Probably Genetic

Raising awareness for fibrodysplasia ossificans progressiva (FOP), a rare and devastating genetic condition. Stories like this are a powerful reminder of why continued research, advocacy, and compassion matter. #RareDisease #FOPAwareness #GivingForAJ

Each month, we explore a gene that connects rare and common disease biology. This month: GBA Last month, we looked at the peroxisome. This month, we turn to another organelle at the center of cellular health: the lysosome, the cell’s recycling system, responsible for breaking down and clearing waste. GBA encodes glucocerebrosidase, an enzyme that breaks down certain lipids inside the lysosome. When both copies of the gene are disrupted, patients develop Gaucher disease, a classic metabolic disorder characterized by enlarged liver and spleen, bone disease, and blood abnormalities [1]. At first glance, this seems far removed from Parkinson’s disease, a neurodegenerative condition affecting the brain. But over time, clinicians began to notice something unexpected. Patients with Gaucher disease and even individuals carrying a single GBA mutation appeared more likely to develop Parkinsonian symptoms later in life. What initially looked like coincidence turned out to be something more fundamental. Large genetic studies have since shown that GBA mutations are among the strongest genetic risk factors for Parkinson’s disease [2,3]. Today, we know that a meaningful fraction of Parkinson’s patients carry GBA variants, with earlier onset and more rapid cognitive decline and motor impairment in many cases [4,5]. The connection comes back to the lysosome. When GBA function is reduced, lipids accumulate and lysosomal activity declines. As a result, proteins like α-synuclein, which play a central role in Parkinson’s pathology, are not cleared effectively and begin to aggregate. In this sense, Parkinson’s disease is, at least in part, a disorder of impaired cellular recycling [6]. What started as a rare disease observation is now shaping how we understand a common neurodegenerative condition. GBA-associated Parkinson’s is increasingly recognized as a distinct subtype, and therapies are now being developed to target lysosomal function, glucocerebrosidase activity, and lipid metabolism [6]. GBA is a reminder that rare diseases are not rare biology. Extreme phenotypes like Gaucher disease can reveal the core mechanisms driving much more common conditions. Rare disease may represent the most extreme breakdown of a system that affects all of us. 🧬 Gene of the Month References in comments

No family should have to wait decades for answers. We’re grateful Betsy trusted Probably Genetic in her search for clarity, and we’re proud to stand alongside families navigating rare genetic conditions every day. Read Betsy and Kali's story: https://lnkd.in/ddiAivMW

Each month, we explore a gene that connects rare and common disease biology. This month: PEX10 PEX10 helps build and maintain an important organelle called the peroxisome, the cell’s behind-the-scenes alchemist. The peroxisome plays an essential role in detoxification, supports a wide range of metabolic functions, and helps keep our cells in balance. Genetic mutations in PEX10, along with other PEX genes, cause Peroxisome Biogenesis Disorders (PBDs), rare conditions that disrupt peroxisome formation and function and can affect many organs, including the brain [1]. Patients often present early in life with neurological symptoms, developmental delay, and dysfunction affecting multiple organ systems [2]. But that’s just where the story starts. In addition to rare genetic disease, peroxisomal dysfunction is involved in many common diseases, including aging, cancer, metabolic diseases such as diabetes, neurodegeneration (including Alzheimer’s, Parkinson’s, ALS, and multiple sclerosis), and viral infections [3, 4]. In these contexts, impaired peroxisome function can lead to the buildup of toxic metabolites and disrupted lipid metabolism, contributing to cellular stress and disease [5]. Peroxisomes are a vital system in every cell in the body, but they have been largely overlooked by modern science. They are severely understudied, receiving just a small fraction of the scientific funding that other organelles like mitochondria receive. Progress in understanding the peroxisome's diverse roles in human disease will depend on building a coordinated ecosystem that connects basic biology to therapeutic development. We’re excited to work with groups like PBD Project and leaders like Andrew Longenecker who are pushing this research forward. Rare disease may represent the most extreme breakdown of a system that affects all of us. 🧬 Gene of the Month References in comments👇

We're honored to see our CEO, Lukas Lange, featured by the Termeer Institute, and very grateful for the partnership and support from this community!

