|
 
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| REVIEW ARTICLE |
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| Year : 2019 | Volume
: 5
| Issue : 4 | Page : 154-161 |
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Precision medicine: Rare diseases and community genetics
Alan H Bittles
School of Medical and Health Sciences, Edith Cowan University; Centre for Comparative Genomics, Murdoch University, Perth, WA, Australia
| Date of Submission | 03-Dec-2019 |
| Date of Decision | 13-Jan-2020 |
| Date of Acceptance | 13-Jan-2020 |
| Date of Web Publication | 13-Apr-2020 |
Correspondence Address:
Alan H Bittles
School of Medical and Health Sciences, Edith Cowan University, 270 Joondalup Drive, Perth, WA 6027
Australia
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/digm.digm_29_19
Precision medicine is based on the premise that genomic analysis radically changes the nature and scope of therapeutic medicine. While genome sequencing has revolutionized the study of human disease, to date progress in translating genomic knowledge into treatments for inherited disorders has been less apparent. However, increasing attention on the relationship(s) between rare diseases (RDs) and precision medicine should significantly accelerate this process, as evidenced by the increasing numbers of molecular therapies receiving approval from the U.S. Food and Drug Administration. There are an estimated 7000 RDs, a majority of which affect <1/million people; but, collectively, it has been calculated that in high-income countries ≥1/17 persons have a RD. RDs represent both a significant health challenge and a major economic burden for many affected individuals and their families, and although many are life-threatening, they often remain undiagnosed or misdiagnosed. Unfortunately, global progress in resolving these issues has been hindered by basic problems such as differing national and regional definitions, from a RD prevalence of 1 to 5/10,000 affected persons in Europe and Australia to 1/500,000 in China. There also has been failure to recognize that many RDs originated as founder mutations and are community-specific, an especially important consideration in populations where community endogamy is the rule and close-kin marriage is traditional. The near-global transition from a communicable to a predominantly noncommunicable disease profile has, however, served to highlight the importance of genetics in medicine, and resulted in a rapidly growing focus on RDs. Against this background, collaborative international programs to facilitate the prevention and curative treatment of RDs merit urgent adoption and support.
Keywords: Consanguinity, founder mutations, marital endogamy, precision medicine, rare diseases
How to cite this article:
Bittles AH. Precision medicine: Rare diseases and community genetics. Digit Med 2019;5:154-61 |
| Introduction | |  |
Precision medicine has been identified as a major positive outcome of the Human Genome Project (HGP), which formally ran from 1990 to 2003. In the 109th Shattuck Lecture, delivered to the Annual Meeting of the Massachusetts Medical Society in 1999, Francis Collins, the Director of the US National Institute of Health (NIH) and the major driving-force behind the HGP, predicted that within 15 to 20 years, genomic analysis would have revolutionized therapeutic medicine.[1] This prediction of the dominant role to be played by genomics has since proved to be somewhat premature. As for many of the common diseases investigated by Genome-wide association studies, including ischemic heart disease, diabetes, cancers and psychiatric disorders, the expression of hundreds and even thousands of mutations, each of small individual effect, is implicated.
Despite this drawback, which has resulted in some degree of skepticism toward the scale of benefits originally claimed for precision medicine,[2] the concept of genomic analysis as the corner-stone of therapeutic medicine has been substantially accepted and, as indicated in [Table 1], through time, it has been extended to include and integrate other forms of omics technology.[3],[4]
From its inception, the actual definition of precision medicine has been vague, but the current description by the U.S. NIH as: “An emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment and lifestyle for each person“[5] encompasses its main intentions. Although, as will become apparent, an earlier NIH description that precision medicine embodied: “Medical care designed to optimize efficiency or therapeutic benefit for particular groups of patients, especially by using genetic or molecular profiling” has particular resonance in many contemporary human populations that are characterized by strict community endogamy and frequently by preferential consanguineous marriage.[6],[7],[8]
| Rare Diseases: an Overview and Definition(S) | | |
Some 7000 rare diseases (RDs) have been diagnosed in humans,[9],[10] and an estimated 350 million people are living with a RD.[11] As with precision medicine, the working definition of a RD can vary, with a prevalence of fewer than 5 affected persons per 10,000 of the general population generally adopted in Europe and countries such as Australia. Whereas in the USA, under the terms of the Orphan Drug Act of 1983,[12] a RD was defined as a disorder affecting fewer than 200,000 persons, which in the current total U.S. population of 329 million is approximately equivalent to <1/1650.
