TBX4, a gene first associated with pediatric pulmonary hypertension (PH) in 2013, is receiving international scrutiny from a 40-plus member consortium formed around research, clinical care and medical advocacy for patients and their families.
Eric D. Austin, M.D., M.S.C.I., director of the pediatric, pulmonary hypertension clinical and research program at Vanderbilt, spearheaded the TBX4Life consortium with Anton Morkin, a TBX4 carrier whose child has the mutation. Austin leads the group’s Scientific Advisory Board and Research Leadership Team.
“Inherently, this work is causing people to be more interested in other developmental lung irregularities that associate with PH as well.”
TBX4Life panelists study the genomic and genetic mutations, clinical features, relevant breakthrough discoveries, and animal and cell-based research models. With a publication on molecular studies under their belt, TBX4Life is poised to publish again in 2024, including a manuscript articulating clinical care recommendations.
“At TBX4Life, we are working to understand the pathogenic events by which TBX4 causes pulmonary hypertension, ultimately allowing us prevent, correct or compensate for TBX4 mutations as well as related gene variations involved in cardiopulmonary disease,” Austin said. “Inherently, this work is causing people to be more interested in other developmental lung irregularities that associate with PH as well.”
Discovery of the BMPR2 gene mutations, in which Vanderbilt emeritus professors James E. Loyd, M.D., and John H. Newman, M.D., and professor John A. Phillips, M.D., Ph.D., were instrumental, was the first genetic breakthrough in identifying a cause for the condition and a research target.
“At Vanderbilt, we’ve had an interest in genetic variation discovery and its impact on clinical care for a long time,” Austin said. “In the last 10 years, it’s been recognized that there are multiple genes that cause PH. BMPR2 accounts for the greatest proportion of mutation-based PH cases; TBX4 is now second on that list.”
Phenotype Variations
Children can develop pulmonary hypertension due to a variety of causes, such as inherent intrinsic abnormalities in their pulmonary or lung vasculature, secondary complications of lung development, regional lung disease, or congenital heart disease.
“Classically, pulmonary hypertension is a pulmonary vascular problem, but it is the heart that often succumbs to the downstream elevated pulmonary vascular pressure elevation,” Austin says.
The phenotypic spectrum caused by variations in the TBX4 and BMPR2 genes may differ significantly. BMPR2 mutations cause a purely pulmonary vascular disease with a cardiopulmonary impact that is often worse than in TBX4 mutations. However, the latter can cause interstitial irregularities and lung matrix problems, as well, and are often associated with congenital heart defects and skeletal abnormalities.
“The disease’s variable expression is poorly understood and a major target of our scrutiny at TBX4Life,” Austin said. “In its purest form, you may just have just a single gene irregularity with TBX4 itself, but there are also cases where not only the TBX4 but neighboring genes are deleted. These neighbors and the genes’ signaling partners are really important for lung development as well.”
Clinical Outcomes
In children, TBX4-associated conditions fall into two buckets. One is a focused, primary pulmonary vascular problem – pulmonary artery hypertension (PAH) – which most PH drugs target. Second is a condition similar to COPD in adults.
“Many newborns with TBX4-associated mutations have persistent PH,” Austin said. “Some of these infants die; some never get fully better and may become transplant candidates.
“Others have some transitional difficulties, then get better. But many eventually have PH symptoms down the road. Predicting which people will eventually develop PH as older children or adults remains an area of research focus. ”
Characterization Study
In 2019, Austin and his colleagues published a paper that was instrumental in prompting formation of TBX4Life. Their study goal was to define the clinical manifestations and histopathology associated with the TBX4 variants in neonates and children with PH.
“We knew there was a developing notion that TBX4 gene mutations were associated with PH,” Austin said. “We took the opportunity to pull together as many pediatric-onset cases, autopsy and biopsy specimens from across the world as we could to give people an initial sense of what we’re seeing in our patients clinically and in the lab.”
Building on Success
TBX4Life just had its second international scientific conference in November, 2023. Held virtually, more than 60 physicians, researchers and advocates attended.
“This was a huge success, leading us to establish more relationships and set the stage for more breakthroughs,” Austin said. “It’s been kind of a grassroots thing. We’re connected with patients and families who provide inspiration.”
Currently, TBX4Life is building a framework for an international registry to follow patients and collect blood specimens to support basic research, as well as facilitating research on TBX4 and related genes.
“People are hearing about us now, and we are pulling in various physicians and scientists,” Austin said. “When more clinicians think about the disease and understand it, that prompts people to think about other development lung diseases associated with PH. I’m interested in making sure that the full spectrum of PH is benefitting from our work together.”
