Clinical genetics and genomic medicine in Qatar

Citations Over TimeTop 21% of 2018 papers

Abstract

Clinical genetics and genomic medicine in Qatar. The State of Qatar (referred to as “Qatar” in this article) is a sovereign Middle Eastern nation located on the northeastern coast of the Arabian Peninsula. Qatar borders Saudi Arabia to the South and is otherwise surrounded by the Arabian/Persian Gulf, with maritime boundaries shared with Bahrain, Iran, and the United Arab Emirates (Figure 1). Qatar's total land area is about 11.5 thousand square kilometers and has a population of approximately 2.7 million, most of which lives in and around the capital, Doha. Qatar has a rich and fascinating history and has been occupied by humans for approximately 50,000 years. Many different populations have inhabited the area, as its location led to an influx of Arab tribes from the surrounding region, especially the Nejd desert to the West. Islam began to flourish in what is now Qatar in the seventh century CE, and the area was important in the spread of Islam. The Portuguese Empire took control of the region early in the sixteenth century, but was soon overthrown by the Ottoman Empire, which subsequently ruled Qatar for several hundred years. Qatar became a British protectorate in 1916 and declared independence on 3 September 1971. Currently, Qatar is a highly developed and influential country in the region. Its economic development has led to major advances in all sectors of the country. The healthcare sector in Qatar is distinguished by its numerous international accreditations, providing the highest standards of care and offering state-of-the-art services both generally and as directly relates to the practice of genetics and genomics in clinical and research settings. Qatar's National Health Strategy (NHS) 2011-2022 was launched by Her Highness Sheikha Moza bint Nasser in April 2011. The NHS consists of two phases: (a) National Health Strategy 2011–2016, which has the structure for current development such as growth of investment in new healthcare facilities, services and healthcare infrastructure to meet the needs of the nation's fast-growing population (Supreme Council of Health, 2013), and (b) the National Health Strategy 2018–2022 for the next period of growth under the theme “Our Health Our Future”, which reflects a shift in thinking by focusing on the seven priority population groups: healthy children and adolescents, healthy women leading to healthy pregnancies, healthy and safe employees, mental health and well-being, improved health for people with multiple chronic conditions, health and well-being for people with special needs, and healthy aging. The new strategy identified 19 national goals against which progress will be measured, including specific goals to promote physical activity among adolescents, to initiate workplace welfare programs, and to offer improved access to mental health services. The strategy focuses on five areas of the health system to ensure an integrated system for high-quality health care and services. Its targets by 2022 include reducing the overall rate of avoidable death by 5% and reducing the rate of hospitalization for preventable primary care cases by 15% (Ministry of Public Health, 2018). This will introduce a new and more integrated approach to Qatar's health challenges and care. Overall, the goal is to shift the focus from diseases among individuals to the health of populations and from acute care to primary care, from health cost as a financial load to a future investment and from patients receiving medical advice to an individual controlling their own health. Annually, the implementation of the strategy will be assessed and reviewed regarding the overall health needs of Qatar's population. Human development is the most important element of Qatar National Vision (QNV) 2030, an ambition plan for Qatar to develop and sustain a healthy population (physically and mentally) by spending 2.2% of the country's GDP on health care. The 2018 budget has allocated QR22.7 billion funds for the health sector, representing 11.2% of the total expenditure in 2018 (General Secretariat For Development Planning, 2008; The Peninsula, 2017). The population of Qatar forms a multiethnic community; approximately 600,000 (22%) of the 2.7 million population are native Qataris (largely tribal) (Ministry of Development Planning and Statistics); expatriates make up the remaining portion of the population. This could be attributed to the country's strong economic performance, fueling and contracting services staff, as well as expatriate professionals returning to the country. The native Qatari population is characterized by a high consanguinity rate. According to one analysis conducted over a decade ago, more than 54% of marriages were between first or second cousins (Bener & Hussain, 2006), though this rate may be increasing. A high rate of consanguinity is similarly seen in numerous expatriate communities in Qatar. Together with consanguinity, the relatively large family size plays a role in the high prevalence of autosomal recessive conditions in the population of Qatar. A more recent analysis (2012–2013) was conducted at two medical centers in Qatar: the Clinical and Metabolic Genetic Division of Hamad Medical Corporation (HMC) and the Shafallah Rehabilitation Center (SRC). In that study, consanguineous marriages were observed in 