A recent point prevalence analysis of the Orphanet database showed that 71.9% of RDs were genetic in etiology and 69.9% had an exclusively pediatric onset.[13] The prevalence of individual RDs varied greatly. In a large majority (84.5%) of diseases, <1/million persons were affected, whereas disorders affecting 1–5/10,000 patients were diagnosed in just 4.2% of all RD patients but accounted for ~80% of the overall RD burden. As indicated by these data, most RDs are individually small in number; but, collectively, they affect a sizeable proportion of the total population. Thus, in countries such as the UK[14] and Australia,[15] an estimated 1/17 of the population have a RD while in the USA, the estimate is ~1/12,[16] reflecting the alternative methods of calculating disease prevalence applied in each population.
| The Influence of Demographic Structure on Rare Diseases | | |
As previously noted, in many contemporary human populations, there is a long tradition of strict marital endogamy with couples contracting marriage within subcommunities that are characterized by factors such as ethnicity, religion, geography, and social custom.[7] In addition, a large proportion of populations and communities in Asia and Africa strongly favor consanguineous unions, usually defined as marriage between couples who are related as second cousins or closer, equivalent to a coefficient of inbreeding of F = 0.0156.[17] It has been conservatively estimated that some 10.4% of global marriages are consanguineous,[6],[7] and a recent national study in India which has a current population of 1392 million showed that 7.5% of present-day marriages are consanguineous, mainly contracted between first cousins (F = 0.0625), but ranging in prevalence from 0.2% in Tripura in Northeast India to 30.0% in the southern state of Tamil Nadu.[18]
As a result, where marital endogamy is the norm and, more particularly, when there also has been a long tradition of consanguineous marriage, founder mutations frequently have resulted in the accumulation of very rare recessive disorders that are unique to specific communities and subcommunities.[19] This outcome is most frequently observed in populations traditionally subdivided along clan, tribe, caste or biraderi lines,[6],[7],[20],[21] and in migrant communities from these populations now resident in Western Europe, North America, and Australasia, for example, the UK Pakistani community in which 50.2% of current marriages are between 1st or 2nd cousins.[22],[23]
However, the residual influence of founder mutations also is seen in European countries such as Finland, where 36 mostly autosomal recessive mutations that are rare or absent in neighboring populations have been mapped to different regions and communities, a phenomenon described as the Finnish Disease Heritage.[24],[25] A similar situation exists in the Dutch town of Volendam, which was established as a fishing village by an estimated 7 to 20 families in the 14th century AD. Following the Reformation in Europe in the 16th century AD the occupants of Volendam retained their Roman Catholic beliefs, which separated them from their surrounding Protestant neighbours. Despite being located <20 km from Amsterdam, this long-term religious endogamy has resulted in the accumulation of four clinically severe founder mutations in the population of Volendam: pontocerebellar hypoplasia type 2, fetal akinesia deformation sequence, rhizomelic chondrodysplasia punctata type 1, and osteogenesis imperfecta type IIB/III,[26] which in other populations have an incidence of 1/100,000 to <1/million.[10]
| Precision Medicine and the Diagnosis and Treatment of Rare Diseases | | |
In a disappointingly large proportion of cases, people with a RD remain undiagnosed for many years, or are misdiagnosed, sometimes on several occasions.[27] In such instances, appropriate treatment either proves impossible to prescribe or is nonefficacious. This situation most commonly occurs in ultra-RDs that affect a very small number of patients globally, resulting in clinical and research expertise being confined to a small number of specialist centers.
For RDs that are relatively common, greater clinical and laboratory-based expertise is more readily available via bodies such as the International RDs Research Consortium, in conjunction with the U.S. National Institutes of Health and the European Commission.[11] Complementary social, financial, and political assistance is provided by umbrella bodies, such as the National Organization for Rare Disorders in the USA, the European Organization for RDs, Rare Voices Australia, the Chinese Organization for Rare Disorders, and by Parent and Patient Support Groups for individual disorders.
Issues that can arise in the diagnosis and treatment of RDs are exemplified by two well-defined and clinically severe disorders, cystic fibrosis (CF), and β-thalassemia major, that primarily affect people in different regions of the world.
| Cystic Fibrosis | | |
CF is a severe progressive disorder, inherited as an autosomal recessive defect in the gene encoding the CF transmembrane conductance regulator (CFTR) protein which results in reduced CFTR function.[28] The disease affects an estimated 80,000 people worldwide, and it is especially prevalent in North-Western Europe, for example, with 1/19 of the population of Ireland identified as CF carriers.[29] CF also affects some 1/2500 to 1/4000 people in countries such as the USA and Australia, where a significant proportion of the population have European ancestry.
