Comprehensive Mapping of the Genetic Disease Landscape
In the era of genomic medicine, the ability to prevent birth defects has been significantly enhanced through the advancements in genetic testing. Traditional genetic screening primarily focused on Down’s syndrome and chromosomal aneuploidies, but the scope has now expanded to cover a large number of genomic imbalance disorders with the availability of non-invasive prenatal testing and chromosomal microarray analysis.
However, many genetic disorders caused by sequence variants remain undetected before conception and during pregnancy. Next-generation sequencing (NGS) offers new testing methods for preventing birth defects caused by sequence variants. NGS can be applied to genomic carrier screening, pre-implantation genetic testing, prenatal genetic testing, and newborn genomic screening, effectively identifying pathogenic variants responsible for genetic birth defects, especially functional birth defects such as metabolic disorders and developmental disorders.
While the perinatal prevalence of birth defects in China is as high as 208.94 per 10,000 in 2020-21, a comprehensive understanding of the genetic disease burden in the Chinese population is crucial for effective prevention strategies. The first critical research need is to conduct nationwide population-level genomic studies to map the breadth of genetic diseases in China.
Traditional methods of assessing disease prevalence have limitations in accurately counting affected individuals within a population. Severe genetic disorders, such as carnitine-acylcarnitine translocase deficiency caused by the SLC25A20 gene mutations, often lead to prenatal or perinatal mortality, resulting in a misleadingly low disease prevalence. This is the case in southern China, where the prevalence of lethal diseases is reported as zero despite a high carrier rate.
Furthermore, the prevalence of genetic diseases is under-reported in China due to the lack of physicians trained to diagnose rare diseases or a reluctance to seek medical help. To effectively prevent birth defects, particularly functional congenital disorders, we advocate a shift to examining rates of gene mutation carriage rather than relying solely on the number of identified patients.
In the genomic medicine era, comprehensive genome sequencing and analysis increasingly promote the determination of disease incidence. Many countries have launched national genome projects, such as the UK Biobank, the All of Us Program, and others, which provide instrumental databases like ClinVar and gnomAD for accurate interpretation of variants and clinical intervention.
However, the genomic landscape in China seems to be notably more diverse than in the rest of the world. The SLC25A20 gene mutation, for example, shows a 10-fold difference in carrier rates between the southern and northern Chinese populations. This highlights the necessity for systematic studies of the diverse Chinese population to accurately estimate nationwide disease incidence and improve the interpretation of variants, particularly for founder or population-specific variants.
Assessing Disease Severity as a Prioritization Criterion
Knowing how many genetic diseases are present across China based on genomic data is just the first step. The next critical question is: How many of these diseases should be targeted for prevention based on disease severity?
Prevention of birth defects aims to reduce the occurrence of severe conditions through screening for carriers and prenatal screening, while improving the prognosis for people with less severe and treatable conditions via newborn screening. To effectively prioritize diseases for genetic screening, the severity of the disease is the most important parameter to be considered.
Besides being a criterion for selection for genetic screening, disease severity is also crucial information needed for parents to make informed decisions about reproduction. With genomic testing uncovering approximately 5,000 monogenic disorders, assessing disease severity becomes a critical factor in birth defect prevention strategies.
However, the criteria for assessing the severity of genetic diseases remain insufficiently explored. Previous approaches have categorized disease conditions into profound, severe, moderate, or mild, based on clinical traits such as early age of onset, shortened lifespan, and cognitive or physical impairments, as well as the availability and accessibility of treatment options.
Yet, disease severity assessments can vary across healthcare settings, depending on the current medical care level of different countries. For instance, Peutz-Jeghers syndrome is assessed differently in terms of treatment effectiveness and intervention costs between China and the US. In the US, comprehensive tumor surveillance is often available, but these procedures may be inaccessible in China due to high costs and lack of recognition.
Therefore, disease severity must be assessed based on the contemporary medical care conditions and the quality of life of patients in China. Additionally, the coverage of newborn screening and the timeliness of diagnosis, which were not considered in previous studies, also need to be evaluated. Initiating pilot studies on the severity of genetic diseases in China is crucial to achieve this goal.
