on the UDN website, it catalyzed the identification of four additional individuals carrying TMEM63B mutations with strikingly similar clinical presentations.
"Through patient matching initiatives and international collaboration, we have successfully identified a novel TMEM63B (search)-associated condition responsible for severe childhood lung disease," said Dr. Sock Hoai Chan, the study's first author and principal medical laboratory scientist at KK Women's and Children's Hospital 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."
Mechanistic Insights: Ion Channel Function in Lung and Brain
TMEM63B (search) encodes an ion channel expressed in epithelial cells of both the nervous system and the lungs. The divergent clinical consequences of different variant types reflect tissue-specific vulnerability. Gain-of-function variants cause the ion channel to remain open when it should be closed, with the brain appearing particularly sensitive to this dysregulation, leading to epilepsy.
In contrast, biallelic loss-of-function variants result in the complete absence of the channel. "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," explained co-author Jill Rosenfeld, associate professor of molecular and human genetics at Baylor and co-principal investigator of the Baylor UDN site.
Functional evaluations confirmed the loss-of-function mechanism for the patients' TMEM63B (search) variants. Importantly, the patient phenotypes paralleled those observed in previously studied Tmem63b-knockout mice, which exhibit neonatal respiratory failure.
Clinical Implications for Surfactant-Related Disorders
Childhood interstitial lung disease (search) can be caused by variants in genes critical to surfactant production and function. Surfactant, the material that enables lung expansion during breathing, is essential for respiratory health, and surfactant-related disorders can be life-threatening, requiring early diagnosis and appropriate management for optimal clinical outcomes.
"Identifying variants in TMEM63B (search) as a novel cause of this condition can significantly impact management of patients with this rare disorder," said co-corresponding author Dr. Keren Machol, assistant professor of molecular and human genetics at Baylor and a clinical geneticist at Texas Children's Hospital.
The study underscores the power of global partnerships in accelerating discoveries for even the rarest genetic conditions. Contributing institutions included KK Women's and Children's Hospital, Duke-NUS Medical School, the Chinese University of Hong Kong, Baylor Genetics, University of Malaya Medical Center, Ludwig-Maximilian University Munich, Nanyang Technological University, University of Lisbon, Universitat Autònoma de Barcelona, SingHealth, the Genome Institute of Singapore, and Universiti Tunku Abdul Rahman, along with the chILD-EU Registry.