罕见病患者数量少，通常难以诊断，但 DNA 检测技术的进步使得早期诊断和适当治疗成为可能。尤其是新一代测序（NGS）和全基因组分析是快速识别致病基因、实现个性化医疗的重要工具。基因治疗和药物研发的进步正在扩大提供新治疗方法的可能性。此外，遗传咨询和早期干预可以改善患者的生活质量，社会支持可以减轻他们的经济负担。基因检测和治疗的进步为罕见病患者带来了新的希望。
In recent years, advances in DNA testing technology have led to dramatic advances in the development of diagnostic and treatment methods for rare diseases. This article provides a detailed explanation of how DNA testing can be used to identify rare diseases and what countermeasures can be taken.
1. What is DNA testing?
DNA testing is a technology that analyzes an individual’s DNA sequence to reveal genetic characteristics and disease risks. DNA can be easily collected from sources such as oral mucosa and blood, and is used in a variety of fields, including proving parent-child relationships and criminal investigations.
2. Overview of Rare Diseases
Rare diseases are diseases that affect a small number of people and are difficult to diagnose and treat. In Japan, the Rare Disease Information Center provides information on these diseases and supports research.
3. Diagnosing rare diseases through DNA testing
DNA testing can play a role in diagnosing rare diseases by:
3.1 Identification of gene mutations
Many rare diseases are caused by genetic mutations, and DNA testing can detect the specific genetic mutations and allow for accurate diagnosis of the disease.
3.2 Detection of asymptomatic carriers
Some genetic diseases may be asymptomatic in carriers. DNA testing can be used to identify carriers who are at risk for the disease in the future and provide appropriate counseling and preventive measures.
4. Measures using DNA testing
If a rare disease is identified through DNA testing, the following measures may be taken:
4.1 Implementation of personalized medicine
This will enable personalized medicine, where optimal treatments and drugs are selected based on the patient’s genetic information, which is expected to improve therapeutic efficacy and reduce side effects.
4.2 Genetic counselling for families
In the case of hereditary diseases, there may be an increased risk of developing the disease within a family. Based on the results of DNA testing, we provide genetic counseling to the family and provide appropriate information and support.
4.3 Early intervention and prevention
If you are identified as being at risk for a disease, it is possible to prevent the onset of the disease or slow the progression of symptoms by reviewing your lifestyle habits and undergoing regular checkups early on.
5. Research and clinical applications
With the advancement of DNA testing technology, research into rare diseases is also becoming more active. New genetic mutations are being discovered and treatments are being developed, and their application in clinical practice is expected.
6. Ethical and social issues
As DNA testing becomes more widespread, ethical and social issues regarding privacy protection and the handling of genetic information have arisen, calling for the establishment of appropriate legislation and guidelines.
DNA testing plays an important role in the diagnosis and treatment of rare diseases. As technology advances, collaboration between research and clinical practice will become increasingly important so that more patients can receive appropriate medical care.
7. Specific examples of rare diseases and their diagnosis through DNA testing
DNA testing is used to diagnose various rare diseases. Here, we will introduce some representative rare diseases that involve genetic factors and explain in detail the role of DNA testing.
Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disease caused by an abnormality in the DMD gene. It is an incurable disease that mainly affects men and causes progressive muscle weakness.
Use of DNA testing
Detection of deletion/duplication mutations in the DMD gene: Abnormalities in the DMD gene can be identified using multiplex ligation-dependent amplification (MLPA) and next-generation sequencing (NGS).
Identifying asymptomatic carriers: Women are unlikely to develop the disease but may be carriers and are advised to undergo testing to determine the genetic risk to their future children.
7.2 Phenylketonuria (PKU)
Phenylketonuria (PKU) is an inborn error of metabolism caused by a mutation in the PAH gene that prevents the body from properly metabolizing the amino acid phenylalanine. If treatment is delayed, it can lead to intellectual disability.
Use of DNA testing
PAH gene mutation analysis: NGS and Sanger sequencing are used to identify abnormalities in the PAH gene for early diagnosis.
Newborn screening: Used in conjunction with a blood test (Guthrie test) immediately after birth to detect phenylalanine metabolic disorders at an early stage.
7.3 Familial hypercholesterolemia (FH)
FH is a lipid metabolism disorder caused by mutations in the LDLR, APOB, and PCSK9 genes, and is associated with a significant increase in the risk of atherosclerosis and cardiovascular disease.
