A study published in the American Journal of Human Genetics has identified a novel disorder caused by biallelic loss-of-function variants in the TMEM63B gene, resulting in severe lung disease. The research, conducted by scientists from Texas Children's Hospital, Baylor College of Medicine, and institutions in Asia and Europe, examined five individuals from four unrelated families.
Background
Previous research associated heterozygous gain-of-function variants in TMEM63B with neurological symptoms, including developmental delays and epilepsy. No prior studies had documented symptoms in patients with biallelic loss-of-function variants of this gene.
Key Findings
Patient IdentificationThe first patient was enrolled at the Texas Children's and Baylor site of the Undiagnosed Diseases Network (UDN), a program funded by the National Institutes of Health. After researchers posted the observed association between pulmonary symptoms and loss-of-function TMEM63B variants on the UDN website, four additional individuals with TMEM63B mutations and similar symptoms were identified.
Clinical PresentationAll five patients exhibited:
- Early onset respiratory distress
- Lung abnormalities
- Developmental delay
- Absence of epilepsy
Functional evaluations confirmed a loss-of-function mechanism. The observed patient phenotypes paralleled those of previously studied Tmem63b-knockout mice, which showed neonatal respiratory failure.
Genetic Mechanism
TMEM63B encodes an ion channel located in epithelial cells of nerves and the lung. The study reported that gain-of-function variants keep the channel open, while loss-of-function variants result in the absence of the channel.
"The brain is sensitive to gain-of-function, causing epilepsy. With loss-of-function, the brain has other channels, but the lung cannot compensate, explaining the different conditions based on variant type."
— Co-author Jill Rosenfeld, associate professor at Baylor and co-principal investigator of the Baylor UDN site.
Implications for Diagnosis and Management
"Childhood interstitial lung disease may be caused by variants in genes important for surfactant production and function. Surfactant-related disorders can be life-threatening, requiring early diagnosis and management. Identifying TMEM63B variants as a novel cause can significantly impact management."
— Dr. Keren Machol, co-corresponding author, clinical geneticist at Texas Children's and assistant professor at Baylor.
Researcher Comments
"Through patient matching and international collaboration, we identified a novel TMEM63B-associated condition causing severe childhood lung disease. This offers answers to families and evidence for future diagnoses. Our effort underscores global partnerships in accelerating discoveries for rare genetic conditions."
— Dr. Sock Hoai Chan, study first author, principal medical laboratory scientist at KK Women's and Children's Hospital and Duke-NUS Medical School.