Rare BMPR2 variant linked to neurodevelopmental disorder in six children

A rare gain-of-function variant in the BMPR2 gene appears to cause a previously unrecognized neurodevelopmental disorder, according to a peer-reviewed study led by researchers at Texas Children’s Duncan Neurological Research Institute and Baylor College of Medicine. The same variant was identified in six unrelated children with overlapping developmental, behavioral and neurological features. Five children had global developmental delay affecting movement and speech or language, four had been diagnosed with autism spectrum disorder, and some experienced seizures, anxiety or hyperactivity. Experiments in fruit flies carrying the human variant showed excessive bone morphogenetic protein signaling and abnormal nervous-system development, providing a possible biological mechanism for the effects observed in the children.

The study, published in The American Journal of Human Genetics, focused on a genetic change that increases rather than reduces the activity of BMPR2. BMPR2 encodes a receptor on the surface of cells. Normally, it responds when a signaling molecule arrives and helps pass carefully timed instructions into the cell. Those signals belong to the bone morphogenetic protein, or BMP, pathway, which has important roles throughout the body, including brain development. In the experimental models used for this research, the newly identified variant made the receptor excessively active, in some settings even when the usual signal was absent. Scientists describe this type of change as a gain-of-function variant.

That direction of effect distinguishes the new finding from well-established disease-causing changes in BMPR2. Variants that reduce BMPR2 activity are already known to cause pulmonary arterial hypertension, a serious condition affecting blood vessels in the lungs. The variant examined here has the opposite effect: it increases BMPR2 activity and pushes BMP signaling into overdrive. The authors said the case illustrates how different alterations in the same gene can produce very different conditions depending on whether they lower or raise its activity. That distinction is important for interpreting genetic findings and for determining which therapeutic strategy, if any, might be appropriate.

Investigators began with genetic data from children who had neurodevelopmental conditions. The same rare BMPR2 variant was found in six unrelated children, a pattern that suggested the change could be responsible for their shared features rather than being an incidental finding. In at least five children, the variant had arisen spontaneously, or de novo, rather than being inherited from either parent. The researchers then recreated the human variant in fruit flies, a well-established model for studying genes involved in human neurological disease. This allowed them to test whether excessive BMPR2 activity could alter nervous-system development in a living organism.

Flies carrying the human BMPR2 variant displayed excessive BMP signaling and abnormalities in nervous-system development. When the variant was active in neurons, the flies developed too many connections known as synapses. Its effects were more severe when the variant was active in glia, the support cells of the brain, producing a much stronger increase in signaling and severe developmental effects. These observations suggest that several types of brain cells may contribute to the condition, although the fruit-fly experiments do not by themselves establish how the variant changes the developing human brain. They do, however, connect the rare human genetic finding to an experimentally observed disruption of developmental signaling.

The researchers also tested two experimental compounds developed at Baylor College of Medicine’s Center for Drug Discovery. In isolated fruit-fly tissues, both compounds reduced the excessive BMP signaling caused by the variant. The result provides early evidence that the overactive pathway can be brought under control in at least one experimental system. It does not demonstrate a treatment for children or establish a clinical benefit in people. Lead author Jung-Wan Mok described the compounds as research tools rather than treatments ready for clinical use. Corresponding author Shinya Yamamoto said the ability to reduce the abnormal signal in a living model provides a starting point for exploring whether the pathway could eventually be targeted safely.

For affected families, the identification of a recurring rare variant may provide a potential molecular explanation for developmental challenges that had not previously been diagnosed at the gene level. The finding also adds BMPR2 to the range of genes that may be relevant in appropriate evaluations of children with developmental delay, autism or related neurological features. However, the evidence presented in the study does not establish the full clinical spectrum of the condition or the frequency of the variant among people with neurodevelopmental disorders. Because only six children were identified, the phenotype and the boundaries of the newly recognized disorder will require further study with larger patient cohorts and additional clinical comparisons.

Several features limit the conclusions that can be drawn from the research. The human evidence came from six unrelated children, and the functional experiments were conducted in fruit flies rather than mammalian cells or animal models that more closely reproduce human brain development. Future work in mammalian systems will be needed to determine how the variant affects specific human brain cells, identify the populations most vulnerable to excessive BMP signaling and evaluate possible treatment approaches. The small human sample also means that the range and frequency of clinical features remain uncertain. The compounds were tested in isolated fly tissues, leaving their effects in people unknown.

Despite those limitations, the combined clinical and experimental evidence supports the conclusion that the rare BMPR2 change can produce a neurodevelopmental phenotype and excessive developmental signaling. The six affected children shared the same variant and overlapping developmental features, while the fly experiments demonstrated corresponding abnormalities in neurons and glia. The compound experiments further showed that the abnormal signal could be reduced experimentally. Taken together, the results expand the biological meaning of BMPR2 beyond its established association with pulmonary arterial hypertension and identify a signaling mechanism for future research, while leaving questions about the human brain, clinical treatment and the full range of associated phenotypes to be addressed in larger and more diverse studies.

Subject of Research: Rare gain-of-function BMPR2 variant associated with neurodevelopmental phenotypes in children and abnormal nervous-system development in fruit flies.

Article Title: Rare gain-of-function variant in BMPR2 identified as new cause of neurodevelopmental disorders

Article References: Rare gain-of-function variant in BMPR2 identified as new cause of neurodevelopmental disorders. Original publication (Bibliographic details unavailable.)

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Keywords: BMPR2, neurodevelopmental disorders, developmental delay, autism spectrum disorder, gain-of-function variant, BMP signaling, genetic diagnosis, fruit-fly model, rare disease, developmental neuroscience, Rare, gain-of-function