Use of DNA testing
Mutation analysis of the LDLR gene: Identifying mutations that impair LDL receptor function and assessing risk for patients and their families.
Early treatment decisions: If genetic risk is high, statin therapy and lifestyle changes are recommended from an early age.
8. Early detection and prevention of rare diseases through DNA testing
Early detection through DNA testing is an important means of preventing rare diseases and slowing the progression of symptoms.
8.1 Newborn screening and DNA analysis
Currently, newborn screening (NBS) is implemented in many countries, allowing for early detection of metabolic disorders and congenital diseases.
Expansion of target diseases: In addition to traditional metabolic disorders, there is a growing trend to target genetic immune deficiencies and neurological diseases.
Introducing whole-genome sequencing (WGS): Combining WGS with newborn screening allows for comprehensive analysis of more genetic diseases.
8.2 Genetic Counseling and Family Risk Assessment
Following a DNA test diagnosis, it is important to assess the impact on the family and provide appropriate counselling.
Family Carrier Testing: Family members at high genetic risk can undergo DNA testing to understand their risk of developing the disease.
Reproductive counseling: Offering options for prenatal testing (NIPT) and preimplantation genetic testing (PGT) to couples at risk of genetic diseases.
9. Rare disease treatment and latest research
If a diagnosis is confirmed by DNA testing, modern treatments are available, including:
9.1 Gene Therapy
Duchenne muscular dystrophy: Using gene editing technology (CRISPR-Cas9), progress is being made in correcting the abnormal DMD gene.
SMA (Spinal Muscular Atrophy): Gene therapy drugs such as Nusinersen and Zolgensma are now available.
9.2 Drug discovery research and personalized medicine
Drug repositioning: Research is ongoing to adapt existing drugs to treat rare diseases.
mRNA technology: Attempts are being made to apply mRNA technology to treat genetic diseases (e.g., treatment of hereditary angioedema).
10. DNA testing and social issues
As DNA testing advances, several ethical and social issues have arisen.
10.1 Protecting the privacy of genetic information
Management of personal information: Genetic information is extremely sensitive and requires appropriate data management.
Preventing genetic discrimination: Laws are in place to prevent the inappropriate use of genetic information in insurance and employment (e.g., GINA).
10.2 Cost-effectiveness of genetic testing
High testing costs: Some genetic tests are expensive, making insurance coverage a challenge.
Collaboration with the public healthcare system: There is a need to increase public subsidies so that patients with rare diseases can receive appropriate testing and treatment.
Advances in DNA testing technology have brought the diagnosis and treatment of rare diseases to a new stage. In the future, further technological innovation and the resolution of ethical issues will be required, and it is expected that support for rare disease patients will be expanded.
11. The Potential of Gene Therapy for Rare Diseases
Among the treatments for rare diseases, gene therapy has been attracting the most attention. Gene therapy is an approach that aims to provide a fundamental cure by correcting the genetic abnormalities that cause the disease. In particular, there are high hopes for future developments in treatment methods using gene therapy as a technology that can compensate for hereditary diseases and lost functions.
11.1 Gene editing with CRISPR-Cas9
CRISPR-Cas9 technology is attracting particular attention as a gene editing technology. This technology allows very precise modification of specific genes, and many studies are being conducted on it as a treatment for rare diseases.
Duchenne Muscular Dystrophy (DMD) Duchenne Muscular Dystrophy is a disease that causes gradual muscle weakness due to a mutation in the DMD gene on the X chromosome. In order to correct this genetic mutation, CRISPR technology is being used to experimentally introduce normal genes. By using CRISPR technology to correct muscle tissue, it may be possible to slow the progression of the disease. Research example : A research team in the United States has successfully repaired a gene in the muscle of a DMD patient by gene editing with CRISPR-Cas9. This is expected to improve muscle function and pave the way for the practical application of a treatment.
However, there are some challenges to the clinical application of CRISPR technology. Because gene editing may affect unintended sites, there is a need to improve editing accuracy and safety. In addition, the immune response of treated patients may affect the therapeutic effect, so long-term observation is necessary
11.2 Gene transfer technology
Another approach to gene therapy is gene transfer technology, which is a method to directly supplement a patient’s missing or abnormal genes. Currently, gene transfer-based therapies are in clinical trials for certain rare diseases.
