Ivan Kairatov has spent years at the intersection of biopharmaceutical innovation and rare disease research, witnessing firsthand how genomic technologies evolve from experimental tools to life-saving clinical standards. As an expert in the field, he brings a deep understanding of the systemic changes required to move beyond traditional diagnostic hurdles that often leave families in limbo for years. In this discussion, he explores the profound impact of large-scale genomic programs like the Telethon Undiagnosed Disease Program, the transition to advanced sequencing modalities, and the emotional relief that a definitive molecular diagnosis provides to those caught in a decade-long search for answers.
Many children wait nearly a decade for answers regarding rare conditions. How does achieving a nearly 50% diagnostic yield fundamentally change daily clinical management, and what specific steps are taken when a pathogenic variant is identified across hundreds of different possible genes?
Achieving a diagnostic yield of 49% is a transformative milestone because it effectively ends what we call the “diagnostic odyssey,” which for many families in the program lasted nearly ten years. When we identify a pathogenic variant among the 330 different genes discovered so far, the clinical management shifts from a broad, reactive approach to a highly specific, proactive strategy. We can immediately move away from inconclusive, repetitive testing and focus on the precise medical needs associated with that specific genetic label, which is often delivered within 12 to 18 months of entering the program. This allows clinicians to tap into a global community of researchers and established protocols, transforming a child’s medical “hope” into a concrete roadmap for treatment and specialized care.
Systematic reanalysis can boost diagnostic rates by over 17% for previously negative cases. What is the standard protocol for revisiting unsolved genomic data, and how do you determine when a case warrants transitioning from exome sequencing to more advanced methods like RNA sequencing?
The protocol for reanalysis is based on the philosophy that unsolved cases are not failures, but rather scientific resources waiting for the right key to unlock them. By systematically revisiting data as our knowledge of disease-gene associations expands, we have seen an overall diagnostic boost of more than 17% for cases that were initially negative. We transition to more advanced methods like RNA sequencing or whole-genome sequencing when traditional exome sequencing fails to explain a severe, complex phenotype, particularly when we suspect deep intronic or splicing variants. This layered approach ensures that as genomic technologies and biological knowledge evolve, the data remains a living asset that can eventually provide the “single word” or name the family has been searching for.
Since more than 70% of causative variants appear spontaneously with no prior family history, how does this affect the initial screening process? How do these findings specifically influence reproductive counseling and the long-term support provided to families once they receive a name for their condition?
The finding that over 70% of causative variants are de novo—meaning they arise spontaneously—fundamentally reshapes how we approach the screening process, moving the focus away from traditional hereditary patterns toward comprehensive trio-based sequencing. For parents, this is often a moment of immense psychological relief, as it clarifies that the condition was not something passed down through generations, which directly informs their future reproductive choices. Once a diagnosis is confirmed, we provide long-term support through services like InfoRare, which connects families to patient associations and clinical trials. This molecular label provides more than just a medical path; it offers a sense of identity and connection to a global patient community, which is vital for the emotional well-being of the entire family unit.
Global platforms now help identify variants in newly discovered genes like RNU4-2 by connecting patients worldwide. How does this international data sharing accelerate the validation of candidate genes, and what are the primary hurdles when collaborating across different borders on rare disease research?
International collaboration is the lifeblood of rare disease research, as evidenced by our recent identification of 11 probands with variants in the RNU4-2 gene through systematic reanalysis. Platforms like Matchmaker Exchange and PhenomeCentral allow us to find matching cases across the globe, which is often the only way to prove that a rare candidate gene is truly causative. The primary hurdles involve harmonizing complex phenotypic data and navigating the different regulatory frameworks of various national health systems, but the payoff is the rapid validation of new disease-gene associations. By contributing to networks like the Undiagnosed Diseases Network International and the Solve-RD project, we turn isolated cases into a collective scientific effort that accelerates the path from discovery to clinical application.
A molecular diagnosis often opens doors to precision pharmacology, antisense oligonucleotides, or gene therapy. Could you describe a scenario where a genetic label directly altered a child’s treatment plan, and how can health systems ensure these targeted therapies remain accessible to families?
A molecular diagnosis is the gateway to precision medicine, where a specific genetic label can lead a child away from general supportive care and toward targeted interventions like antisense oligonucleotides or gene therapy. For example, in our cohort, identifying specific variants has allowed families to access pilot initiatives for personalized treatments that address the underlying genetic cause rather than just managing symptoms. To ensure these therapies remain accessible, we must advocate for the integration of structured genomic programs into national health systems rather than relying on fragmented clinical efforts. By proving that early genomic testing prevents years of inconclusive and expensive medical visits, we build a strong economic and ethical case for making these life-changing therapies a standard part of pediatric care.
Integrating artificial intelligence and long-read sequencing represents the next frontier in genomic medicine. How will these tools help solve structurally complex cases that escape traditional testing, and what training is required for clinicians to interpret these increasingly complex data sets effectively?
Artificial intelligence and long-read sequencing are essential for tackling the “dark matter” of the genome, such as structurally complex rearrangements and optical mapping of regions that traditional short-read sequencing simply cannot see. These tools allow us to classify variants with much higher precision, but they also require clinicians to undergo significant training in bioinformatic interpretation and data management. We are currently integrating trio whole-genome sequencing and AI-driven classification as entry-level testing to catch these complex cases earlier in the diagnostic process. This shift requires a collaborative environment where TIGEM scientists and frontline clinicians work together to translate these high-tech outputs into actionable medical advice for the patient.
What is your forecast for pediatric genomic medicine?
I believe we are moving toward a future where the “diagnostic odyssey” is eliminated entirely, with trio whole-genome sequencing becoming the standard of care at the first sign of a complex neurodevelopmental disorder. We will see a shift from a focus on diagnosis to a focus on immediate therapeutic intervention, where identifying a variant like RNU4-2 leads directly to a personalized treatment pathway within months, not years. As our international databases grow, the number of “undiscovered” genes will shrink, and today’s unsolved cases will provide the foundational knowledge for the gene therapies of tomorrow. Ultimately, pediatric genomic medicine will become a proactive, integrated part of the national health system, ensuring that every child has the right to a molecular identity and the hope of a targeted cure.
