Asia Pacific Society of Human Genetics (APSHG) from conception to 2019: 13 years of collaboration to tackle congenital malformation and genetic disorders in Asia

1 MEDICAL GENETICS IN ASIA AND THE ORIGINS OF APSHG: A TRIBUTE TO THE PAST

Infant mortality rates in Asia have been on a decline since the Second World War in many countries in Asia in tandem with improvements in access to healthcare, management of infectious diseases and nutritional problems and the implementation of screening programs. In the 1960s, some of the more common single-gene disorders contributing to significant infant mortality and morbidity, particularly in South East Asian countries, were glucose-6-phosphate dehydrogenase (G6PD) deficiency and hemoglobinopathies (Wong, 1965). Neonatal jaundice and kernicterus associated with G6PD deficiency was the leading cause of death for infants in many countries like Singapore until the introduction of neonatal population screening programs which significantly reduced this disease burden (Wong, 1980). Nonetheless, the burden of congenital disorders in this region was still significant with an estimated prevalence of 52.9 per 1,000 livebirths with single gene disorders contributing towards more than 10% of birth defects while chromosomal disorders and malformations accounting for about 4–5% and 63%, respectively (Padilla & Cutiongco-de la Paz, 2016). Among the monogenic disorders, thalassemias also pose a significant disease burden in many countries in Southeast Asia (Fucharoen & Winichagoon, 2011). The early work on this group of disorders include reports on the prevalence of hemoglobin E-thalassemia disease in Indonesia (Eng, Mursadik, Lioe, & Odang, 1956) and the description of 32 cases with Mediterranean anemia in Thailand (Minnich, Na-Nakorn, Chong-Chareonsuk, & Kochaseni, 1954) and 5 cases of alpha-chain thalassemia and hydrops fetalis in Malaya (Lie-Injo, 1962), and observations of beta-thalassemia in Philippines (Motulsky, Stransky, & Fraser, 1964). Subsequently, there has been much investigations to characterize and diagnose the hemoglobinopathies and related variants (Fucharoen et al., 1990; George et al., 1992; Lynch et al., 1987; Ng, Ong, Tan, & Law, 1994, 1996; Setianingsih, Williamson, Marzuk, Tamam, & Forrest, 1998; Tan et al., 1993; Tan, Tay, Alain, Wong, & Lai, 1990; Wasi, 1981, 1986).

The common challenges faced in disease prevention and control inspired some researchers and medical geneticists in the region to meet in the 1990s and 2000s to discuss the common genetics conditions encountered in individual countries. A number of seminars were organized such as Japan Society for Promotion of Science (JSPS) Seminar on Human Genetics in Perinatal Medicine (August 1–8, 1993) in Jakarta, Indonesia; National Research Council of Thailand-Japan Society for Promotion of Science (NRCT-JSPS) Regional Seminar on Medical Genetics and Molecular Biology (July 27–29, 1994) in Bangkok, Thailand; International Seminar on Child Health (September 29–30, 1995) in Singapore; International Symposium on Human Genetics and Gene Therapy (February 5–6, 1999) in Singapore; Seminar on Advances in Neonatology (March 1–2, 1999) in Yogyakarta, Indonesia; Asian Symposium in Neonatology: G6PD deficiency and related conditions (August 8–9, 2000) in Yogyakarta, Indonesia; Asian Symposium on Inherited Metabolic Disorders (November 6–9, 2002) in Kobe, Japan; and so on. These small meetings provided the opportunity for those working in the field of genetics in some of the Asian countries such as Thailand, Indonesia, Philippines, Japan, Malaysia, and Singapore to share expertise and to network with each other.

The formalization of a larger network of professionals in medical genetics was first mooted with a conference in Bangkok, Thailand organized by Suthat Fucharoen and Pornswan Wasant which was designated as the first Asia Pacific Conference of Human Genetics (APCHG) that was held from July 27–29, 1994. However, despite much discussion over the subsequent years, the network was not yet ready to form a formal Society. Nonetheless, regional conferences were held once in two to three years organized by the network of key geneticists in various countries in Asia (Table 1). Five of these conferences were jointly organized with the Human Genome Organization (HUGO) when one of the regional offices of the latter was opened in Osaka, Japan (http://www.hugo-international.org/history). These joint meetings were continued until the closure of the regional HUGO Pacific office with the last of such meeting being the Joint 7th HUGO-Pacific and 8th Asia Pacific Conference on Human Genetics held in Cebu, Philippines in 2008.