Spinal Muscular Atrophy (SMA) SMA is a disease caused by a defect in the SMN1 gene, which causes a loss of motor neurons and muscle atrophy. Zolgensma has been commercialized as a treatment using gene transfer. This drug involves administering a viral vector carrying a normal SMN1 gene to patients, which complements the function of the missing gene. Zolgensma has shown clinical effectiveness in patients with severe SMA and is a hope for treatment. Research example: Zolgensma, used to treat SMA patients, has shown improvement in motor function after treatment, demonstrating the importance of treatment, especially in the early stages of onset. (Reference: NEJM)
The future of gene therapy Gene transfer technology is currently being used for new rare diseases, and in the future, it may be possible to apply it to the treatment of diseases that were previously difficult to treat. However, issues such as immune reactions and long-term safety associated with gene transfer remain to be resolved. It is hoped that future research will lead to the establishment of more effective and safer treatment methods.
12. Next-generation sequencing (NGS) for genetic analysis of rare diseases
Next-generation sequencing (NGS) is a technology that rapidly analyzes the entire genetic information of DNA with high accuracy, and is revolutionizing the diagnosis of rare diseases. NGS can be used to identify the causative genes of rare diseases that are complex and have few cases.
12.1 Identifying disease-causing genes using NGS
Traditionally, diagnosing rare diseases required a long time and a lot of trial and error, but the widespread use of NGS has made it possible to quickly identify genetic mutations related to the disease. In particular, even when multiple genetic mutations are involved, NGS can analyze the entire genome, making diagnosis proceed smoothly.
Whole-genome analysis: NGS analyzes a patient’s entire genome to identify all genetic variants associated with disease, dramatically improving disease diagnosis by capturing minute mutations that would otherwise be missed by traditional methods.
Genetic panels: NGS is also used to analyze only genes related to specific disease groups, which is useful for diagnosing specific rare disease groups. For example, gene panels related to neuromuscular diseases and metabolic disorders have been developed to support early diagnosis. Research example : In the United States, there have been successful cases of diagnosing more than 150 rare diseases using NGS, demonstrating the usefulness of this technology.
12.2 NGS and Early Detection of Rare Diseases
NGS technology is increasingly being used in newborn screening and early detection programs, which is resulting in an increase in the early detection of rare diseases that previously went undiagnosed.
Newborn screening: By introducing whole genome analysis to newborns, it becomes possible to provide preventive treatment before the onset of genetic diseases. Early detection of metabolic disorders and genetic immune deficiencies is particularly important.
Early intervention: Early diagnosis allows for early intervention to prevent disease progression and worsening of symptoms. Advances in treatment mean that early detection can significantly improve patient outcomes.
13. Social support for patients with rare diseases
Patients with rare diseases not only have limited treatment options but also face various challenges in terms of medical expenses and living support. Improving social support for these patients will help ensure a better life for them.
13.1 Medical assistance and insurance
Treating rare diseases tends to be expensive. Gene therapy drugs and new treatments in particular often cost a lot of money, and patients may not be able to receive adequate treatment. How governments and insurance systems respond to this is important.
Patient support systems: In some countries, rare disease patients may have public health insurance that covers part of the treatment costs or may be provided with medical subsidies for certain rare diseases.
Drug pricing and regulation: There are efforts to regulate the pricing of new drugs and treatments to prevent them from becoming excessively expensive, and there are also efforts to expedite drug approval for rare disease drugs that meet certain conditions.
13.2 Social support and the law
Social support is also essential for rare disease patients. Progress is being made in establishing laws that allow them to receive consideration at the workplace and lifestyle support.
Disability benefits and welfare assistance: Patients with serious rare diseases often face difficulties in living and working, so they need support systems such as disability benefits and welfare assistance.
Consideration of the working environment: In order to prevent discrimination against patients with intractable diseases, it is important for companies and society to take measures to provide a good working environment and employment options.
Discovering rare diseases through DNA testing and countermeasures
Rare diseases tend to be diagnosed late in the general medical system because the number of patients is small. However, with the development of genetic analysis technology, diseases that were previously difficult to detect can now be diagnosed early, and appropriate treatment can be provided to patients. In this article, we will take an in-depth look at how rare diseases can be diagnosed using DNA testing and the countermeasures that genetic testing can bring.