397 (67.7%) of 599 Qatari families seen. As anticipated, this was observed to confer a significantly higher incidence of autosomal recessive disorders compared to nonconsanguineous marriages ([total cohort HMC and SRC; (odds ratio = 1.72; 95% CI: 1.10, 2.71; p = 0.02)] [HMC; (odds ratio = 2.98; 95% CI: 1.37, 6.09; p = 0.005)]) (unpublished data). Further, autosomal recessive disorders were found to be more likely predicted by couples involving paternal first cousin (OR: 3.70; 95% CI: 1.44–9.52; p = 0.007), double first cousin (OR: 6.17; 95% CI: 1.25–30.32; p = 0.025) and first cousin (OR: 4.44; 95% CI: 1.49–13.23; p = 0.007) (unpublished data). Additionally, the high rate of consanguinity favors the coexistence of multiple distinct autosomal recessive disorders within single families. Even more complex families have been diagnosed with a combination of autosomal recessive disorders and other single-gene disorders with different inheritance patterns. The recent advances in genomic sequencing technologies have helped identify patients affected by more than one genetic condition, such as LIG4 syndrome and urofacial syndrome (Fadda et al., 2016) and cystic fibrosis and apparent mineralocorticoid excess (AME) syndrome (Zahraldin et al., 2015). Clinicians and researchers working in Qatar have to be particularly mindful of the possibility that a patient's overall phenotype may be due to a combination of different, coincidental genetic conditions (versus directly interacting genetic factors) (Retterer et al., 2016). In other words, geneticists are mindful not to “stop” analyses at the identification of one genetic condition when features of a patient's overall phenotype remain unexplained. As with all modern societies, religious, cultural, and ideological beliefs play a central role in the practice of medicine and clinical genetics. For example, over the past years, prenatal genetic services have become more accepted and requested by Arab families not only to provide reassurance or early diagnosis, but also to inform pregnancy management options. The option of termination of pregnancy is becoming more permissible and accepted not only if the mother's life is endangered (Al Aqeel, 2010; Al-Aqeel, 2005; Albar, 2002; El-Hazmi & Ai-Aqeel, 2006; Hathout, 1992), but also for severe and life-threatening fetal conditions. Assisted reproductive technologies (ARTs) such as in vitro fertilization (IVF) and preimplantation genetic diagnosis (PGD) may be used when indicated as long as the couple's gametes are used (Teebi, 2010). Other recent bioethical issues at the heart of heated discussions across the world, such as secondary or incidental findings found through exome/genome analyses, have also been addressed from an Islamic bioethical perspective by Qatar's leadership in conjunction with other genomics leaders. Major recommendations and conclusions of this initiative are summarized and directly quoted as follows: potential recipients of incidental findings should be properly informed; incidental findings that can lead to actionable lifesaving procedures should be disclosed; incidental findings related to (misattributed) paternity should not be disclosed; a one-size-fits-all approach does not work with many incidental findings. Notably, the overall work provides background as well as specific case studies to illustrate situations related to these points (Sadoun et al., 2018). Extensive discussions have been published on this topic, both related to specific countries and populations as well as more broadly; see Teebi's textbook on the subject for a comprehensive overview (Teebi, 2010). While the purpose of this review article is not to recapitulate previous works such as that textbook, several themes emerge that are worth noting. First, Qatar and other countries in the region have served as key areas for the discovery of novel genetic causes of human disease (Scott et al., 2016). In many cases, these causes were first identified in this region through clinically oriented research endeavors and then extrapolated to other parts of the world. That is, after identifying individuals with causative genetic changes in the population of Qatar and the region, individuals in other parts of the world with the same phenotypes were found, tested, and identified to have the same underlying genes involved, though sometimes with compound heterozygosity rather than homozygosity for pathogenic variants. There are several explanations for this history of discovery, including strong economic resources and the willingness to invest in and use genomic technologies and research, histories of collaborative work with other large and international partners (e.g., Weill Cornell University, USA; University Children's Hospital of Heidelberg, Germany; Boston Children Hospital, USA; Rockefeller University, USA; University of Zurich, Switzerland – see more details below), and cultural practices that enable the investigations of the causes of conditions such as via homozygosity mapping. As mentioned (Teebi, 2010), the genetic causes of hundreds of individual conditions were first described in these populations, and new explanations for genetic diseases are continually being reported and published. Importantly, these studies have lent themselves to translational work that have helped dissect the underlying biological causes of disease. A few of many recent examples include TBC1D23 (OMIM 