Patients with CF typically exhibit a wide spectrum of respiratory tract, pancreas, gastrointestinal system, and sweat gland defects. To date, approximately 2000 CF mutations have been identified,[30] a majority of which affect relatively few families. However, the ability to identify the specific CFTR mutation(s) within a family or community clearly is highly advantageous in the design and implementation of appropriate treatment regimens.
Phe508del is the most common CFTR mutation in North-western European populations, and following precision medicine principles, specific molecular therapeutic treatments for patients with this mutation have recently been formulated. For example, Orkambi (a combination of two drugs lumacaftor and ivacaftor) was formulated by Vertex Pharmaceuticals in the USA and prescribed for children with CF aged from 1 to 2 years onward. It has been estimated that some 53% of the 8200 people with CF in the UK could benefit from this treatment.[31]
However, with approval granted by the U.S. Food and Drug Administration in October 2019 for a new triple therapy Trikafta (comprising elexacaftor/tezacaftor/ivacaftor) in children with CF aged 12+ years,[30] this figure could rise to 90%,[31] since the triple therapy is efficacious in CF patients who are compound heterozygotes for CF, i.e., who have inherited a single copy of Phe508del mutation in combination with a different CFTR mutation.[28] Not surprisingly, the high success rate of this new treatment, and its demonstrated safety and efficacy in CF patients homozygous for the Phe508del mutation,[32] was welcomed by Francis Collins as “Realizing the dream of molecularly targeted therapies for CF.”[33]
The imperative to design a molecular therapy for CF is less acute in countries such as China, with an estimated CF prevalence of 1/64,000 and symptoms that clinically are quite mild and mainly affect lung function.[34] To date, the causative Chinese CF mutations that have been identified differ from those reported in Caucasian populations,[35] indicating the need for a China-specific CFTR screening panel.[34]
Beta-thalassemia
By comparison with the geographical distribution of CF, β-thalassemia major is an inherited form of anemia that occurs in traditionally malarial locations, including Mediterranean countries, the Middle East, and Southeast and South Asia. Global estimates suggest that there are 80–90 million carriers of β-thalassemia,[36] with more than 350 β-thalassemia mutations reported.[37] In India, up to 150,000 people currently are estimated to have the disease which usually is treated by regular blood or red cell transfusions and iron chelation therapy.[38]
A study on the projected impact of β-thalassemia in India to 2026 illustrates the major advantages of prevention over treatment.[38] As summarized in [Table 2], by 2026 it is predicted that there will be some 275,000 people in India with β-thalassemia who are transfusion-dependent, including a minority of persons for whom a suitable donor for allogeneic hematopoietic stem cell transplantation (HSCT) will be available. | Table 2: India, β-thalassemia major: Projected annual costs of treatment, 2026
Click here to view |
Based on the present experience in India and other Asian countries and assuming optimum levels of care, by 2026 the blood donation requirement for these patients would be 8.25 million units (of 350 ml or 450 ml). The projected yearly costs for the treatment of people with β-thalassemia by transfusion and chelation alone would therefore be USD 820 million, plus an additional USD 261 million for up to 10% cases where HSCT could prove to be an option. By comparison, by 2026, prevention of the disorder by school-based screening to identify carriers of the disorder, with subsequent antenatal testing and prenatal diagnosis, would cost a fraction of that sum, estimated at USD 33.3 million [Table 3]. In addition, screening would help circumvent the birth of children with β-thalassemia whose life-style would necessarily be significantly constrained despite treatment, and would lead to the gradual elimination of the disorder, as has been demonstrated in countries such as Greece,[39] and Iran.[40] | Table 3: India, β-thalassemia major: Projected annual costs of screening and prenatal diagnosis, 2026
Click here to view |
| Precision Medicine and Rare Diseases in China | | |
