A new report in the American Journal of Human Genetics describes a new disease caused by a biallelic loss-of-function variant. TMEM63B A gene that causes severe lung disease. Researchers from Baylor College of Medicine, Texas Children’s Hospital, and collaborating institutions in Asia and Europe describe how five people in four unrelated families developed the disorder.
Variants that lead to gain of function in one copy of TMEM63B The gene (heterozygous variant) has previously been associated with developmental delay and neurological conditions such as epilepsy. However, previous studies have not reported symptoms in patients with biallelic loss-of-function variants. In this variant, a person inherits two abnormal copies of a non-functional gene, one from each parent.
The first patients in the report enrolled at the Baylor and Texas pediatric sites of the Undiagnosed Disease Network, a research program funded by the National Institutes of Health. Post a link between lung symptoms and loss of function TMEM63B Confirmation of this patient’s mutation on the UDN website ultimately facilitated the identification of four additional infected individuals. TMEM63B There are mutations and similar symptoms such as early-onset breathing difficulties, lung abnormalities, and growth retardation, but epilepsy is not present.
Patient functional assessment TMEM63B The mutant exhibited a loss-of-function mechanism, and the patient’s phenotype was similar to those studied previously Tmem63b– Knockout mice with neonatal respiratory failure.
Interstitial lung disease in children may be caused by mutations in genes important for the production and function of surfactants, substances that help the lungs expand during breathing. Surfactant-related diseases can be life-threatening and require early diagnosis and appropriate management to achieve the best clinical outcome. Identifying variants TMEM63B This new cause of the condition may have a major impact on the management of patients with this rare disease. ”
Dr. Kellen McCall, co-corresponding author, assistant professor of molecular and human genetics at Baylor University and clinical geneticist at Texas Children’s Hospital
TMEM63B Encodes an ion channel found in nerve and lung epithelial cells. If an individual has a gain-of-function variant, ion channels remain open when they should be closed. “The brain seems to be very sensitive to that, and that’s why these patients have epilepsy,” said co-author Jill Rosenfeld, associate professor of molecular and human genetics at Baylor University and co-principal investigator of the Baylor UDN site.
If an individual has two loss-of-function variants, the channel is completely lost. “The brain has other channels that can compensate for the deficit. But the lungs don’t have the ability to compensate for the loss of that channel. Perhaps this is why we see differences in conditions affecting the brain and lungs based on the type of mutation,” Rosenfeld said.
“Through patient matching efforts and international collaboration, we have succeeded in identifying new treatments. TMEM63B– Associated diseases that cause severe childhood lung disease. “This discovery provides important answers for affected families and provides clinicians and diagnostic laboratories with new evidence for future diagnoses,” said the study’s lead author and principal investigator at KK Women’s and Children’s Hospital and Duke-NUS School of Medicine. “Our joint efforts highlight the power of global partnerships to accelerate the discovery of even the rarest genetic diseases, and we are honored to have contributed to this impactful research,” said Dr. Soc Hoai Chan, Chief Clinical Laboratory Scientist.
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Baylor College of Medicine
Reference magazines:
Chan, S.H. others. (2026). Biallelic loss-of-function mutants of TMEM63B cause a syndromic surfactant dysfunction disorder. American Journal of Human Genetics. DOI: 10.1016/j.ajhg.2026.05.008. https://www.cell.com/ajhg/abstract/S0002-9297(26)00195-3