617687) and pontocerebellar hypoplasia (Marin-Valencia et al., 2017); SLC7A5 (OMIM 600182) and autism spectrum disorder (Tarlungeanu et al., 2016); TMTC3 (OMIM 617218) and cobblestone lissencephaly (Jerber et al., 2016); MBOAT7 (OMIM 606048) and autism with seizures and intellectual disability (Johansen et al., 2016). In addition to gene/condition-specific work, larger studies that incorporate statistical analyses of the underlying genomic architecture of the population have also yielded novel gene discovery techniques (Scott et al., 2016). Second, other studies focusing on patients and genomic data from Qatar continue to address a wide spectrum of other hypotheses and areas. These include using the population to explore the effects (or lack thereof) of “knock-out” alleles in humans (Maddirevula et al., 2018), as well as defining well-known conditions in the Qatari populace. Recently, the importance of ancestry-specific descriptions has been recognized and emphasized. That is, even supposedly well-defined conditions have primarily (or sometimes only) been described in populations of Western European descent, and genetic and nongenetic factors, including patterns of clinical care, modulate and influence the ultimate phenotype and outcomes (Muenke, Adeyemo, & Kruszka, 2016). Knowledge of clinical similarities and differences is especially important for practitioners and researchers caring for diverse sets of patients. Recent examples of conditions with studies involving patients from Qatar include Aicardi-Goutières syndrome (Al Mutairi et al., 2018) and classic homocystinuria (El Bashir, Dekair, Mahmoud, & Ben-Omran, 2015). Third, related to the factors described above, as well as due to having available resources (and the mindset) to adopt newer clinical diagnostic practices early, Qatar has been able to achieve high diagnostic rates through broad application of clinical exome sequencing (CES). Early analyses (2012–2014) of 149 probands undergoing CES identified a causative explanation in 89 (60%) of the studied probands (Yavarna et al., 2015). More recent analyses of a larger cohort of >500 patients show a diagnostic yield of >48% (Al-Dewik et al., 2017). This still high but slightly lower yield may involve factors such as evolving differences in variant classification techniques and guidelines as well as underlying cohort differences and practices in terms of which patients receive CES and when. Finally, though somewhat separately, prevalences and characteristics of certain types of congenital anomalies have been studied specifically in the Qatari population. For example, congenital cardiovascular malformations (1984–1994) were reported as having an incidence of ~12:1,000 live births (Robida, Folger, & Hajar, 1997). From another study on congenital brain malformations (1986–1989), the incidence of hydrocephalus was 157:100,000 live births and of meningomyelocele was 41:100,000 (Nogueira, 1992). Different healthcare services are delivered through the country by private, private/government, and public providers, who organize the most of healthcare activity. Hamad Medical Corporation (HMC) is the main public healthcare provider in the State of Qatar. Hamad Medical Corporation (HMC) has also been the main provider of clinical and metabolic genetic services for the population of Qatar since 2002. HMC includes 10 hospitals (7 specialty hospitals and 3 community hospitals) as well as ambulance, home, and residential care services (Table 1). HMC's Clinical and Metabolic Genetics (C&MG) Division is the only national referral center for genetic diseases in Qatar. This division provides state-of-the-art medical care for patients (both pediatric and adult) and families affected by a variety of inherited or genetic disorders. Clinical services include clinical genetics and dysmorphology, inherited metabolic disorders, prenatal genetics, and follow-up and care for positive cases discovered through the National Expanded Metabolic and National Genetic and details medical care, the division provides genetic for genetics, prenatal and Genetic (PGD) services and patients from In the Clinical and Metabolic Genetics over cases in addition to for or genetic and metabolic disorders. As by the the division is especially in the diagnosis and management of of (e.g., for patients with and disorders (Figure As the high consanguinity with large family size and population growth in the has led to a high of metabolic and genetic For example, homocystinuria is highly in Qatar highest incidence in the world, As for the overall conditions of positive patients are identified through Qatar's National Expanded Metabolic from work that may be by and are diagnosed at the HMC with the and rate of diagnosis after the of & For example, the most diagnosed disorder is which at an incidence of live births in attributed to = (Teebi, 2010). diagnosed and include both and genetic conditions, including genetic disorders that are more in the country of Qatar than other parts of the world, as well as conditions that to at approximately the same rate across the such as forms of recessive and many (Teebi, 2010). As all major inheritance patterns have been for a of conditions, see (Teebi, 2010). These clinical genetic services continue to many of families from the region and have clinical and to many patients. As this approach has the identification of many novel conditions due to new