anna MacDonald（am）：诊断罕见疾病可能需要几年的时间。您能解释一下这样的原因吗？

Madhuri Hegde（MH）：对于一些罕见病患者，需要7到10年才能获得准确的诊断。 According to a 30-year comparative analysis conducted by the National Organization for Rare Disorders (NORD), during that time the average patient will have had made eight attempts to reach a diagnosis. Other studies show these individuals will have seen more than seven physicians for that diagnosis, and possibly more than double that number of specialists since first exhibiting symptoms. Limited awareness and lack of training and information for physicians are what ultimately make accurately and expediently diagnosing a rare disease so challenging.

Rare diseases are classified as such because they affect a smaller population of individuals. In the United States, each rare disease affects 200,000 people or fewer. Because of this, aggregating information about the symptoms of each and the potential genetic factors that make a person more likely to develop that condition takes time. Geneticists, genetic counselors and physicians from different specialties must all work together to ultimately reach a diagnosis. Another major factor to consider is access to testing and approval/coverage for testing by the insurance company. Testing technologies have evolved significantly but getting access or ordering the right test is not easy.

Other reasons for delayed diagnoses identified in the NORD study include longer wait times to see rare disease specialists, limited communication and understanding about symptoms between physicians, and the commonality of certain symptoms with other conditions. The last of these lead to inaccurate diagnoses, which are believed to affect 10 to 20 percent of rare disease cases.

AM: What are the implications of a delayed diagnosis? Why is it important to reduce the time to diagnosis?

MH: A delayed diagnosis delays appropriate medical management, treatment and other interventions, which in turn creates a whole host of problems. Rare diseases are chronic and can be progressive, so allowing months or years to pass without proper treatment could mean worsening symptoms that impede quality of life. In cases where there is an inaccurate diagnosis, an inaccurate or inappropriate treatment may be prescribed, which offers little benefit and can become a financial burden. In addition to the direct medical expenses incurred by a rare disease – e.g., inpatient or outpatient care, prescriptions and visits to rare disease specialists – there are indirect costs for patients and their families too. Living or caring for someone with a rare disease may limit one’s ability to work regularly. Over time, all of these consequences of a delayed diagnosis can compound mental and emotional stress that already weighs heavily on the patients, their families and other caregivers. That’s why reducing the time to an accurate rare disease diagnosis is so important.

AM: It is now possible to identify a number of rare diseases early through newborn screening programs. Can you tell us more about some of the rare diseases that can be detected in this way and the difference early diagnosis can make?

MH: Newborn screening programs are a great example of the impact that timely intervention for rare diseases can have, and the lessons learned through the implementation of these programs hold great promise for rare disease patients—especially when those programs incorporate whole genome sequencing (WGS). Today there are over 7,000 rare diseases that have been identified using sequencing technologies, and the capabilities exist to conduct WGS of newborns at birth. Using a cord blood, saliva sample, and most importantly a dried blood spot punch collected at birth PerkinElmer Genomics is able to sequence all 22,000 genes in a newborn’s genome and analyze the results against 2,500 genes that have known causation with childhood-onset conditions. That analysis includes the 50+ genes identified as medically actionable by the American College of Medical Genetics (ACMG), and could help diagnose lysosomal storage disorders like Pompe disease and Batten disease; Marfan syndrome, which affects a person’s connective tissue; and certain hereditary cancers.

AM: How have advances in genomic and molecular testing impacted rare disease diagnosis in recent years?

MH: Technologies used to diagnose rare diseases are evolving at a rapid pace. This includes omics-based approaches using genomics, transcriptiomics and proteomics. While it once took years to sequence the human genome, next-generation sequencing (NGS) technologies have shortened that timeline to just a few days. We can expect continued innovation and advances in omics, which in turn may necessitate a re-evaluation of the diagnostic and testing algorithms.

While biochemical testing at birth helps identify and thus treat various health problems before the onset of symptoms, WGS could do the same and with a high-level of accuracy and maybe faster if done at day 0 whereas biochemical testing necessitates a waiting period of 24-48 hrs.

AM: Can you tell us about the advantages that whole exome sequencing can bring to rare disease patients?

MH: Both WGS and whole exome sequencing (WES) are enabled by NGS technologies and unlock information in a person’s DNA about their unique genetic make-up. While WGS investigates both coding and non-coding regions of the genome, WES analyzes just the coding regions (exome). Although it is well-known that certain DNA variations outside of the coding regions (exons) can also affect gene activity and protein production – which in turn lead to genetic predispositions to a variety of conditions – WES services like those offered by PerkinElmer Genomics have faster turnaround time (i.e., 4-6 weeks versus 6-8 weeks for WGS) and could be a more cost-effective option for some patients. The design of WES is critical to success of the test and today WGS can inform WES design by incorporating baits for those regions/nucleotides which have been shown to be causative of diseases. Though WGS is still in its early days of being accepted as a first-tier clinical test, WES is recognized and reimbursed by many insurance companies.

AM: What hurdles need to be overcome to further improve the diagnostic process for rare disease patients?

MH: Improving the rare disease diagnostic process demands a programmatic approach. The test itself is a single piece of the puzzle. While the ACMG has established its recommended guidelines for clinical exome and genome sequencing, the governments and public health authorities of individual countries are responsible for establishing local standards. Genomics England and to a certain extent the Victorian Clinical Genetics Service (VCGS) in Melbourne, Australia, are doing impressive work to advance a programmatic approach and have set a great example for others to follow. In the United States, NIH had funded several newborn WGS programs to assess feasibility, though newborn screening remains the only well-established program. The NIH All of Us program is expected to also give us a programmatic view of deploying population scale genomics programs.

Cost and access to sequencing services are also significant obstacles globally—but hopefully ones that could be lessened over time. It may be another 5 to 10 years before WGS for rare disease diagnostics becomes a universal approach, but there is tremendous work being done today to make that idea a reality.

AM: Will we see the time taken to identify diseases shorten further in coming years?

MH: I am optimistic that in the coming years, we will see improvements in rare disease diagnostics. Along with the aforementioned technological advances, especially in omics and integrating data from genomics, transcriptomics and proteomics, collaborations across the scientific and clinical communities continually add to a growing body of research around the human genome and specific genetic variants that lead to rare disease. Improving variant classification using omics-based strategies could help end the diagnostic odyssey for more rare disease patients around the world. Through PerkinElmer’s foundation and leadership role in newborn screening, omics-based platforms, a global network of laboratories contributing to shared publicly accessible databases like ClinVar, PerkinElmer Genomics is driving this change in rare disease diagnostics.

Madhuri Hegde was speaking to Anna MacDonald, Science Writer for Technology Networks.

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Moving Towards the Next Era in Rare Disease Therapeutics

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In part two, we learn how advances in technologies are helping to further our understanding of rare diseases and explore efforts to accelerate drug discovery for rare diseases.