Down Syndrome: History and Treatment

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Down Syndrome: History and Treatment

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Subject: Pediatrics

Table of Contents The role of the aforementioned factors Down Syndrome Case The impact of genetics Ethical challenges and the role of genomics References The role of the aforementioned factors Down syndrome remains one of the most commonly diagnosed genetic diseases in modern practice. Current grant sponsorship for scientific advances, updated FDA regulations for the pharmaceutical agents, and increased level of family involvement in the child’s care sufficiently increased the likelihood of the successful treatment. This case report will focus on the role of the aforementioned factors in the current status of Down syndrome, followed by the possible laboratory testing of the disease.

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One of the lifelong chronic intellectual disabilities, Down syndrome, develops due to genetic modification. According to Ambreen, Ashok, Srinivasan, Shalu, and Sarita (2015), the phenotype of the disease results from the imbalance of genes on Has 21 (human chromosome 21), in particular, the presence of an extra copy of chromosome 21. Shortly after birth, infants diagnosed with trisomy 21 begin sharing some inherent features, such as craniofacial abnormality, decreased muscle tone, small chin, and a flat nasal bridge. In the most severe cases of the illness, individuals develop other staggering comorbidities, including atrioventricular septal defects, leukemia, and Attention-Deficit/Hyperactivity disorder (Ambreen et al., 2015). Early diagnosis and suitable treatment allow addressing the aforementioned health complications effectively, improving the patient’s quality of life. Until now, Down syndrome is believed to be the most prevalent chromosomal condition in the world. Although its ubiquity slightly differs depending on the country, the average prevalence and incidence rates remain relatively the same. As followed by Al-Biltagi (2015), in North America, the birth prevalence of children with Down Syndrome today is approximately 1.18 in 1000 births, compared to 0.9 in 1000, in the late 1990s. The growing tendency is explained by the increased maternal age (35 years) and multiparity. The average incidence rate, estimated disregarding the influence of race and ethnicity, is 1 in 691 (Al-Biltagi, 2015). Ambreen et al. (2015) emphasized that the range of the trisomy 21 incidence is mostly influenced by maternal age and ranges from 1 in 319 to 1 in 1000 births. The scope of this report does not allow to discuss the role of demographic factors in the prevalence and incidence rates, resulting in the usage of mean numbers. A variety of methods is used to diagnose Down syndrome; however, the safest laboratory procedure is non-invasive prenatal testing (NIPT). As explained by Chitty et al. (2016), NIPT is developed based on “sequencing of cell-free DNA in maternal plasma” (p.1). With a false positive rate of 0.1%, this laboratory testing provides a possibility of the increased detection of trisomy 21 without invasion and association with iatrogenic miscarriages. Despite the aforementioned advantages of the method, NIPT is still not incorporated in the public healthcare systems because of its high procedural costs, accessible mostly in the private sector (Chitty et al., 2016). According to Kazemi, Salehi, and Kheirollahi (2016), an alternative method to NIPT is amniocentesis, an invasive prenatal diagnostic procedure, based on testing amniotic fluid for karyotyping starting at 15 weeks. Though reliable, it increases the risk of miscarriage up to 1%. Other screening methods used include serum markers and ultrasonography in the second trimester, which allow identifying increased fetal risk for Down syndrome (Kazemi et al., 2016). The best testing method from all the aforementioned procedures may only be determined based on the individual’s record.