2 THE FORMALIZATION OF A SOCIETY

The network of genetics professionals has thus been interacting and organizing regional level conferences in human genetics for many years without the umbrella of a formally registered Society. In July 2003, Eric Haan who was then President of the International Federation Human Genetics Societies (IFHGS) invited Sangkot Marzuki and Pornswan Wasant to attend the IFHGS Executive meeting during XIX International Congress of Genetics (ICG) in Melbourne, Australia and encouraged the network to establish The Asia Pacific Society of Human Genetics (APSHG). An inaugural meeting was held in Bangkok, Thailand on November 12, 2005. The Society was officially registered on February 17, 2006 in Singapore with 14 founding members, with two each representing Hong Kong, Indonesia, Malaysia, Philippines, Singapore, Taiwan, and Thailand (Table 2). The drafting of the Society's constitution and formal registration to the Registry of Societies in Singapore was led by the critical efforts of Ivy SL Ng from Singapore. Together with Hai-Yang Law and Poh-San Lai, an operating bank account was opened in Singapore under three signatories with seed funding from the life membership fees of the initial founding members.

The first inaugural President was Pornswan Wasant from Thailand and subsequent Presidents were elected from different countries (Table 3). The main objectives for the Society are to promote research in basic and applied human and medical genetics and to facilitate networking and interactions in these areas, reflecting the historic roots of this network of professionals (https://www.apshg.info/). The Society has thus been a conduit and forum for increasing or spreading the knowledge and understanding of human and medical genetics in the Asia Pacific region.

Since the formal incorporation of the Society, a total of five more conferences have been organized with the next upcoming conference to be held in Manila, Philippines later this year (Table 1).

3 AFFILIATION WITH THE INTERNATIONAL FEDERATION OF HUMAN GENETICS AND COLLABORATING ACTIVITIES

Soon after its official establishment, the APSHG successfully applied for and attained full membership of the IFHGS in August 2006. For the past decade, APSHG has taken part in the activities of IFHGS and played an active role in establishing a close collaborative relationship between the two organizations. To facilitate our understanding of the importance of this collaboration, it is imperative to outline the objective, membership, and activities of the IFHGS. The purpose of IFHGS is manifold which includes, (1) to encourage communication and interactions among member societies; (2) to promote meetings; (3) to develop a consensus on policy matters of international concern, transmitting policy statements and opinions to appropriate parties and organizations ; and (4) to promote and help organize an International Congress every five years, which will be hosted by one of the full-member societies (http://www.ifhgs.org/). There are four types of membership of IFHGS (Table 4) and currently there are seven full members, 48 corresponding members and nine affiliate members. The seven full members of the Federation are multinational societies (Table 5).

Once APSHG was admitted as a full member of the IFHGS, the Society participated at the annual Board meetings of the IFHGS and this facilitated discussions and promotion of activities of common interest. APSHG actively promoted the organization of the International Congress of Human Genetics (ICHG) which was held once in five years, including the conferences in Brisbane in 2006, Montreal in 2011 and Kyoto in 2016 by supporting the respective international scientific committees and organizing scientific sessions for these meetings.

The strong relationship with the Federation was bolstered when one of the past President of APHSG, Stephen Lam took up the challenge to serve as the President of the IFHGS from 2011 to 2013 and presided over its proceedings. As President, Stephen Lam promoted the Federation by introducing the roles and objectives of IFHGS at the Annual or Biannual meetings of member Human Genetics Societies as well as other related organizations such as the Human Variome Project. APSHG actively interacted with the other members of IFHGS. For example, in 2017, APSHG engaged its members in endorsing the Policy Statement on Human Germline Genome Editing by the American Society of Human Genetics (ASHG) which was also supported by other regional human genetics societies (Ormond et al., 2017).

