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Understanding the breadth of genetic diseases from genomic data in China is the first step in this effort. However, traditional methods of assessing disease prevalence have limitations in 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. The mortality results in a misleadingly low disease prevalence, such as the situation in southern China, where the prevalence of lethal disease is reported as zero despite a high carrier rate.9 Correspondingly, the medical community and affected families remain largely unaware of such severe diseases, leading to repeated neonatal fatalities. Including the SLC25A20 gene in the carrier screening panel could potentially reduce the occurrence of such related severe birth defects inherited in a recessive genetic model. This approach could also be beneficial for many other similar disorders. Furthermore, the prevalence of genetic diseases is under-reported in China owing 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 carriage of gene mutation rather than the disease prevalence based on the number of identified patients who were screened for the particular diseases.

eases or a reluctance to seek medical help. To effectively prevent birth defects, particularly functional congenital disorders, we advocate a shift to examining rates of carriage of gene mutation rather than the disease prevalence based on the number of identified patients who were screened for the particular diseases. In the genomic medicine era, comprehensive genome sequencing and analysis increasingly promotes the determination of disease incidence. Many countries have launched national genome projects with unique features specifically serving different populations. Prominent examples are the UK Biobank,10 the All of Us Program,11 and several others.12 Databases such as ClinVar, which classifies variants, and gnomAD, a population based resource, are instrumental for accurate interpretation of variants and clinical intervention.13 However, the genomic landscape in China seems to be notably more diverse than in the rest of the world. The SLC25A20 gene mutation serves as a typical example, showing a 10-fold difference in carrier rates between the south Chinese and north Chinese populations. This highlights the necessity for systematic studies of the diverse population to accurately estimate nationwide disease incidence and improve the interpretation of variants, particularly for founder or population specific variants. Knowing how many diseases are present across China on the basis of the genomic data is the first step. We next need to know how many of these diseases should be targeted for prevention on the basis of 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 who have less severe and treatable conditions via newborn screening. To effectively prioritise diseases for genetic screening, the severity of 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 5000 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.

parents to make informed decisions about reproduction. With genomic testing uncovering approximately 5000 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 categorised disease conditions into profound, severe, moderate, or mild,14 on the basis of 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.18 Only genes linked to conditions with moderate or higher severity are selected for expanded carrier screening. However, 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, tumour surveillance for Peutz-Jeghers syndrome includes baseline colonoscopy, upper endoscopy from age 8, and small bowel video capsule endoscopy or magnetic resonance imaging enterography. These procedures are often unavailable in China owing to high costs and lack of recognition. Therefore, disease severity must be assessed on the basis of contemporary medical care conditions and the life quality 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.

As the costs for genetic testing have significantly decreased, genomic screening based approaches are available for prevention of birth defects on the basis of these advances. 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 counselling while offering genetic testing. Genetic counselling, a healthcare profession that has flourished in many countries over the past 30 years,19 remains underdeveloped in China. Trained genetic counsellors are scarce in China, leaving a gap in professional services for families seeking genetic testing. Genetic counsellors play a multifaceted role across various medical specialties. Their expertise extends beyond mere technical knowledge; they provide education and emotional support and empower individuals to make decisions by understanding potential risks and available options. As genomic testing becomes more prevalent, the demand for genetic counselling services is rising. In China, challenges for clinicians include a lack of genetic counsellors and well developed genetic training programmes. Most medical providers are unaware of genetic screening and lack the ability to interpret the genetic variants, thus hindering the integration of genetic testing into clinical practice. Without proper counselling, genetic testing can impose a psychological burden on families, potentially reducing their willingness to participate in genetic screening and even resulting in adverse outcomes.

ility to interpret the genetic variants, thus hindering the integration of genetic testing into clinical practice. Without proper counselling, 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 counsellors 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 programme for the next generation of genetic counsellors has not yet been established in China, although training programmes and certification systems for genetic counsellors are well established in the US and other countries. Promisingly, some pilot training programmes in China have shown good responses in this field.18 20 We urge the government to promptly establish the position of genetic counselling in healthcare facilities and communities and to develop professional training programmes that equip genetic counsellors with expertise in genomics. Additionally, these programmes should raise awareness about discrimination, privacy and confidentiality, and personal and family related social factors.

genetic counselling in healthcare facilities and communities and to develop professional training programmes that equip genetic counsellors with expertise in genomics. Additionally, these programmes should raise awareness about discrimination, privacy and confidentiality, and personal and family related social factors. 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 counselling 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 done in other countries,16 17 along with studies on the cost effectiveness of genomic testing.15 21 Comparatively, only a few studies have explored the cost effectiveness of genomic testing in China, such as non-invasive prenatal testing for Down’s syndrome22; further research on this aspect is needed for 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 generalised from studies conducted in other nations. Therefore, cost effectiveness analyses need to be conducted in China to justify the benefits over the costs, maximise the benefits, and minimise the adverse effects of genetic screening.

In summary, to optimise the benefits of the genomic medicine era and empower new prevention strategies for birth defects, we have identified four urgent needs based on the current situation in China. These include comprehensively understanding 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 counsellors, and 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. Moreover, this serves as a demonstrative model to showcase the effectiveness of these approaches, offering valuable insights for other nations.