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Though currently, there exists no medicine to treat trisomy 21, it is possible to improve the patient’s well-being by following FDA regulations regarding pharmaceutical agents. According to Gardiner (2015), two new FDA’s policies limit the usage of convulsive drugs and approve rapamycin (MTOR) pathway inhibitors. On the one hand, the federal agency recommends abstaining from the prescription of convulsants, such as PTZ, since children with trisomy 21 have an increased risk for seizures. Although convulsants were used for treating the disease for many years, in 2014, the FDA withdrew the approval. On the other hand, the institution accepted the utilization of MTOR, claiming that it may potentially treat cognitive deficits in Down syndrome. The reasoning behind their decision is based “on the observation of elevated phosphorylation of MTOR and AKT in the Ts1Cje mouse model of DS” (Gardiner, 2015, p.120). FDA predicts that active elements in the drug may increase mental impairments in patients with trisomy 21, similar to rodents in the experiment (Gardiner, 2015). With no treatment for Down syndrome existing at the moment, FDA aims at approving the best medicine for lessening the symptoms of the disease. Until the 2000s, trisomy 21 remained one of the most underfunded genetic disorders worldwide. Without substantial monetary investments, few scientific advances have been possible in the capitalist healthcare system in North America. However, according to Majumder, Bhaumik, Ghosh, Bhattacharya, and Ghosh (2015), the situation was remedied recently. Designated grants from several governmental institutions contributed to significant scientific advances in the area. As specified by Majumder et al. (2015), researchers conducted meaningful studies on the association between trisomy 21 and congenital heart disease, Alzheimer’s disease, and mitochondrial dysfunction. Furthermore, the recently developed theory of chromosomal missegregation and mitochondrial DNA analysis for patients with Down syndrome helped to minimize cases of apoptosis (Majumder et al., 2015). Future investments in the area allow hoping for further scientific breakthroughs in treating trisomy 21. From many perspectives, the future well-being of children diagnosed with Down syndrome depends on their families. Parental involvement in the healthcare decision starts before the baby’s birth, when a mother chooses between the suggested screening methods, accounting for risks associated with the procedure (Chitty et al., 2016). Further course of the treatment, including pharmacological agents, therapies, and surgeries, is also approved by the parents. Finally, the child’s mental development depends on the immediate family’s emotional and physical involvement in the upbringing. Ultimately, the process of treating Down syndrome poses challenges to the healthcare system. Nevertheless, current FDA regulations in the area and monetary investments in scientific research increased the accuracy of the suggested treatment. Newly developed drugs and methods for early diagnosis of the disease, as well as a general tendency for higher parental involvement in the healthcare decisions, help to improve the patient’s quality of life. Down Syndrome Case A better understanding of the general patterns of Down Syndrome requires a close analysis of the individual cases of the patients diagnosed with this genetic disorder. A recent example from personal practice constitutes the basis for this case study. In particular, the paper discusses details from the health record of Louisa S., a 3-year old girl suffering from trisomy 21. The real names of the people involved were changed to protect their confidentiality. This case report discusses in detail Louisa’s results of the chromosomal analysis, personal causes, origin of the disorder, the nature of the gene mutation, and implications for further clinical practice and patient education.

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To confirm Louisa’s diagnosis, healthcare professionals performed a conventional karyotype test from the peripheral blood. The chromosomal analysis indicated changes in the girl’s genetic make-up, in accordance with the third cytogenetic form of Down Syndrome: Robertsonian Translocation Trisomy 21. As explained by Plaiasu (2017), this condition is diagnosed quite rarely: only four times in 100 patients with Down Syndrome. Since the nature of the Robertsonian Translocation Trisomy 21 may be either genetic or environmental, Louisa’s parents, Samuel. D.and Tracy H., were tested for being the carriers of the translocation. The results of the chromosomal analysis appeared negative for both of the parents, signifying that the infant’s form of the disorder is “de novo.” As followed by Plaiasu (2017), in the “de novo” cases, the genetic mutation of the twenty-first chromosome occurs spontaneously as a result of the nondisjunction in meiosis I, meaning that parents do not have any abnormalities in their karyotypes. Unlike in the instances of free trisomy 21 or mosaicism, patients who have Down Syndrome, caused by the “de novo” cases of Robertsonian translocation, do not have specific causes for the disorder. Ambreen, Ashok, Srinivasan, Shalu, and Sarita (2015) suggested that the abnormality of the chromosome happens because “the long arm of the chromosome 21 is attached to another chromosome,” usually number 14 (p. 2). As discussed earlier in the report, the causes of Robertsonian translocation may be genetic or environmental. Since none of Louisa’s parents were diagnosed as carriers of the chromosomal translocation, the cause for the girl’s genetic mutation lays in the nondisjunction in meiosis I. Israni and Mandal (2017) specified that at least one pair of homologous chromosomes failed to separate during the first stage of the meiosis I, leading to the Robertsonian translocation. As to the best scientific knowledge, no maternal actions before or during the conception of the child increase the risk of nondisjunction, which estimates to 1% in “de novo cases” (Israni & Mandal, 2017). In other words, when both parents have normal karyotypes, the risk of consecutive unhealthy pregnancies is minimal. Laboratory testing performed on Louisa and her parents provides sufficient evidence to claim that the genetic disease has been acquired. The process of gene mutation is characterized as unbalanced translocation. As explained by Zhao et al. (2015), the third cytogenetics of Down Syndrome, caused by Robertsonian translocation, occurs when there is an unequal exchange of chromosomal material, resulting in extra copies or missing genes. An analysis of Louisa’s case allows assuming that the process of mutation involving Has 3 is the most likely type of structural abnormality, which could lead to the girl’s Down syndrome. Zhao et al. (2015) elaborated that the vast majority of de novo cases of Robertsonian translocation form “in the stage of meiosis I of oogenesis whereas almost all ROBs form de novo mitotically” (p. 2). The high prevalence of such gene mutation is explained by the acrocentric chromosomes’ susceptibility to the rearrangement due to the short arms near one end (Zhao et al., 2015). In other words, the abnormality on Has 3 happens because of the changes in one of the four main types of chromosomes: acrocentric.