4 EDUCATIONAL OUTREACH

The Society launched a new initiative to provide training and education in genetics and genomics for trainees, fellows, and early career professionals in 2015. The President of APSHG at that time, Poh-San Lai, mooted that schools could be organized as a form of outreach to young members and for the training of the next generation of professionals in the Asia-Pacific region. These events would be held on alternate years in between the Society's biennial conferences.

The inaugural Summer School was organized by Brian Chung and hosted by the University of Hong Kong from August 26 to 28, 2016. This school was followed by a two-day post-summer workshop on bioinformatics. This summer school was themed on clinical genetics (dysmorphology and genetic counseling) and well attended by over 100 delegates, including trainees and young faculty from 14 countries in Asia who participated in lectures, case study presentations and discussions facilitated by local and international faculty from USA, Canada, Australia, and Japan.

Following this well received educational program, the second school was organized by Poh-San Lai at the National University of Singapore from October 31 to November 2, 2018. This second APSHG Autumn School followed on the success of the first school with more than 130 participants from all over Asia attending the intensive three days program led by 15 international and regional faculty including lecturers such as Leslie G. Biesecker, Han Brunner, John Carey, Maximillian Muenke, Kathleen Leppig, Gail Jarvik, Anne Tsai, Christian Gillisen, Lisenka Vissers, Madhuri Hegde and Mercy Laurino. A post-school workshop on clinical interpretation of next-gen sequencing data followed from November 3 to 4, 2018. The educational sessions of this autumn school were focused on the basics of clinical genetics and the applications of next-gen sequencing. Sessions were organized to facilitate discussions on challenges faced in diagnostic interpretations, genetic counseling, and clinical management in the practice of genomic medicine. The education program of this school was also noteworthy in including an intensive half day session on genetic counseling topics led by Mercy Laurino that drew on lessons learnt from different ethnic and cultural perspectives among the communities in Asia. On the back of these two well received events, the Society plans to continue this initiative to organize or co-support future educational outreaches as it appears that there is a big demand for such courses in this region.

5 SPECIAL INTEREST GROUPS AND ACTIVITIES

As part of the Society's professional outreach, special interest groups in the areas of human genetics such as genetic counseling, clinical genetics, newborn screening, birth defects and population genetics were formed over the years. Genetic counseling gained prominence during the 10^th APCHG in 2012 where a workshop was organized with a core group of genetic counselors and clinical geneticists in Kuala Lumpur (Zayts et al., 2013). The genetic counseling group was formalized and organized as a Special Interest Group within APSHG and registered as the Professional Genetic Counselors Society in Asia (PGCSA) spearheaded by Mercy Laurino. Its membership consists of certified genetic counselors as well as students or professionals having certificate or diploma degrees in genetic counseling or having an interest in this field (https://www.psgca.org/index.html). Among the many activities organized, the PGCSA had been very active in putting together full day workshops in conjunction with the society's biennial conferences (Laurino et al., 2018). Besides the genetic counseling interest group, activities by other interest groups were also held. Meetings on birth defects and disabilities were led by Pornswan Wasant in Thailand. Regional workshops on newborn screening were organized by Carmencita Padilla and Bradford Therrell which produced declaration papers on consolidating newborn screening efforts in the Asia Pacific region on behalf of the APSHG Working Group (Padilla & Therrell, 2012). Board members of the Society also actively promoted seminars on rare disorders and dysmorphology hosted in their respective countries.

It is also worth highlighting the initiatives made toward promoting scientific collaborations among members. In this regard, a number of key members of the Society had previously participated in the HUGO Pan-Asian SNP Consortium which had contributed toward efforts to map the genetic variations in 73 Asian populations (Abdulla et al., 2009). The idea for the countries to come together as a consortium to work on this project was first mooted during the biennial conferences of the Society in Shanghai (2000) and Pattaya (2002) before being formally ratified in Singapore (2004) with the efforts led by Edison Liu from the Genome Institute of Singapore and Poh-San Lai from the APSHG. Subsequently, the Society also endorsed the work of the second phase of the consortium's initiative led by Jong Bhak from Korea to systematically analyze and understand the genetic diversity of the Asian populations using whole genome sequencing technologies (http://www.hugo-international.org/HUGO-PAPGI). The co-chairs of the Policy Review Board of the consortium were Jong Bhak (Korea), Maude Phipps (Malaysia), and Poh-San Lai (Singapore).