1. Rare diseases and their characteristics
A rare disease is a disease that affects less than one in every 10,000 people worldwide. In Japan, a rare disease is defined as a disease that affects less than 0.1% of the population. Many of these diseases are caused by genetic mutations, and it is difficult to find a standard treatment. Therefore, early diagnosis and appropriate treatment are important, but because the symptoms at the time of onset are diverse, diagnosis is often delayed.
Rare diseases include nervous system diseases, metabolic disorders, muscular dystrophies, immunodeficiencies, etc. These diseases are strongly influenced by genetic factors, and genetic testing allows for early detection and early intervention of the disease.
2. DNA testing and rare disease diagnosis
Advances in DNA testing technology have made rare disease diagnosis much faster and more accurate. Traditionally, rare diseases have few cases and symptoms are often similar to other diseases, so diagnosis has tended to take a long time. However, DNA testing can directly detect genetic mutations that cause the disease, making it possible to diagnose quickly. In particular, next-generation sequencing (NGS) and whole genome analysis are widely used as methods to quickly identify the cause of rare diseases, as they can efficiently analyze vast amounts of genetic information.
2.1 Next Generation Sequencing (NGS)
Next-generation sequencing (NGS) is a technology that analyzes huge amounts of genetic information in a short period of time. This technology has revolutionized the diagnosis of rare diseases by identifying minute genetic mutations that are easily overlooked by conventional diagnostic methods. NGS can analyze multiple genes simultaneously, making it effective even when a disease is caused by multiple genetic mutations.
For example, in muscular dystrophy and neuromuscular diseases, NGS can comprehensively examine the genes involved in the disease using gene panels. This approach can significantly shorten the time to a confirmed diagnosis, leading to earlier treatment and improved prognosis for patients.
2.2 Whole genome analysis
Whole genome analysis is a method of analyzing all of an individual’s genetic information and is particularly effective for genetically complex diseases. Many rare diseases involve multiple genes, so whole genome analysis allows for a more comprehensive investigation of the causes of these diseases. Whole genome analysis is particularly effective for familial diseases, hereditary metabolic disorders, and neurological diseases.
The strength of whole genome sequencing is that it cannot only identify disease-associated genetic mutations but also detect asymptomatic carriers who are potentially at risk, for example by identifying individuals who carry a genetic mutation for a disease but do not yet show symptoms, allowing early intervention and lifestyle changes to be initiated.
3. Development of new treatments for rare diseases
In rare diseases, there are many cases where there is no established treatment, and patients often face limited treatment options. However, with the advancement of gene therapy, new treatments are being developed. These new treatments target specific gene mutations and aim to provide a fundamental cure.
3.1 Advances in gene therapy
Gene therapy is a treatment that corrects defects or abnormalities in a patient’s genes. This makes it possible to treat diseases fundamentally, giving new hope to patients with rare diseases. For example, the gene therapy drug Zolgensma is used to treat spinal muscular atrophy (SMA), and an increasing number of patients are now able to be treated with this treatment. Zolgensma is a treatment that promotes the recovery of the nervous system by introducing new normal genes into the patient’s genes.
Gene editing is also being used to treat Duchenne muscular dystrophy, with research being conducted using CRISPR-Cas9 to repair abnormal genes and restore muscle function.
3.2 Progress in drug discovery
Advances in drug discovery have also been attracting attention in the treatment of rare diseases. New drugs are being developed for diseases that were previously thought to have no treatment, providing patients with more options.
For example, drugs such as angiotensin II receptor antagonists and statins have been shown to be effective for some patients with rare diseases. In addition, new treatments have been developed through drug repositioning (a method of applying existing drugs to a different disease), and these drugs are attracting attention as treatments for rare diseases.
Summary
Rare diseases have a small number of patients and are often difficult to diagnose, but advances in DNA testing technology have made early diagnosis and appropriate treatment possible. In particular, next-generation sequencing (NGS) and whole genome analysis are important tools for quickly identifying disease-causing genes and realizing personalized medicine. Advances in gene therapy and drug discovery are expanding the possibilities for providing new treatments. In addition, genetic counseling and early intervention improve patients’ quality of life, and social support reduces the economic burden on patients. Advances in genetic testing and treatment are bringing new hope to rare disease patients.