With 1,398 million inhabitants, China accounts for some 18% of the total world population. Until recently, data on the overall health status of the population have been limited, but this situation is rapidly changing, as evidenced by the publication of detailed information on the health patterns reported in the 34 province-level administration units of China from 1990 to 2017, as part of the Global Burden of Diseases Study 2017.[41]
Information on the profile and incidence of RDs has been equivalently scant, with an estimate of 16 million cases of RDs cited.[42],[43] Given the large national population, this estimate seems improbably low by global standards, and it may be based on a definition of RDs proposed by the Genetics Branch of the Chinese Medical Association in 2010 of disorders with a prevalence of 1/500,000.[42],[44] However, a government-supported research program, the RDs Clinical Cohort Study, was launched in 2016, and a National RDs Registry System of China is schedueld for release in 2020.[42],[45] In the interim, a hospital-based Target RDs List was compiled in 2017,[46] followed by publication in 2018 of the first National List of Chinese RDs based on patients with 121 RDs,[44] and a database of 15,942 RDs incorporating information on their clinical manifestations and molecular mechanisms.[47]
In China, hemoglobinopathies provide an example of rare inherited disorders where prevalence data are available, with an estimated 36,000 affected babies born per year,[48] principally in provinces south of the river Yangtze, i.e., Guangdong, Guangxi, Fujian, Yunnan, Guizhou, and Sichuan, where malaria was previously endemic. The carrier frequency of β-thalassemia major alone in China ranges from 0.5% to 6.8%,[49] with studies conducted in a number of major research centers.[50],[51],[52],[53],[54],[55],[56]
Although an estimated 91.6% of the Chinese population are of Han ethnicity, there also are 55 officially recognized ethnic minorities (minzu), many of which traditionally are resident in peripheral rural areas of the country. However, with the exception of the Jino ethnic minority in Yunnan province,[57] the influence of ethnicity on the distribution patterns and severity of diseases such as β-thalassemia major has yet to be investigated in detail.
An answer to this question would be particularly useful in provinces such as Guizhou in Southwest China, where 13 resident ethnic minorities account for 36.2% of the provincial population of 34.8 million.[58] In an earlier study of individuals recruited from ethnic minorities in Guizhou, 5.4% were found to be carriers of β-thalassemia.[59] In Guizhou and other Chinese provinces with sizeable ethnic minorities, marriage has usually been contracted within each separate ethnic community, and the ban on first cousin marriage stipulated in the Marriage Law of 1981 may not be applied in communities with a tradition of consanguinity, especially those resident in remote areas.[7],[60] Thus, in a largely mountainous province such as Guizhou, with multiple ethnic minorities, community-specific disease data are required if the diagnosis, treatment, and prevention of β-thalassemia and other hemoglobinopathies is to be efficiently addressed.
| Precision Medicine, Rare Diseases, and Community Genetics: the Future | | |
The very rapid recent progress in the treatment of CF strongly indicates that effective treatment protocols can and will be designed for other RDs, an example being patient-customized therapy for a novel mutation in a child with neuronal ceroid lipofuscinosis 7, a rare fatal neurodegenerative condition.[61] However, a major practical problem to be faced in meeting the health needs of people with RDs is the cost of treatment, and whether affected patients and their families will receive an appropriate level of governmental financial support and/or have access to medical insurance.
This situation already exists for patients with CF in high-income countries, where treatment with Orkambi has been costed at USD 200,000 per patient per year in the USA and Trikafta at USD 311,500 per year.[62] Orkambi has been the subject of extended price negotiations between the manufacturer Vertex Pharmaceuticals and the UK National Health Service (NHS).[63] To add to the complexity of the UK cost negotiations, separate discussions were undertaken between Vertex and NHS Scotland, and between the company and NHS England, the latter also acting on behalf of NHS Wales and NHS Northern Ireland. Details of the financial agreements reached have remained confidential.[31]