6 BIRTH DEFECTS

According to March of Dimes Reports on Birth Defects, an estimated 6% of total births globally are associated with a serious birth defect due to genetic or environment causes (https://www.marchofdimes.org/mission/march-of-dimes-global-report-on-birth-defects.aspx). In a WHO Report on Prevention and Surveillance of Birth Defects (2015), South East Asia region was reported to have the second highest prevalence of birth defects in the world with 1.13 million cases annually (World Health Organization, 2015). There has thus been increased focus on this issue for many years. The 63rd World Health Assembly recognized the importance of birth defects as a cause of stillbirths and neonatal mortality with the adoption of Resolution WHA 63.17 in 2010 calling for the prevention of birth defects in the South-East Asia Region (World Health Organization, 2013).

Because of the significant health and economic burdens to this region, initiatives or taskforces have been established in many countries to work on the surveillance, prevention, and management of birth defects. For example, in Thailand, a Task Force on Birth Defects and Disabilities was first organized in 2008 and since then, it has established a birth defects registry and engaged policymakers and stakeholders on prevention and care of birth defects and disabilities (Wasant, 2015). Efforts have also been put toward piloting or setting up of birth defects or disease registries in other countries (Noori et al., 2019; Padilla & de la Paz, 2013; Tan et al., 2005; Thong, 2014). Further activities in education, counseling, screening and surveillance programs are expected to reduce and control the overall incidence of birth defects. The challenges faced in tackling congenital malformations and genetic disorders in this region present great opportunities for countries to work together in developing cost effective medical genetics services, especially in the current genomics era (Thong, See-Toh, Hassan, & Ali, 2018).

7 NEWBORN SCREENING

Newborn screening (NBS) in the Asia Pacific Region (APR) has had its share of challenges. Of the total 138 million babies born across the globe, about half (67 million) are born in the Asia Pacific Region (APR), which extends from New Zealand on the South to Mongolia on the North, and Pakistan in the East. A large majority of the births in the APR (80%) occur in the five countries—China, Indonesia, Bangladesh, India and Pakistan. Infant mortality rate (IMR) is a good predictor of when competing health issues acknowledge the need for NBS. All countries with an IMR below 7 per 1,000 live births have attained NBS coverage of more than 90% (Howson et al., 2018; Padilla & Therrell, 2012; Therrell et al., 2015).

Newborn screening in the APR began in the 1960s in New Zealand and Australia, followed by Japan and Singapore. In the 1980s, pilots occurred in China (Shanghai), Hong Kong, India, Malaysia, Pakistan and Taiwan. In the 1990s, NBS began in Korea, Thailand, China and the Philippines. In the late 1990s, funding and expert assistance were provided by the International Atomic Energy Agency (IAEA) to Bangladesh, China, Cambodia, Indonesia, Korea, Mongolia, Myanmar, Nepal, Philippines, Pakistan, Sri Lanka, Thailand and Vietnam. With IAEA funding support, NBS for congenital hypothyroidism (CH) was started in many countries without NBS and other countries with existing programs expanded to include other conditions. IAEA funding ended in 2005, but countries just beginning screening had not yet integrated it into their public health systems, which presented significant challenges. By this time, countries with growing programs had included screening for at least congenital hypothyroidism (CH), congenital adrenal hyperplasia (CAH),G6PD deficiency, and phenylketonuria (PKU). Screening panel selection processes varied across the APR but generally were the prerogative of the health ministry and this process continues today (Padilla & Therrell, 2007; Therrell et al., 2015; Therrell & Padilla, 2018).