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Louisa’s translocation of Down Syndrome has a complex inheritance origin. As noted by Antonarakis (2016), the most precise characterization of gene dysregulation in trisomy 21 is attributed to the genome-wide effect. In other words, the disease is caused by the substantial changes in chromosomes rather than the inheritance of a single altered allele. The complex nature of the health condition requires a holistic approach toward patient education and further clinical practices. As followed by Huiracocha et al. (2017), both healthcare professionals and family members find it emotionally difficult to cope with the child’s chronic disability. To improve the patient’s quality of life, practitioners should first provide assistance and support to the immediate family, who might experience feelings of shock, denial, and guilt (Huiracocha et al., 2017). In Louisa’s case, nurses referred the girl’s parents, Samuel and Tracey, to the institution’s support group to manage the conflicting emotions after the diagnosis. Apart from helping parents overcome the grief, healthcare professionals are responsible for developing experimental treatments to treat the comorbidities of Down syndrome, including vaccinations, cardiac surgeries, hormone therapies, prescription of anticonvulsive drugs, and antibiotics. Appropriate care at the early stages of the disease increases the likelihood of the child’s fulfilling life. As mentioned by Kazemi, Salehi, and Kheirollahi (2016), patient education is critical for the improvement of one’s cognitive abilities. To help Louisa better integrate into society in the future, practitioners advised parents to use speech and physical therapy. The child may also benefit from art classes, moderate sports exercises, and music courses. Ultimately, the chromosomal analysis performed after the child’s birth confirmed Louisa’s diagnosis with “de novo” Robertsonian Translocation Trisomy 21. Acquired during meiosis I, the gene mutation is labeled as unbalanced chromosomal translocation, which is not related to the genetic inheritance of the abnormal karyotype. Though no treatment currently exists for the condition, patient education and future clinical research leave hope for the individuals’ improved quality of life. The impact of genetics Treatment and diagnosis of genetic disorders require close attention and specific qualifications from healthcare professionals on all levels. To achieve the best prognostics and treatment effectiveness, practitioners advocate for changes in the current public policies on genetic diseases and use a holistic approach, when assessing patients’ overall health condition. For the basis of this paper, a case study of an infant with Down Syndrome, described in part 2 of the report, is used. The case report focuses on the impact of genetics on policy issues, examining the nutritional influences, the process of assessment, counseling, and the role of human nutrition in terms of prevalence rates, diagnostics, and treatment. With recent advances in the field of genomics, Congress has addressed numerous legislation pieces concerning genetics issues. Sarata (2015), an expert on public health policies, stated that categories of policy issues in genetics include discrimination of individuals with genetic disabilities, legalization of new testing methods, and patent of the genetic material. Major trends captured in the bills are associated with the inclusion of individuals with genetic abnormalities in the educational institutions and at the workplace while providing them with assistance, support, and value-based care. As noted in the “Proceedings and debate of the 116th congress” (2019), advocates for social change appeal to the government officials with provision to equal working and educational opportunities for individuals with genetic disabilities. More specifically, recent bills protecting patients with Trisomy 21 emphasize the need for conflict prevention, management, and prohibition of seclusion. The aforementioned discriminative factors at work and schools are efficiently addressed in the recent public policies from 2019. In particular, subminimum wages for patients with genetic abnormalities are to be eliminated from the Transformation to Competitive Employment Act (H.R. 873/S.260). Meanwhile, a less restrictive educational environment and access to free public education remain acute federal issues under the Retention of Protections of the Individuals with Disabilities Education Act (2004) (“Proceedings of the 116th congress,” 2019). The overall improved quality of life in individuals with Down Syndrome leaves hope for their further inclusion in the life of the community. Though contemporary research does not identify