in this population as well as about conditions that are more such as due to the of certain alleles related to autosomal recessive conditions (Table These have also Qatari In addition to and its clinical the Qatar was in by Highness Moza of the Qatar The was within the of a comprehensive national plan and is on seven the National National National National human genomics research in of genomics in the clinical has been in as a that provides care in all including genetic and genomic Qatar was one of the first Arab countries to a national which was in (Table This has been conducted through a with University Children's Hospital of Heidelberg, From in the State of Qatar were for of and disorders, an incidence of these conditions of compared to in The higher incidence in Qatar primarily relates to of congenital approximately the same incidence as observed in et al., Importantly, analyses of this implementation for on this over were in healthcare and In a follow-up study conducted from of in were positive for conditions patients with metabolic and with of metabolic and disorders were and the congenital congenital other or disorders, disorders, and As with other in other countries and these services continue to with of conditions with available as well as related to et al., 2017). In the National Genetic was launched as a for all couples for in Qatar. The is by primary healthcare centers and hospitals for cystic and The conditions were for of high in the population of Qatar. for is by and by genetic as for homocystinuria and cystic fibrosis is primarily for for is by to the in the A in for in Qatar was after the identification of with to couples in which one was an with two of the gene (OMIM on one and a second with as The prenatal genetic was in as of Clinical and Metabolic Genetic services at in to meet the needs of the population of Qatar. This is a first and still and leading in the region and to clinical practice guidelines related to prenatal genetic diagnosis for all in prenatal care, including family and There is a for this due to high rate of consanguinity leading to high prevalence of genetic and metabolic diseases in Qatar. The prenatal genetic provides comprehensive prenatal genetic services case of genetic of pregnancy management and for family and The prenatal genetics consists of a prenatal genetic and genetic who work in with and other to and care. The HMC Clinical & Metabolic Genetics Division their research within their area of focus by collaborative translational and research with as well as centers and is to the of the genetic of inherited diseases to the population of Qatar and the region, including homocystinuria and other autosomal recessive conditions relatively to this population. This research is specifically to major current research include a approach to identify the underlying genetic factors of metabolic and genetic disorders as well as the effects of in the Qatari population for certain diseases such as homocystinuria and disorders, as well as related clinical to research and findings This has from the Qatar National and Qatar from The Clinical & Metabolic Genetics Division has been recognized at the international for the of clinical to and which are in and of and clinical studies of human conducted around the world under the National of and are receiving several to in future clinical involving for and disease. Additionally, the work of the Clinical & Metabolic Genetics Division to and translational with the international including centers and such as University and the Boston Children's Hospital, USA; The Rockefeller University & USA; University Hospital Germany; University of Zurich, as well as such as Weill Cornell Medical Qatar University, and Shafallah Medical Genetic These and other have led to findings published in and at national and international example, et al., et al., et al., et al., 2016). The genetic findings have been and integrated in the and several are in to develop several 2018). The will continue several research in their in with and on past their future research HMC has a in the Clinical Genetics & Metabolic which is to provide comprehensive clinical and research The has also been by the Medical at this has of are Further, the Clinical Genetics & Metabolic in and in several across the country and and to their In Hamad University launched a and in This is a to the next of professionals and who will the use of and medicine in the healthcare The and in state-of-the-art and analysis The goal is to of that focuses on other clinical the and implementation of medicine in health care within Qatar and the region. Overall, are a to study all key of genomics and medicine in one Recently, Qatar University has a new in genetic The overall of the is to and who can become of providing genetic to patients and families in Qatar with or genetic conditions. Qatar is a fascinating of clinical practice of genetics, genomic and translational research due to the strong investment in genetics and in both and large and early and of new diagnostic and related genetic services in Qatar provide state-of-the-art care for the population of Qatar and the region. and are of the described of Clinical and Metabolic Genetics of Hamad Medical is an of an Health and has in and HMC and the work in multiple clinical and research areas. is the of of Medical The that are other of

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