Meantime, in Australia from August 2019, the drug Kalydeco (ivacaftor), also produced by Vertex and which previously could be accessed by children >2 years and adults, has been approved for use in 12–24-month-old children with a G551D or an equivalent class III channel gating CF mutation, at a yearly cost of up to AUD 300,000 (~USD 206,000) per patient. Under the terms of the Australian government-funded Pharmaceutical Benefit Scheme, some of these CF patients, who collectively account for ~ 6% of all CF cases, could qualify for concessional monthly prescriptions for Kalydeco for as little as AUD 6.50 (AUD 4.50).[64]
As yet, no equivalent scenario has arisen with treatment provision and costs for hemoglobinopathies, but it has been predicted that by 2026, the total global screening and treatment budget for hemoglobinopathies will be USD 12.6 billion, with the Asia-Pacific region a major developing cost contributor.[65] In the intervening years, it will be interesting to follow the level of progress made with gene therapy, and gene editing, for the treatment of disorders such as β-thalassemia.[66]
| Conclusions | | |
Precision medicine has resulted in substantial, unprecedented progress in the design and introduction of molecular therapies for the treatment of RDs. However, for many countries, including the mega-populations of China and India, the profile and prevalence of the diseases to be addressed remains to be determined, in part because of the markedly different definitions of RDs that currently are used in different countries, for example, <1/500,000 in China[42],[44] versus 1–5/10,000 in Europe and Australasia.[10] Comprehensive RD registries are therefore urgently needed, based on a common agreed definition and detailing not only the clinical aspects of the diseases but also including information on the population profiles and molecular spectra of specific disorders by country, region, and subpopulation. In such patient registries, it has been proposed that the incorporation of analytics could ensure the optimum utilization of health data and the evaluation of individual outcomes of health interventions in real time.[67]
An ambitious Action Plan on RDs has been approved for the 21 Asia Pacific Economic Cooperation (APEC) member countries in Asia, Australasia, North and South America. According to the Action Plan, by 2025 the APEC member economies, including China, will aim for consensus in areas such as governance, capacity-building measures for managing and storing patient data, and cross-border data flows.[68] In tandem with private social insurance, they also will have established policies and programs to provide some level of publicly funded social insurance for RD patients and their families.[68]
If successful, this will be a remarkable multinational achievement. Given the size of APEC, with a current combined population of 2915 million, which is 37.9% of the world total,[69] and its potential financial clout, it could go a long way to addressing the major international unease that increasingly has been expressed concerning the costs of orphan drugs.[70]
The computational power required for such large-scale registries is, however, very considerable. Thus, for China, the development during the last 5 years of major international cloud computing and big data facilities in Guiyang, the capital of Guizhou, is particularly timely in facilitating the modeling and development of cross-community RD research nationally and for residents of the province. Improved accessibility to international sources of drugs for the treatment of a small number of RDs has been approved by the Government of China, and the number of RD drugs included in the National Medical Insurance Catalogue has recently increased.[71] But, in the near- to medium-term future, the design and manufacture of orphan medicinal products should appropriately be regarded as a priority for all countries with the requisite expertise.
However, as previously indicated, a problem already faced by all countries is the major disconnect between the cost of treatments for RDs and the financial capacity of private individuals and families to pay for their purchase. Especially since most treatments alleviate symptoms and extend lifespans rather than representing a cure per se. In countries such as the UK and Australia, the financial support provided by Government agencies to date has been vital. However, as more and more treatments become available for ever-greater numbers of patients with RDs, decisions prioritizing which groups of patients, and which individuals, should qualify for and receive this support will become critical, and potentially contentious.[72]