In 2007, Australia, New Zealand, and Taiwan reported offering expanded metabolic screening using tandem mass spectrometry (MS/MS). Japan and Korea soon followed. In Thailand, an expanded NBS program was launched in 2014 and successfully detected a number of inborn errors of metabolisms (IEMs) leading to early treatment, preventing disabilities and survival in many babies (Liammongkolkul et al., 2017). Additionally, some APR countries expanded NBS to include conditions not detected by MS/MS (e.g., cystic fibrosis, biotinidase deficiency, and so on), sometimes necessitating a fee (Therrell et al., 2015). Expanded metabolic NBS is now being implemented in many countries in the APR either as part of a national program, independently in some hospitals or as a pilot. Research into other disorders for possible NBS inclusion has resulted in successful integration of some disorders and pilot studies for others. Included are various lysosomal storage diseases (LSDs) (Hwu et al., 2014; Inoue et al., 2013; Liao et al., 2014; Lin et al., 2013), citrin deficiency (Wang et al., 2013), severe combined immunodeficiency (SCID) (Morinishi et al., 2009), Fragile X syndrome (Adayev et al., 2014), X-linked adrenoleukodystrophy (X-ALD) (X-ALD) (Wu et al., 2017), Wilson's Disease (Kim et al., 2008), and spinal muscular atrophy (SMA) (Chien et al., 2017). Particularly noteworthy has been the successful enzyme replacement therapies for the LSDs (Pompe, MPS, Fabry) which have hastened NBS in some of the more developed programs, for example, in Taiwan, Japan and Korea (Andersson, 2015; Inoue et al., 2013). Additionally, FDA approval of nusinersen (Spinraza) as a treatment for SMA has led to increased interest in its possible addition into NBS panels. In Taiwan, pilot NBS for SMA using a RT-PCR assay followed by second-tier ddPCR has accurately identified SMA in NBS samples. While genetic counseling and management of early diagnosed late-onset SMA is important, the presymptomatic diagnosis of early onset SMA provides patients with the opportunity to receive well-timed treatment (Chien et al., 2017; Messina, 2018).

Despite more than a decade of pilot testing, some APR countries withlarge birth cohorts, eg. Bangladesh, Indonesia, Pakistan, and India, continuetheir struggles in obtaining government support (Therrell & Padilla, 2014). In 2008, APSHG endorsed a Working Group on Consolidating Newborn Screening Efforts in the APR. This activity built on an informal network of IAEA-supported countries either lacking NBS or having screening coverage of less than 50%. The first Working Group Workshop was held in Cebu, Philippines, as a satellite meeting of the 7^th Asia Pacific Conference on Human Genetics in 2008. It was attended by NBS champions from 11 countries (Bangladesh, China, India, Indonesia, Laos, Mongolia, Pakistan, Palau, Philippines, Sri Lanka and Vietnam). The 2^nd workshop in Manila in 2010 included the same participants except for Palau, each accompanied by representative(s) from their respective Ministry of Health. Building on the successes of these two workshops, additional workshops were held in Manila, Philippines (2012), Cebu, Philippines (2013), Penang, Malaysia (2015) and Ulaanbaatar, Mongolia (2017).

Each workshop focused on the issues and challenges routinely faced in developing programs and their shared solutions, with input from international experts. While collaborative and cooperative networking was uniformly included to facilitate development of sustainable NBS systems, each workshop program was unique. Most workshops resulted in unanimous declarations from the participants to share meeting outcomes and set future goals. These declarations have provided useful guidance for discussions with policy makers and reminders of the commitments made by working group members as they work to move NBS forward in their local setting. The 2008 Cebu Declaration focused on developing a policy to screen for at least one condition and conducting prevalence studies. The 2010 Manila Declaration recommended creating a national policy and developing creative financing. The 2015 Penang Declaration focused on refining systems' operations, building capacity, addressing specimen storage, and ensuring laboratory proficiency (http://www.newbornscreening.ph/images/stories/ResourcesTechnicalDocuments/penang-declaration.pdf). The 2017 Ulaanbaatar Declaration focused on integrating NBS into the public health system, refining policies for retaining and using leftover blood spots, ensuring privacy and creating quality systems beyond the screening laboratory (http://www.newbornscreening.ph/images/stories/ResourcesTechnicalDocuments/ulaanbaatar-declaration.pdf). Until the goal of universal NBS is met in all countries, it is anticipated that such meetings will continue to take place in order to assist and encourage the growth of NBS across the region (Padilla & Therrell, 2012).

