Decoding Rare Diseases: How Genomics Is Transforming Diagnosis

Decoding Rare Diseases How Genomics Is Transforming Diagnosis Rare diseases can affect individuals of all ages and often have severe, life-limiting consequences. With around 80% of rare diseases having a genetic basis, advancements in genomics are helping to transform how these conditions are diagnosed and treated. This infographic will explore the importance of understanding the genomics of rare diseases and how genomic technologies are enabling earlier and more precise diagnoses for patients. 01 Introduction EUROPEAN UNION A disease that affects fewer than 1 in 2,000 What are rare people diseases? A rare disease is a condition that affects a small percentage of the population, with definitions varying slightly by region. UNITED STATES JAPAN Collectively, over 300 million people A disease that affects A disease that affects worldwide are living with a rare disease. fewer than 200,000 fewer than 50,000 people people More than 7,000 rare diseases have been identified. Examples include: Fibrodysplasia ossificans Duchenne muscular dystrophy progressiva Tyrosinemia type 1 Spinal muscular atrophy Ehlers–Danlos syndrome Alkaptonuria 02 Diagnosis Visit to the primary First symptoms care physician Online research Why is diagnosing Visit to specialist rare diseases so No diagnosis / Wrong treatment misdiagnosis difficult? Referral to another Visit to another The journey to a rare disease diagnosis is often long specialist specialist and complex; taking an average of 4.7 years to achieve a diagnosis and involving numerous visits to multiple healthcare professionals. Genetic testing results Genetic testing Over 60% of rare disease patients may initially receive a misdiagnosis. No diagnosis Retesting Many patients experience worsening symptoms or miss critical treatment opportunities during this time. Therefore, an early, accurate diagnosis is crucial to Diagnosis improve patient outcomes and quality of life. The “diagnostic odyssey” many rare disease patients face is a result of factors such as: Non-specific symptoms common Clinical heterogeneity Lack of access to genetic testing to other diseases Clinicians unfamiliar with a Patient is the first recorded to have specific condition a particular genetic variant 03 Technologies Revolutionizing diagnosis: The role of genomic In the Deciphering Developmental Disorders study, whole technologies exome sequencing data gave a high diagnostic yield in previously undiagnosed children and several novel causal genes were identified. Advances in genomic technologies are helping to improve rare disease diagnosis, providing unprecedented insight into the genetic mutations responsible for many of these conditions. While early technologies such as PCR and Sanger sequencing allowed detailed studies of genes associated with specific rare In a 100,000 Genomes Project pilot study, whole diseases, developments in next-generation genome sequencing led to a new diagnosis for 25% of the sequencing (NGS) have transformed the participants, 14% of which would be missed by conventional field – shortening the diagnostic timeline methods. and paving the way for personalized treatments. Clinicians can now use a variety of NGS methods to help diagnose rare diseases: Targeted gene Whole-exome Whole-genome panels sequencing (WES) sequencing (WGS) Exon 1 Exon N Whole genome Gene 1 Gene 2 Gene N Targets specific sets of genes known Focuses on protein-coding regions Analyzes the entire genome, to be associated with certain rare of DNA, which contain most identifying mutations in coding and diseases. Can include 2–300+ disease-causing mutations. non-coding regions of DNA, as well genes. as structural and intronic variants. Faster and more cost- Provides a focused, cost- effective than WGS for certain Most comprehensive genomic efficient approach for diseases applications test with known genetic links Generates a smaller, more Ideal for complex or Deep coverage enables more manageable dataset than WGS undiagnosed cases with unclear sensitive detection of mosaicism genetic causes Structural rearrangements not Novel causative genes not detected. Copy number variants Large datasets present storage identified may not be detected and analysis challenges Difficult to update Increased risk of incidental Generates more variants of findings uncertain significance Some genetic variants, such as complex rearrangements, Long-read sequencing is attracting growing attention from the inversions or insertions and variants in repetitive regions, can be clinical genomics community as it generates longer, contiguous challenging to detect using short-read sequencing (currently the reads and can enhance the identification of complex variants. most used form of NGS). 04 The Future The future of rare disease genomics The progress made in rare disease genomics in recent years has helped to make earlier and more accurate diagnoses possible. However, the road to diagnosis is still too long and complex for many patients, with a large proportion remaining undiagnosed. Key areas to overcome the remaining challenges and advance rare disease diagnostics include: Data bias Cost and accessibility Current genomic databases are skewed toward Access to advanced diagnostic testing varies significantly European ancestry. This can limit diagnostic accuracy for between and within countries. underrepresented populations. Reducing costs, demonstrating the cost-effectiveness Increasing the representation of diverse genetic of early testing and introducing policies that expand backgrounds through initiatives such as GenomeAsia affordable genomic testing could support wider 100K and All of Us and creating pan-genome references adoption. could help to improve mapping accuracy. Artificial intelligence (AI) and machine learning Integration of multiomics data Analyzing large datasets can be complex and time- Combining genomic data with transcriptomic, proteomic consuming. and metabolomic data can provide a holistic view of disease mechanisms. Increased adoption of AI-assisted tools could accelerate the identification of genetic variants associated with rare This could aid in understanding rare diseases with complex diseases, aiding faster diagnosis. genetic and environmental interactions. Global collaboration Advances in genomic technology Larger, shared datasets improve disease variant Continued developments in genomic technology could help classification. to improve the precision and accessibility of diagnosis. Collaborative projects such as the 100,000 Genomes Increased clinical adoption of long-read sequencing Project will help to foster international data exchange. could help to detect genetic variants difficult to detect using short-read sequencing. Portable devices could enable testing in remote areas. Fragments Reads >500x Reads >50-100x Fragments Reads >30x Fragments