Predictably, the situation will be even more difficult in medium- and low-income countries where a major transition from communicable to noncommunicable diseases has already occurred. As illustrated in China, an as-yet limited number of RDs are covered by medical insurance to differing extents,[71],[73] and poverty caused by the burden of disease has been described as a common experience in families dealing with RDs.[43] A prompt response to this ethical dilemma merits urgent attention by world governments and international health agencies, including appropriate weighting to support cost-effective prevention programs.
Acknowledgment
An earlier version of this article was presented by the author as part of the 2019 Medical Frontier Summit Forum Agenda at Guiqian International General Hospital, Guiyang, China on October 18, 2019.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | Collins FS. Shattuck lecture – Medical and societal consequences of the human genome project. N Engl J Med 1999;341:28-37.  |
| 2. | Joyner MJ, Paneth N. Promises, promises, and precision medicine. J Clin Invest 2019;129:946-8. |
| 3. | Hasin Y, Seldin M, Lusis A. Multi-omics approaches to disease. Genome Biol 2017;18:83. |
| 4. | Manzoni C, Kia DA, Vandrovcova J, Hardy J, Wood NW, Lewis PA, et al. Genome, transcriptome and proteome: The rise of omics data and their integration in biomedical sciences. Brief Bioinform 2018;19:286-302. |
| 5. | National Institutes of Health. Genetics Home Reference: What is Precision Medicine? Washington, DC: National Institutes of Health; 2019. |
| 6. | Bittles AH, Black ML. Evolution in health and medicine Sackler colloquium: Consanguinity, human evolution, and complex diseases. Proc Natl Acad Sci U S A 2010;107 Suppl 1:1779-86. |
| 7. | Bittles AH. Consanguinity in Context. Cambridge: Cambridge University Press; 2012. |
| 8. | Blencowe H, Moorthie S, Petrou M, Hamamy H, Povey S, Bittles A, et al. Rare single gene disorders: Estimating baseline prevalence and outcomes worldwide. J Community Genet 2018;9:397-406. |
| 9. | Griggs RC, Batshaw M, Dunkle M, Gopal-Srivastava R, Kaye E, Krischer J, et al. Clinical research for rare disease: Opportunities, challenges, and solutions. Mol Genet Metab 2009;96:20-6. |
| 10. | Orphanet. List of Rare Disease and Synonyms. Orphanet Report Series; 2019. |
| 11. | Lochmüller H, Torrent I Farnell J, Le Cam Y, Jonker AH, Lau LP, Baynam G, et al. The international rare diseases research consortium: Policies and guidelines to maximize impact. Eur J Hum Genet 2017;25:1293-302. |
| 12. | Herder M. What is the purpose of the orphan drug act? PLoS Med 2017;14:e1002191. |
| 13. | Nguengang Wakap S, Lambert DM, Olry A, Rodwell C, Gueydan C, Lanneau V, et al. Estimating cumulative point prevalence of rare diseases: Analysis of the Orphanet database. Eur J Hum Genet 2020;28:165-73. |
| 14. | National Congenital Anomaly and Rare Disease Registration Service (NCARDRS). Congenital anomaly status. Public Health England, London, 2017. Available from: www.gov.uk/phe. [Last accessed on 2019 Aug 21]. |
| 15. | Lacaze P, Millis N, Fookes M, Zurynski Y, Jaffe A, Bellgard M, et al. Rare disease registries: A call to action. Intern Med J 2017;47:1075-9. |
| 16. | Jo A, Larson S, Carek P, Peabody MR, Peterson LE, Mainous AG. Prevalence and practice for rare diseases in primary care: A national cross-sectional study in the USA. BMJ Open 2019;9:e027248. |
| 17. | Bittles A. Consanguinity and its relevance to clinical genetics. Clin Genet 2001;60:89-98. |
| 18. | Kumari N, Bittles AH, Saxena P. Has the long-predicted decline in consanguineous marriage in India occurred? J Biosoc Sci 2019;1-10. doi: 10.1017/S2002193201932019000762. |
| 19. | Bittles AH. Consanguinity, genetic drift and genetic diseases in populations with reduced numbers of founders. In: Speicher M, Antonarakis SE, Motulsky AG, editors. Human Genetics – Principles and Approaches. 4 th ed. Heidelberg: Springer; 2010. p. 507-28. |
| 20. | Nakatsuka N, Moorjani P, Rai N, Sarkar B, Tandon A, Patterson N, et al. The promise of discovering population-specific disease-associated genes in South Asia. Nat Genet 2017;49:1403-7. |
| 21. | Zlotogora J. Autosomal recessive diseases among the Israeli Arabs. Hum Genet 2019;138:1117-22. |
| 22. | Small N, Bittles AH, Petherick ES, Wright J. Endogamy, consanguinity and the health implications of changing marital choices in the UK Pakistani community. J Biosoc Sci 2017;49:435-46. |