In addition to the traditional biochemical testing that has defined NBS, there is growing emphasis on certain bedside or point-of-care (POC) testing as part of NBS. In particular, newborn hearing screening (NHS) (Chu et al., 2015; Gupta et al., 2015; Huang et al., 2014; Ricalde, Chiong, & Labra, 2017) and critical congenital heart disease (CCHD) screening are of increasing interest (Jawin, Ang, Omar, & Thong, 2015; Tsao et al., 2016; Zhao et al., 2014). There is a need to accumulate local data in the Asia Pacific to assess potential impact of routine NBS for each country. Centralized data collection will be important moving forward in order to determine if there is a need to formally include as part of NBS. Recent developments in whole genome sequencing and its simpler corollary, whole exome sequencing (WES), have the potential to change the landscape of newborn screening in the future (Berg et al., 2017) (https://www.med.unc.edu/genetics/berglab/research/past-projects/nc-nexus-project).

8 RARE DISEASES IN THE ASIA-PACIFIC REGION: IN SEARCH OF SOLUTIONS

There is no universal definition of a rare disease (RD). A systematic review showed that the average prevalence thresholds used to define RDs ranged among different jurisdictions from between 5 to 76 cases/100,000 people, with a global average prevalence threshold of 40 cases/100,000 people (Richter et al., 2015). The United States (USA) considers a condition rare if it affects less than 200,000 persons. For the European Union, it is fewer than 5 in 10,000 of the general population. Children constitute 75% of the patients (Darmstadt et al., 2016). About 9% or 45,000,000 people in South East Asia are reported to be afflicted by RD (Shafie et al., 2016). However, this is based on calculated extrapolations of various prevalence or incidence rates against the populations of developed countries such as the USA, Canada or Australia and does not use data sources or statistics about any country other than its population. Hence caution must be exercised as this may be applied inappropriately, particularly, in developing or low and middle-income countries. Clinical geneticists are aware of many RDs that are common in the Asia-Pacific region such as citrin deficiency, barts hydrops, and distal renal tubular acidosis-Southeast Asian ovalocytosis syndromes that may be unfamiliar to researchers or clinicians outside this geographic area. Conversely there may be other “common” RDs in other populations that may be “ultra-rare” in the region (Thong et al., 2018).

In concert with the reduction in mortality rates from malnutrition and infectious diseases, NCDs such as genetic conditions and RD are now the main cause of morbidity and mortality (https://www.un.org/sustainabledevelopment/blog/2015/07/mdg-2015-report/). Hence there is a need to develop strategies to obtain accurate data on the epidemiology and burden of RD in this region. This may include disease registries, population, or newborn screening for RD and “quality-of-life” surveys or morbidity studies. The lack of data hampers healthcare planning and diminishes the urgent needs of patients with RDs.

Many healthcare personnel do not recognize the symptoms and signs of rare diseases or even know how to investigate or treat them due to the limited exposure and number of patients with RDs in their care. Many patients endure “diagnostic odysseys” and misdiagnosis with delayed diagnosis which often results in long-term complications and recurrence of similar condition in other family members. Having early diagnosis of an RD is important to reduce long term complications in the patients, allow genetic counseling to be provided for the family and offer options for prenatal diagnosis and support services. Patient support groups play a major role in dissemination of information to increase awareness, provide advisory services, fund-raising and patient advocacy and even help to advance national legislations for RDs. Some of the more prominent patient support groups included the Taiwan Foundation for Rare Diseases (TFRD), Philippines Society for Orphan Disorders, Malaysian Rare Disorders Society (MRDS), Rare Disorders Society (Singapore) and Genetic LSD Foundation (Thailand) (Shafie et al., 2016). The TFRD was amongst the first support groups that advocated for medical reimbursements and legislation for RD in 1998 and held a conference in 2005 in Taiwan (http://www.tfrd.org.tw/eng/intro_c/index/category_id/2). Similar MRDS organized the First and Second Conference on Rare Disease in SEA region in 2010 and 2013, respectively (http://www.mrds.org.my/second-msia-conference-on-rare-disorders-2013/). Other support groups had followed suit. In China, the Chinese Organization for Rare Disorders, a founding member of the Asia-Pacific Alliance of Rare Disease Organizations hosted the Rare Disease International Meeting (2014), a global alliance of RD patients and advocates, to exchange information, raise awareness and increase the support for RDs (Dharssi, Wong-Rieger, Harold, & Terry, 2017).

