Research needs for birth defect prevention and control in China in the genomic screening era
BMJ 2024; 386 doi: https://doi.org/10.1136/bmj-2023-078637 (Published 30 August 2024) Cite this as: BMJ 2024;386:e078637Read the collection: Promoting women's health in China
- Yu An, associate professor1,
- Yiping Shen, medical director2 3,
- Yanlin Ma, professor4,
- Hongyan Wang, professor5 6
- 1Human Phenome Institute, Institute of Medical Genetics and Genomics, Zhangjiang Fudan International Innovation Center, MOE Key Laboratory of Contemporary Anthropology, Fudan University, Shanghai, China
- 2Division of Genetics and Genomics, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA
- 3Hejun College; Synergene (Jiangxi) Education, Huichang, Jiangxi, China
- 4Hainan Provincial Prenatal Diagnosis Center, Hainan Provincial Key Laboratory for Human Reproductive Medicine and Genetic Research, Department of Reproductive Medicine, Hainan Provincial Clinical Research Center for Thalassemia, Key Laboratory of Reproductive Health Diseases Research and Translation, Ministry of Education, the First Affiliated Hospital of Hainan Medical University, Hainan Medical University, Haikou, Hainan, China
- 5Obstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering, Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Children’s Hospital, Fudan University, Shanghai, China
- 6Prenatal Diagnosis Center of Shenzhen Maternity and Child Healthcare Hospital, Shenzhen, China
- Correspondence to: H Wang wanghy{at}fudan.edu.cn
Key messages
Genomic medicine provides novel approaches to reduce birth defects that disproportionately affect the lives of children and parents in China, but the research priorities identified in this article are of global relevance
Doing incidence based rather than prevalence based disease burden analyses using comprehensive population genomic data would provide a more accurate understanding of the portfolio of genetic diseases in China to facilitate effective prevention
Disease severity assessment based on the current healthcare settings in China is a key step for determining the inclusion of diseases to be covered by the birth defect prevention policy to avoid over-screening
Genetic counselling is an indispensible component to ensure informed decision making for participating in genomic screening and to minimise adverse outcomes
Cost effectiveness studies are needed before the new genomic medicine based birth defect prevention approaches are implemented in China to leverage benefits over costs
Birth defects are a global health concern, not only contributing significantly to infant morbidity and mortality but also negatively affecting mothers’ lives. The burden on women with children who have birth defects is particularly heavy during pregnancy and even greater after the birth. They face increased physical, emotional, and financial challenges, along with the risk of adverse obstetric outcomes and the burden of raising children with birth defects. Thus, birth defects are highly relevant to women’s health.
Approximately 900 000 infants are born with birth defects each year in China.12 Consequently, the incentive to prevent birth defects is so strong that it has become a national policy and an unremitting goal.34 A “three stage prevention strategy” was developed to serve as a nationwide approach to prevention of birth defects,4 focusing primarily on pre-conception education and folic acid fortification, prenatal screening for various aneuploidies and structural defects, and screening of newborns for congenital genetic diseases (fig1). This strategy has led to notable changes in the incidence of major birth defects in China. For example, free pre-conception folic acid supplementation to approximately 102 million women between 2009 and 2018 decreased the incidence of prenatal neural tube defects from 27.4 per 10 000 in 1987 to 1.5 per 10 000 in 2017.5 Additionally, offering free pre-pregnancy health examinations to 11.73 million people nationwide in 2017 had a significant impact in reducing congenital disorders with high prevelance.6 The thalassaemia carrier screening for about 1 645 000 couples dramatically decreased the incidence of thalassaemia in Guangxi Province and Guangdong Province from 21.7 and 44.6 per 10 000, respectively, in 2006 to 1.93 and 3.15 per 10 000 in 2017.5
Three stage prevention and control scheme for birth defects. A comprehensive multistage approach for prevention and control of birth defects is carried out at three stages: pre-conception, prenatal, and newborn. The roles of each stage are complementary. At the pre-conception stage, genetic carrier screening is provided to all prospective parents to assess the genetic variants that carry a risk of causing genetic disorders in the next generation; the parents can choose the most appropriate reproductive option (eg, pre-implantation genetic testing (PGT)) depending on the risk and the findings of genetic counselling. Most couples then proceed to stage II, except in cases of adoption or opting out of parenthood. At the prenatal stage, traditional non-invasive prenatal testing (NIPT) and ultrasound examinations are offered to all pregnant women. In addition, genetic diagnostic testing using samples collected by chorionic villus sampling or amniocentesis should be considered to detect genetic disorders caused by genomic imbalances or sequence variants; again, genetic counselling should be an integral part of prenatal tests. At the newborn stage, heel prick blood samples are collected for almost all babies. Newborn screening using tandem mass spectrometry for metabolic disorders and genomic sequencing for mendelian disorders should be offered to uncover diseases that are treatable at the pre-symptomatic stage. Both pre-test and post-test genetic counselling sessions are crucial at all stages to ensure that parents can make informed decisions