Super fascinating work, Karl Heilbron. Can’t wait to try CALDERA on our dataset at Probably Genetic!

Evaluate Ltd Pharma’s 2026 Orphan Drug Report was recently released and if you haven’t seen it yet, we highly recommend checking out [1]. The main takeaways are that orphan drugs are projected to exceed $400B in annual sales by 2032, accounting for 21% of all prescription drug revenue (up from 15% in 2022). To put that in perspective, that’s roughly the size of the entire pharma market just 20 years ago. What’s notable is that this growth is happening despite a challenging backdrop: ° pricing pressure ° regulatory volatility ° capital shifting toward common diseases (e.g., obesity) What’s driving this is fairly straightforward: we’ve barely scratched the surface. 95% of rare diseases still have no approved treatment [2], the long-term opportunity here is still largely untapped. At the same time, the underlying economics and development dynamics are stronger than many people expect. Orphan drugs are more likely to succeed in clinical development, with higher probabilities of advancing from Phase 1 to approval [3][4]. And despite targeting smaller populations, they’re just as lucrative as non-orphan drugs on median sales [5]. So we have strong science, strong economics, and growing investment, but there’s still a gap between building these therapies and finding the patients they’re built for. In our experience, the key bottleneck is patient finding - orphan drugs typically target small populations, so for getting these drugs to market, identifying and recruiting patients quickly is critical. That’s a big part of why the work in this space matters so much. As more therapies are developed, solving patient identification isn’t just an operational challenge, it’s increasingly central to whether these drugs can actually be developed and reach the people they’re developed for. What stood out to you in the Evaluate Pharma report, and where do you think the biggest constraints are as the orphan drug space continues to scale? References in comments👇

For decades, one of the most cited claims in drug discovery has been that targets supported by human genetic evidence are 2-3x as likely to lead to an approved drug in a world where 90% of drugs fail due to lack of safety or efficacy (see Marios Georgakis' excellent in-depth discussion of this finding [1]). The underlying hypothesis is that perturbations in biological pathways driven by naturally occurring genetic variants provide a window into the efficacy and safety margins associated with interfering with a specific target. Phase 1 of the industry’s approach to genetically informed target discovery focused largely on target validation and prioritization. Genetic evidence helped confirm that modulating certain pathways could produce meaningful clinical effects. Examples include: • PCSK9, where LOF variants have been shown to be linked to lower LDL cholesterol levels [2] and reduced cardiovascular risk, resulting in targeted monoclonal antibody therapies, and • GPR75, where rare variants associated with protection from obesity [3] suggested a previously unknown mechanism, resulting in the development of BEBT-809. This phase relied heavily on large cohort genetics studies to identify protective or risk variants and then ask whether those genes are druggable [4]. As sequencing is becoming cheaper and cohorts are becoming larger, finding genetic associations is no longer the bottleneck. At the same time, moving from variant to causal gene to mechanism to treatment remains as difficult as ever. Enter Phase 2 of genetically informed target discovery: Rather than studying genetics in isolation, the field is increasingly integrating population genetics with multi-omics, (longitudinal) clinical phenotypes, and functional perturbation screens to move toward complete causal models of disease biology (Jean-Philippe Vert recently discussed the case for foundation models for rare diseases on The Bio Report [5]). This shift is evident in the wave of recent biopharma partnerships built around large-scale human datasets and AI-driven analysis. So where is genetics-driven drug discovery headed? Probably toward a model where: • Population-scale human genetic evidence defines the search space, and • Foundational AI models help translate associations into mechanisms and, ultimately, treatments. If this works, it might help us develop therapies we would never have found otherwise. I’d be curious to hear how others think about this shift! References in comments 👇

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Thank you to Fidji Simo, CEO of OpenAI Applications, and Becky Quick of CNBC for mentioning our work at the CNBC Cures Summit! https://lnkd.in/gvF_8tSw