A new report in the American Journal of Human Genetics describes a novel disorder caused by biallelic loss-of-function variants in the TMEM63B gene, which results in severe lung disease, according to researchers at Baylor College of Medicine, Texas Children's Hospital and collaborating institutions in Asia and Europe on June 8. The disorder was observed in five individuals from four unrelated families.
Variants leading to gain-of-function of one copy of the TMEM63B gene had previously been associated with neurological symptoms such as developmental delays and epilepsy. However, no previous studies had described symptoms resulting from biallelic loss-of-function variants, where an individual inherits two abnormal copies of the gene that do not function.
The first patient described enrolled at the Baylor and Texas Children's site of the Undiagnosed Diseases Network, a National Institutes of Health-funded research program. After posting information about pulmonary symptoms and loss-of-function TMEM63B variants on the network's website, researchers identified four additional individuals with similar mutations and early onset respiratory distress, lung abnormalities and developmental delay but no epilepsy.
Functional evaluations confirmed a loss-of-function mechanism for these TMEM63B variants. The patient phenotypes were found to parallel those seen in previously studied Tmem63b-knockout mice that experienced neonatal respiratory failure. TMEM63B encodes an ion channel present in epithelial cells within nerves and lungs.
"It seems like the brain is really sensitive to that, and that's why those patients have epilepsy," said Jill Rosenfeld, associate professor of molecular and human genetics at Baylor College of Medicine and co-principal investigator of the Baylor UDN site. "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 lungs based on type of variant," Rosenfeld said.
"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 Dr. Sock Hoai Chan, principal medical laboratory scientist at KK Women's & Children's Hospital and Duke-NUS Medical School.