Currently, there are limited legislations pertaining to orphan drugs in many countries in the Asia-Pacific region. Only Singapore (1991), Japan (1993), Taiwan (Ho Chan, 2010), and South Korea (2003) have enacted legislations recognizing orphan drugs. Whilst these legislations expedite the framework for approval of RD treatment, many healthcare authorities do not provide financial incentives or health budgets to fund the treatment of RDs. The Rare Diseases Act (2016) in the Philippines is a comprehensive law that provides for integration of health care of patients with rare diseases in the public health system; access to diagnosis and treatment (drugs and other healthcare products); educational campaigns to the health professionals and the public; and regulatory and fiscal incentives to support research and development studies on rare diseases and to facilitate the manufacture and importation of affordable orphan drugs and orphan products (https://www.officialgazette.gov.ph/2016/03/03/republic-act-no-10747/). Other countries such as Malaysia do not have Orphan Drug legislations; instead it has a National Medicines Policy (2012) by the Ministry of Health that outlined procedures to enhance accessibility of orphan medicines and to provide public funding for treatment of selected groups of RDs (http://apps.who.int/medicinedocs/documents/s22203en/s22203en.pdf) while South Korea and Taiwan have comprehensive RD management governance, including providing up to 70–100% reimbursements for orphan drugs (Ho Chan, 2010). Increasingly, support groups and patients have expressed a sense of urgency and concern that there are many newly approved orphan drugs for other rare diseases in the pipeline and innovative funding sources are needed. In the past, various methods were used to raise funding for RDs, including compassionate use of drugs by industry, health insurance, employer benefits, donations from charities or nongovernmental organizations, crowd-funding or simply out-of-pocket payments which were catastrophic for the individual family. However, most of these approaches are not sustainable in the medium and long term. Recently the Asia Pacific Economic Cooperation (APEC) initiated the “APEC Policy Dialogue on Rare Diseases” in 2018 and it is hoped that this policy will help raise awareness to governments in the region (https://www.apec.org/rarediseases/Policy-Dialogue).

In an era of competing healthcare needs, treatment options to patients with rare diseases remained unaffordable to most patients in the region (Gammie, Lu, & Babar, 2015). Due to the high cost of RD medicines and the small number of patients, the standard methodology of using health technology assessment (HTA) criteria, especially for incremental cost-effectiveness ratio, may be an inappropriate approach for evaluation of these RD drugs (Tangcharoensathien et al., 2011). Other innovative strategies such as outcomes-based managed entry agreements as well as arguments for ethical and equitable access to healthcare for patients with RDs may be considered (Bouvy, Sapede, & Garner, 2018). Ultimately in view of the improving gross domestic products (GDPs) in many countries in this region, governments will need to increase the healthcare expenditures accordingly. Finally, there is a tremendous need for capacity-building of genetic services in the Asia-Pacific region. The existing medical curricula are in need of reforms and should consider innovation in genetic education for the training of the new generation of healthcare providers in NCDs such as RDs. An integrated public health approach to prevention and care of patients with RDs is required. An example of a cost-effective strategy is newborn screening for RDs in this region (Therrell & Padilla, 2018).