| 23. | Bishop C, Small N, Mason D, Corry P, Wright J, Parslow RC, et al. Improving case ascertainment of congenital anomalies: Findings from a prospective birth cohort with detailed primary care record linkage. BMJ Paediatr Open 2017;1:e000171. |
| 24. | Norio R. Finnish disease heritage I: Characteristics, causes, background. Hum Genet 2003;112:441-56. |
| 25. | Norio R. The Finnish disease heritage III: The individual diseases. Hum Genet 2003;112:470-526. |
| 26. | Mathijssen IB, Henneman L, van Eeten-Nijman JM, Lakeman P, Ottenheim CP, Redeker EJ, et al. Targeted carrier screening for four recessive disorders: High detection rate within a founder population. Eur J Med Genet 2015;58:123-8. |
| 27. | Dharssi S, Wong-Rieger D, Harold M, Terry S. Review of 11 national policies for rare diseases in the context of key patient needs. Orphanet J Rare Dis 2017;12:63. |
| 28. | Middleton PG, Mall MA, Dřevínek P, Lands LC, McKone EF, Polineni D, et al. Elexacaftor-tezacaftor-ivacaftor for cystic fibrosis with a single Phe508del Allele. N Engl J Med 2019;381:1809-19. |
| 29. | Paluck F, Linnane B. Liver tests in F508del homozygous cystic fibrosis patients on Orkambi. Arch Dis Child 2019;104 Suppl 3:A144-5. |
| 30. | U.S. Food and Drug Administration. FDA Approves New Breakthrough Therapy for Cystic Fibrosis. U.S. Food and Drug Administration; 2019. Available from: www.fda.gov/news-events/pressannouncements. See Attachment. [Last accessed on 2019 Oct 21]. |
| 31. | Kmietowicz Z. Cystic fibrosis drugs to be available on NHS in England within 30 days. BMJ 2019;367:1. |
| 32. | Heijerman HG, McKone EF, Downey DG, Van Braeckel E, Rowe SM, Tullis E, et al. Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: A double-blind, randomised, phase 3 trial. Lancet 2019;394:1940-8. |
| 33. | Collins FS. Realizing the dream of molecularly targeted therapies for cystic fibrosis. N Engl J Med 2019;381:1863-5. |
| 34. | Guo X, Liu K, Liu Y, Situ Y, Tian X, Xu KF, et al. Clinical and genetic characteristics of cystic fibrosis in Chinese patients: A systemic review of reported cases. Orphanet J Rare Dis 2018;13:224. |
| 35. | Zheng B, Cao L. Differences in gene mutations between Chinese and Caucasian cystic fibrosis patients. Pediatr Pulmonol 2017;52:E11-E14. |
| 36. | Galanello R, Origa R. Beta-thalassemia. Orphanet J Rare Dis 2010;5:11. |
| 37. | De Sanctis V, Kattamis C, Canatan D, Soliman AT, Elsedfy H, Karimi M, et al. β-Thalassemia distribution in the old world: An ancient disease seen from a historical standpoint. Mediterr J Hematol Infect Dis 2017;9:e2017018. |
| 38. | Sinha S, Seth T, Colah RB, Bittles AH. Haemoglobinopathies in India: Estimates of blood requirements and treatment costs for the decade 2017-2026. J Community Genet 2020;11:39-45. |
| 39. | Loukopoulos D. Haemoglobinopathies in Greece: Prevention programme over the past 35 years. Indian J Med Res 2011;134:572-6. [ PUBMED] [Full text] |
| 40. | Samavat A, Modell B. Iranian national thalassaemia screening programme. BMJ 2004;329:1134-7. |
| 41. | Zhou M, Wang H, Zeng X, Yin P, Zhu J, Chen W, et al. Mortality, morbidity, and risk factors in China and its provinces, 1990-2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet 2019;394:1145-58. |
| 42. | Song P, He J, Li F, Jin C. Innovative measures to combat rare diseases in China: The national rare diseases registry system, larger-scale clinical cohort studies, and studies in combination with precision medicine research. Intractable Rare Dis Res 2017;6:1-5. |
| 43. | Zhang S, Chen L, Zhang Z, Zhao Y. Orphan drug development in China: Progress and challenges. Lancet 2019;394:1127-8. |
| 44. | He J, Kang Q, Hu J, Song P, Jin C. China has officially released its first national list of rare diseases. Intractable Rare Dis Res 2018;7:145-7. |
| 45. | Feng S, Liu S, Zhu C, Gong M, Zhu Y, Zhang S. National rare diseases registry system of China and related cohort studies: Vision and roadmap. Hum Gene Ther 2018;29:128-35. |
| 46. | Shi X, Liu H, Zhan S, Wang Z, Wang L, Dong C, et al. Rare diseases in China: Analysis of 2014-2015 hospitalization summary reports for 281 rare diseases from 96 tertiary hospitals. Orphanet J Rare Dis 2019;14:160. |
| 47. | Jia J, An Z, Ming Y, Guo Y, Li W, Liang Y, et al. eRAM: Encyclopedia of rare disease annotations for precision medicine. Nucleic Acids Res 2018;46:D937-43. |
| 48. | Zhang L, Zhang Q, Tang Y, Cong P, Ye Y, Chen S, et al. LOVD-DASH: A comprehensive LOVD database coupled with diagnosis and an at-risk assessment system for hemoglobinopathies. Hum Mutat 2019;40:2221-9. |