The ability to prevent birth defects has been further improved with advances in genetic testing. Traditional genetic screening primarily focused on Down’s syndrome and chromosomal aneuploidies. With the availability of non-invasive prenatal testing and chromosomal microarray analysis, the scope for detecting birth defects has expanded to cover a large number of genomic imbalance disorders. However, many genetic disorders caused by sequence variants remain undetected before conception and during pregnancy. Next generation sequencing offers new testing methods for preventing birth defects caused by sequence variants. Next generation sequencing can be applied to genomic carrier screening and 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. Next generation sequencing has proved highly effective in diagnostic testing, with greater than 95% sensitivity and 99% specificity.7 As a result, next generation sequencing based testing is considered to be a promising solution for preventing many genetic birth defects that were elusive to traditional approaches. A recent systematic survey found the perinatal prevalence of birth defects in China to be as high as 208.94 per 10 000 in 2020-21,8 highlighting the need for comprehensive genomic testing across pre-conception, prenatal, and neonatal stages.
For successful implementation of this promising novel approach, we highlight critical concerns to meet the associated challenges (table 1). These concerns are critical for providing more precise disease risk predictions, preventing over-diagnosis and screening induced family stress, and maximising benefits. Although this discussion is tailored to China’s distinct situation and challenges, our analysis also aims to provide beneficial insights for other countries encountering similar concerns in the era of genomic medicine development.
Current status of and potential solutions to key research concerns for implementation of genomic strategies for prevention of birth defects
Systematic studies on incidence of genetic disorders across China
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.
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.
Assessment 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.
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.
Enhancing genetic counselling
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.
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.1820 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.
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
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,1617 along with studies on the cost effectiveness of genomic testing.1521 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.
Conclusions
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.
Acknowledgments
This work was jointly supported by grants from the National Key Research and Development Program of China (2021YFC2701100 to HW), National Natural Science Foundation of China (82150008, 81930036 to HW; 82071276 to YS), Hainan Province Science and Technology Project (LCYX202102, LCYX202203, LCYX202301 to YM), and the specific research fund of the Innovation Platform for Academicians of Hainan Province Project, Hainan Province Clinical Medical Center Project, Ningbo science and technology project (2023Z178).
Footnotes
Contributors and sources: All four authors discussed the main topics of this article. YA collected information, wrote the manuscript, and participated in revision. YS is an ABMGG certified medical geneticist who is focusing on promoting the implementation of novel genomic tests for birth defect prevention and population healthcare, as well as on training a new generation of genetic counsellors in China. He conceived the project and edited the manuscript. YM and HW reviewed and revised the manuscript. YA and YS contributed equally to this article. YA is the guarantor.
Competing interests: We have read and understood BMJ policy on declaration of interests and have no interests to declare.
Provenance and peer review: Commissioned; externally peer reviewed.
This article is part of a collection proposed by the Peking University, led by Jie Qiao. Open access fees were funded by individual institutions. The BMJ commissioned, peer reviewed, edited, and made the decision to publish. Jin-Ling Tang and Jocalyn Clark were the lead editors for The BMJ.
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