Strengthening Genetic Counseling Capacity
As the costs for genetic testing have significantly decreased, genomic screening-based approaches are available for the prevention of birth defects. However, concerns, including potential over-diagnosis, variants of uncertain significance, and the lack of effective interventions, have been raised. These factors underscore the critical importance of genetic counseling while offering genetic testing.
Genetic counseling, a healthcare profession that has flourished in many countries over the past 30 years, remains underdeveloped in China. Trained genetic counselors are scarce in China, leaving a gap in professional services for families seeking genetic testing.
Genetic counselors play a multifaceted role across various medical specialties. Their expertise extends beyond mere technical knowledge; they provide education, emotional support, and empower individuals to make informed decisions by understanding potential risks and available options. As genomic testing becomes more prevalent, the demand for genetic counseling services is rising.
In China, challenges for clinicians include a lack of genetic counselors and well-developed genetic training programs. Most medical providers are unaware of genetic screening and lack the ability to interpret genetic variants, thus hindering the integration of genetic testing into clinical practice. Without proper counseling, genetic testing can impose a psychological burden on families, potentially reducing their willingness to participate in genetic screening and even resulting in adverse outcomes.
Genetic counselors serve as intermediaries among various stakeholders, including physicians, nurses, and researchers, assisting them in navigating medical, social, ethical, and legal matters. Unfortunately, a comprehensive training program for the next generation of genetic counselors has not yet been established in China, although training programs and certification systems for genetic counselors are well-established in the US and other countries.
We urge the government to promptly establish the position of genetic counseling in healthcare facilities and communities and to develop professional training programs that equip genetic counselors with expertise in genomics. Additionally, these programs should raise awareness about discrimination, privacy and confidentiality, and personal and family-related social factors.
Assessing the Cost-Effectiveness of Genomic Screening
The research needs mentioned above can pave the way for the application of genomic testing (also called next-generation sequencing-based testing) aimed at further reducing the burden of birth defects in China. Although advances in genomic testing have increased the ability to prevent and diagnose genetic disorders, cost-effectiveness analyses are needed to determine whether it can be accommodated within healthcare budgets before routine implementation, compared with traditional approaches and single-gene testing.
Cost-effectiveness analyses are designed to evaluate the costs and clinical benefits of specific interventions, guiding decisions on which strategies offer optimal value for a given population. Such analyses enable understanding of the short-term and long-term benefits and outcomes of different strategies on the healthcare system at a national, societal, and individual level, as well as the time needed for counseling on tests and their outcomes, psychosocial influences, and deviations from expected decision-making paths.
Cost-effectiveness analyses assessing the effectiveness of interventions such as pre-implantation genetic diagnosis and screening for carriers of fragile X and spinal muscular atrophy have been conducted in other countries, along with studies on the cost-effectiveness of genomic testing. Comparatively, only a few studies have explored the cost-effectiveness of genomic testing in China, such as non-invasive prenatal testing for Down’s syndrome; further research on this aspect is needed for the application of novel technology and strategies.
In addition, the economic evaluations during cost-effectiveness analyses are heavily influenced by a nation’s economic status, its capacity to implement diagnostic procedures, and its cultural characteristics. These factors are often unique to each country and cannot be adequately generalized from studies conducted in other nations. Therefore, cost-effectiveness analyses need to be conducted in China to justify the benefits over the costs, maximize the benefits, and minimize the adverse effects of genetic screening.
Conclusion
To optimize the benefits of the genomic medicine era and empower new prevention strategies for birth defects in China, we have identified four urgent research needs:
- Comprehensively understanding the disease burden through nationwide population genome data
- Evaluating disease severity as a pivotal criterion for constructing genetic screening panels
- Training a new generation of genetic counselors
- Initiating pilot studies to assess the cost-effectiveness of genetic screening
By tackling these essential concerns, more informed policies can be made for funding the proper research, establishing the appropriate infrastructure, and using the most suitable and practical approaches for population-wide genomic screening. This serves as a demonstrative model to showcase the effectiveness of these approaches, offering valuable insights for other nations facing similar challenges in birth defect prevention and control.
The Joint Action for Water blog is dedicated to sharing knowledge and promoting collaborative action for sustainable water and sanitation services. As a seasoned expert in this field, I hope this comprehensive article has provided insightful research needs to empower the prevention and control of birth defects in China, ultimately improving the health and well-being of mothers and children.