9 ETHICAL, LEGAL AND SOCIAL ISSUES (ELSI) IN APSHG

For the past few decades, medical genetics has undergone a dramatic phase of development. In the face of this growth, common issues in medical ethics, such as doctor patient relation, informed consent, and confidentiality have been re-examined against the objectives of medical genetics. Some argue that no new ethical issues have arisen from the advent of modern medical genetics. Others are increasingly concerned about the role of genetic counseling particularly in the context of a whole family as a unit, and the issues of the right to know or not to know of individuals' genetic disadvantage. Advances in prenatal diagnosis also arouse discussions on the moral status of the fetus and corollary issues of human dignity and the choice of individuals. The advent of public health approaches in application of genetic knowledge, as highlighted by neonatal genetic screening programs, has called forth discussions on distributive justice, informed consent, stigmatization, discrimination and decision making in public policies. As genetic technologies further advance, their use has uncovered more complex ethical and social issues. In the past two decades, these kinds of issues had been approached predominantly by the application of principalism. The major principles of autonomy, beneficience, nonmaleficience, and justice are commonly used as guidelines for ethical discourse. However, such emphasis has its limitations. Ethics of Care is an additional approach that specifically suits the requirements of many healthcare settings. However, as most of these issues have cultural and social components, it is logical to ask whether these various approaches are applicable as if they are universal, or whether regional modifications are more appropriate. The debate of so-called Asian Values in the last decade or two is of relevance here, since issues of morality and rights are central to our discussion, and how these issues can be resolved in an Asian context is of practical significance. These issues have been raised and discussed regularly in most of the conferences and meetings organized by APSHG.

In November 2018 during the Second International Summit on Human Genome Editing in Hong Kong, the birth of twins whose genomes were edited during in vitro fertilization (IVF) was announced by a Chinese scientist, He Jiankui (Daley, Lovell-Badge, & Steffann, 2019). This startling news was greeted with condemnation and unhappiness from many quarters regarding the use of CRISPR-Cas9 genome editing technology in human embryos. This germline gene editing announcement attracted two major types of criticisms. First was related to the issues about the lack of oversight of the procedure, the various conflicts of interest involved, the weak study design, the lack of informed consent used, and the accuracy of the reported results. Secondly, it was of strong concern to the community that the ethics regarding the alteration of the human embryo in reproductive health has yet to be fully and satisfactorily debated (Daley et al., 2019; Lantos, 2019). It evident that our community will continue to debate on how we can forge a responsible way forward in harnessing this technology amid the contentious issues surrounding this latest controversy.

10 FUTURE DIRECTIONS

Asia is the most populous continent with Asia Pacific region contributing to more than 60% of the world's population at approximately 4.5 billion people according to the United Nations Economic & Social Commission for Asia and Pacific Population Data Sheet 2018 (https://www.unescap.org/resources/2018-escap-population-data-sheet). Although the overall population growth in the region is recently slowing down, at different rates for different countries, the burden of genetic diseases is still a significant challenge given the overall large population in this region. Genetics services are in different stages of development in the countries in Asia Pacific and it is important now more than ever that a Society like APSHG play a critical role in raising awareness and promoting human genetics to all stakeholders including policy makers and the public. Concerns on issues such as rising health care costs due to emerging genetic testing technologies, access to genetic services, privacy and incidental findings, and so on are common issues faced by all countries that can be tackled as a group, sharing resources and knowledge to guide regulators and other stakeholders in individual countries. This article has attempted to trace the history of APSHG and its role in facilitating collaborations and exchange of information in this field among the Asia Pacific region. One limitation of this report is the incomplete representation of all the activities in Asia due to the large number of countries in this region. Nonetheless, it provides a glimpse of the founding of the APSHG and how a network of professionals in this field contributed towards promoting and developing the field of human genetics in this region. The Society has and will continue to contribute toward capacity building and promotion of education in human genetics through its activities in this region. Building on past examples in the history and origins of the Society, regional collaborative efforts will serve well in further developing this field in Asia given the shared and yet diverse cultural and social-economic backgrounds. It may be some time before the Society matures into the stature of societies like the American Society of Human Genetics and European Society of Human Genetics given its relatively young history. Nonetheless, we are optimistic that APSHG will continue to grow and serve the future generations of researchers, academicians, clinicians, laboratory practice professionals, genetic counselors, nurses, students and others who have a special interest in the field of human genetics in the Asia Pacific region.

CONFLICT OF INTEREST

The authors declare no potential conflict of interest.