Novel disorder causing severe respiratory dysfunction linked to loss-of-function TMEM63B variant

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. Researchers at Baylor College of Medicine, Texas Children’s Hospital and collaborating institutions in Asia and Europe explain how this disorder presented in five individuals from four unrelated families.

Variants leading to gain-of-function of one copy of the TMEM63B gene (heterozygous variants) were previously associated with neurological symptoms, including developmental delays and epilepsy. However, no previous studies have described symptoms of patients with biallelic loss-of-function variants, in which the individual inherits two abnormal copies of the gene that do not work, one from each parent.

The first patient in the report enrolled at the Baylor and Texas Children’s site of the Undiagnosed Diseases Network, a National Institutes of Health-funded research program. Posting the association of pulmonary symptoms and loss-of-function TMEM63B variants in this patient on the UDN website ultimately facilitated the identification of four additional individuals with TMEM63B mutations and similar symptoms of early onset respiratory distress, lung abnormalities and developmental delay, but no epilepsy.

Functional evaluations of the patients’ TMEM63B variants showed a loss-of-function mechanism, and patient phenotypes paralleled previously studied Tmem63b-knockout mice with neonatal respiratory failure.

“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 co-corresponding author Dr. Keren Machol, assistant professor of molecular and human genetics at Baylor and a clinical geneticist at Texas Children’s.

TMEM63B encodes an ion channel found in epithelial cells in the nerves and the lung. When an individual has a gain-of-function variant, the ion channel remains open when it should be closed. “It seems like the brain is really sensitive to that, and that’s why those patients have epilepsy,” said co-author Jill Rosenfeld, associate professor of molecular and human genetics at Baylor and co-principal investigator of the Baylor UDN site.

When an individual has two loss-of-function variants, 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,” 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 the study’s first author, Dr. Sock Hoai Chan, principal medical laboratory scientist at KK Women’s and Children’s Hospital and Duke-NUS Medical School. “Our collective effort underscores the power of global partnerships in accelerating discoveries for even the rarest genetic conditions, and we are privileged to have contributed to this impactful research.”

Other contributors to this work include: Audra N. Iness, Mir Reza Bekheirnia, Lindsay C. Burrage, Matthew Hoi Kin Chau, Chaerish Eint Myet Chae Htoo, Eric C. Kao, Shamika Ketkar, Wan Wan Lim, Xi Luo, Rifhan Mazlan, Elizabeth Mizerik, Kein Seong Mun, Kalyani R. Patel, Lorraine Potocki, Christina K. Rapp, Xavier Roca, Ana Saianda, Ignacio Iglesias-Serrano, Everlyn C. Siew, Donald Yuhui Sim, David R. Spielberg, Sok-Kun Tae, Jing Xian Teo, Julian Warfsmann, Fan Xia, chILD-EU Registry, Saumya S. Jamuar, Ee Shien Tan, Matthias Griese, Weng Khong Lim and Meow-Keong Thong. They are affiliated with one or more of the following institutions: Baylor College of Medicine, Texas Children’s Hospital, 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, Genome Institute of Singapore and Universiti Tunku Abdul Rahman.

See the publication for a full list of funding for this work.