Researchers first discovered the cause of achondroplasia and hypochondroplasia in 1994. They learned that changes in the gene that encodes for fibroblast growth factor receptor 3 (FGFR3) lead to overactive signaling by the FGFR3 receptor, which can impair skeletal development and growth, compress bodily systems, and lead to a number of impacts on health and quality of life.

While both conditions stem from variants in FGFR3, the path to diagnosis varies drastically.

“On a genetic level, achondroplasia is relatively simple – it is almost always caused by a single protein change in FGFR3, there is well-defined genetic screening and it’s quite straightforward to diagnose at or before birth,” says Dan Gaffney, Vice President and Head of Genomics at BioMarin. “Hypochondroplasia is completely different. Sometimes genetic screening results will come back with a variant that is on the FGFR3 gene, but it’s a variant that no one has ever seen before, so an official diagnosis can’t be made. These are called variants of uncertain significance, and they leave patients, families and clinicians in a sort of limbo.”

BioMarin is working to change this paradigm in hypochondroplasia, a skeletal dysplasia caused by multiple genetic variants that often presents with more subtle symptoms than achondroplasia. Using genetic screening data, in vitro studies, clinician interviews and family histories, BioMarin scientists published findings on significant DNA variations in the gene encoding FGFR3. These findings could reclassify some FGFR3 gene variants of uncertain significance as pathogenic for hypochondroplasia, potentially enabling definitive diagnoses and broader access to specialized care.

BioMarin presented this research at the annual meeting of the American College of Medical Genetics and Genomics in March. The company plans to keep working to identify additional FGFR3 variants, in the hope of identifying further links to hypochondroplasia to help enable clinicians to provide the best possible care.

“This project exemplifies BioMarin’s expertise in genetics, and our commitment to make an impact beyond a new medicine,” says Greg Friberg, Chief Research and Development Officer. “Efforts like these can help enhance scientific understanding, improve diagnosis and transform medical practice, all for the betterment of patients living with these conditions.”

Changing the Diagnostic Landscape of Hypochondroplasia

The use of genetic tests to help diagnose certain health conditions began in the 1950s when scientists were first able to detect large changes in chromosome structure, such as those seen in Down syndrome. As the collective understanding of genomics has evolved, genetic screening has become a key tool to help identify or confirm the diagnosis of a range of genetic conditions and predispositions.

Still, variants of uncertain significance remain a challenge. One study published in 2023 found that 41% of nearly 1.7 million people screened for hereditary conditions had at least one variant of uncertain significance. The study also showed that of the more than 500,000 variants discovered, only 7.3 percent had been reclassified as pathogenic or benign.

“This is a real puzzle, because even if there are potential signs of a condition, clinicians are often unable to make an official diagnosis and are left treating symptoms instead of a definitive condition,” says Dan.

This situation often leads to more questions than answers, contributing to the underdiagnosis of many conditions, including hypochondroplasia. Without definitive genetic diagnosis, individuals may be classified as having idiopathic short stature, a term used when no medical cause of short stature can be identified.

“Uncertain diagnoses can affect the timeliness and quality of an individual’s care and has led to insufficient natural history data in hypochondroplasia,” says Marcia Kayath, Senior Vice President and Head of Global Medical Affairs, who began her career as a physician and endocrinologist. “This contributes to the often incorrect perception of hypochondroplasia as a milder form of achondroplasia.”

BioMarin scientists sought to understand the FGFR3 gene’s role in genetic short stature by combining internal expertise with external databanks. In collaboration with Medical Affairs teammates, statistical geneticist Chris Bauer utilized de-identified results from a skeletal dysplasia genetic screening initiative.

“We built on BioMarin’s existing knowledge base around FGFR3 variants and noticed a significant number of variants of uncertain significance associated with various degrees of short stature,” says Chris, who is Associate Director, Statistical Genetics. “When we looked at overlapping datasets, we found that the same variants were coming up over and over again.”

In all, the team has reviewed 119 variants for a possible link to hypochondroplasia. While this practice is not new, this application represents BioMarin’s most holistic effort to reclassify variants of uncertain significance to date.

“Historically, we’ve acted as a central hub for data from global researchers and testing facilities, which we evaluate to determine whether they’ve captured some of these same variants,” says Mitch Bailey, Associate Director, Medical Diagnostics. “This FGFR3 initiative takes that to the next level because it’s powered by additional data from our teams and information from one-to-one clinician interviews. Putting all these pieces together, we are meaningfully advancing our shared understanding of the genetics of hypochondroplasia.”

Ashley Volz, Associate Medical Director, Global Medical Affairs, led clinician interviews involving a questionnaire, patient chart review and family history discussion for variant reclassification. The team identified three variants for evaluation by impartial reviewers, with more to follow.

“Many clinicians are not as familiar with interpreting results from gene panels, particularly when variants of uncertain significance are found. This project has motivated some to change the way in which they order testing, and for whom,” says Ashley, who worked as a genetic counselor prior to joining BioMarin. “It’s a great example of what coordinated efforts from healthcare professionals, researchers, statisticians and labs can achieve in variant reclassification.”

Looking Ahead

Chris notes the team is close to building on the number of variants it puts forward for reclassification, and committed to continue sharing these findings along the way.

“We’re zeroing in on 10 to 12 additional variants that we think may ultimately be reclassified as pathogenic,” he says.

The plan is to keep using state-of-the-art data science technologies to build a fuller diagnostic profile of hypochondroplasia.

“We’re going to try and test every possible variant in this gene, using an innovative new experimental technique that leverages modeling, to give clinicians even more data to help them confidently make a hypochondroplasia diagnosis,” says Dan. “We have to know absolutely everything about this gene to help the most people we can.”