| 49. | Lai K, Huang G, Su L, He Y. The prevalence of thalassemia in mainland China: Evidence from epidemiological surveys. Sci Rep 2017;7:920. |
| 50. | Zeng Y, Huang S. The studies of hemoglobinopathies and thalassemia in China – The experiences in Shanghai Institute of Medical Genetics. Clin Chim Acta 2001;313:107-11. |
| 51. | Xu XM, Zhou YQ, Luo GX, Liao C, Zhou M, Chen PY, et al. The prevalence and spectrum of alpha and beta thalassaemia in Guangdong Province: Implications for the future health burden and population screening. J Clin Pathol 2004;57:517-22. |
| 52. | Liao C, Mo QH, Li J, Li LY, Huang YN, Hua L, et al. Carrier screening for alpha- and beta-thalassemia in pregnancy: The results of an 11-year prospective program in Guangzhou Maternal and Neonatal hospital. Prenat Diagn 2005;25:163-71. |
| 53. | Lin M, Wen YF, Wu JR, Wang Q, Zheng L, Liu GR, et al. Hemoglobinopathy: Molecular epidemiological characteristics and health effects on Hakka people in the Meizhou region, southern China. PLoS One 2013;8:e55024. |
| 54. | Ding ZY, Shen GS, Zhang S, He PY. Epidemiology of hemoglobinopathies in the Huzhou Region, Zhejiang Province, Southeast China. Hemoglobin 2016;40:304-9. |
| 55. | He J, Zeng H, Zhu L, Li H, Shi L, Hu L. Prevalence and spectrum of thalassaemia in Changsha, Hunan province, China: Discussion of an innovative screening strategy. J Genet 2017;96:327-32. |
| 56. | Huang H, Xu L, Chen M, Lin N, Xue H, Chen L, et al. Molecular characterization of thalassemia and hemoglobinopathy in Southeastern China. Sci Rep 2019;9:3493. |
| 57. | Wang S, Zhang R, Xiang G, Li Y, Hou X, Jiang F, et al. Mutation screening for thalassaemia in the Jino ethnic minority population of Yunnan Province, Southwest China. BMJ Open 2015;5:e010047. |
| 58. | Huang SW, Liu XM, Li GF, Su L, Wu X, Wang RL. Spectrum of β-thalassemia mutations in Guizhou Province, PR China, including first observation of codon 121 (GAA>TAA) in Chinese population. Clin Biochem 2013;46:1865-8. |
| 59. | Yu F, Zhong C, Zhou Q, Yang Y, Li W, Liu B, et al. Genetic analysis of β -thalassemia mutations in the minority populations of Guizhou province. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2010;27:700-3. |
| 60. | Government of PR China. The marriage law of the people's republic of China. Beijing: Foreign Languages Press; 1982. |
| 61. | Kim J, Hu C, Al Achkar CM, Black LE, Douville J, Larson A. Patient-customized oligonucleotide therapy for a rare genetic disease. New Engl J Med 2019;381:1644-52. |
| 62. | Brainard J. News in brief: Cystic fibrosis drug approved. Science 2019;366:554. |
| 63. | Smyth RL. New drug treatments for cystic fibrosis. Patients are finally seeing the benefits after a long and agonising wait. BMJ 2020;368:m118. |
| 64. | Government of Australia. Infants with Cystic Fibrosis to Breathe Easier with New PBS Listing. Canberra: Department of Health; 2019. Available from: www.health.gov.au. [Last accessed on 2019 Sep 09]. |
| 65. | Grand View Research. Global hemoglobinopathies market size. San Francisco: Grand View Research; 2019. |
| 66. | Karponi G, Zogas N. Gene therapy for beta-thalassemia: Updated perspectives. Appl Clin Genet 2019;12:167-80. |
| 67. | Bellgard MI, Snelling T, McGree JM. RD-RAP: Beyond rare disease patient registries, devising a comprehensive data and analytic framework. Orphanet J Rare Dis 2019;14:176. |
| 68. | Asia-Pacific Economic Cooperation. Action Plan on Rare Diseases. Singapore: Asia-Pacific Economic Cooperation; 2019. |
| 69. | Population Reference Bureau. World Population Data Sheet 2019. Washington, DC: Population Reference Bureau; 2019. |
| 70. | Luzzatto L, Hyry HI, Schieppati A, Costa E, Simoens S, Schaefer F, et al. Outrageous prices of orphan drugs: A call for collaboration. Lancet 2018;392:791-4. |
| 71. | Yang Y, Kang Q, Hu J, Kong F, Tang M, He J, et al. Accessibility of drugs for rare diseases in China: Policies and current situation. Intractable Rare Dis Res 2019;8:80-8. |
| 72. | Tabor HK, Goldenberg A. What precision medicine can learn from rare genetic disease research and translation. AMA J Ethics 2018;20:E834-840. |
| 73. | Min R, Zhang X, Fang P, Wang B, Wang H. Health service security of patients with 8 certain rare diseases: Evidence from China's national system for health service utilization of patients with healthcare insurance. Orphanet J Rare Dis 2019;14:204. |
[Table 1], [Table 2], [Table 3]
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