nutritional influences as potential causes for Trisomy 21, specific patterns were found in patients with Down Syndrome. According to Mazurek and Wyka (2015), intellectual disability is often associated with deficiency of vitamin B, as the majority of infants tested for Down Syndrome in the study showed low blood levels of B1, B2, B6, and B12. Apart from mental retardation, such nutritional specialty contributes to children’s weakness, decreased mobility, and lack of concentration. Another laboratory testing indicated substantial deficiencies in zinc, calcium, and selenium, which leads to reduced immune response, incorrect posture, and provokes abnormal gene expressions (Mazurek & Wyka, 2015). Dieting also has a significant role in the severity of Down Syndrome’s symptoms manifestations. Inadequate caloric intake, low quantity of vegetables and fruit consumed in comparison to the high ratio of carbohydrates in the diet result in common concomitant diseases, such as congenital heart disease, type-2 diabetes, and obesity (Mazurek & Wyka, 2015). While nutritional influences do not directly cause the development of Trisomy 21, balancing one’s diet once diagnosed with the disease decreases the chances of developing related health complications. As mentioned previously, patients’ nutrition may affect the likelihood of developing concomitant diseases; thus, a thorough process of nutritional assessment and counseling is essential for individuals with Down Syndrome. According to Ptorney and Wittenbrook (2015), two steps to the proper nutritional assessment include “collection of dietary intake data and determining energy needs” (p. 604). Since patients with Trisomy 21 have a tendency toward obesity, maintaining a healthy diet serves as a preventative technique for type-2 diabetes and heart diseases. DS adults with a healthy BMI do not only have a better prognostic in terms of life expectancy but also react better to the prescribed treatment, experiencing fewer issues with the gastrointestinal act. Adequate calorie intake, established after the nutritional assessment, also decreases the risks of individuals’ contraindications to specific medicine associated with the developed concomitant diseases, extending the array for treatment selection and monitoring of its effectiveness (Ptorney & Wittenbrook, 2015). While nutritional counseling appears beneficial for all the aforementioned factors, it has little implications for the screening and diagnostics of both Trisomy 21 and its related health complications. With regards to human nutrition, patients with Down Syndrome who regularly consume dietary supplements have a better prognosis and response to treatment than those who abstain from additional nutrition intake. As followed by Lewanda, Gallegos, and Summar (2018), usage of antioxidants, herbal supplements, single, and multivitamin complexes of different origins has shown repeatedly positive associations with individuals’ increased cognitive function and better emotional wellness. Mazurek and Wyka (2015) also indicated that those with Trisomy 21 might benefit from zinc, calcium, and selenium supplements, as well as consumption of food, which is naturally high in the mentioned elements. In terms of prevalence rates, DS patients who prefer food, which is high in fat, cholesterol, and carbohydrates, are diagnosed more frequently with gastrointestinal, endocrine, and heart disorders. Even though laboratory testing, showing deficiencies in vitamin B, zinc, selenium, and calcium, may predict the severity of symptoms manifestations, little research exists to prove the causality between human nutrition and the development of Down Syndrome. Consequently, in a holistic approach toward treating patients with Down Syndrome, a critical place belongs to the nutritional assessment and counseling. The establishment of a balanced diet and regular intake of prescribed supplements allows reducing the risk of developing concomitant gastrointestinal, endocrine, and heart conditions. Apart from medical interventions, a better quality of life for DS patients can be achieved through changes in the public policies, which promote social inclusion, equal opportunities at school, and the workplace for people with genetic disabilities. Ethical challenges and the role of genomics In a holistic approach to healthcare, providers should focus on a variety of factors when conducting a comprehensive assessment of patients’ health and choosing an effective treatment. Along the course of the three previous case reports, Down Syndrome’s symptoms, background, treatment, laboratory methods, governmental regulations, and available counseling were briefly discussed to set a premise for the role of genetics in the industry. The fourth part of the paper will finalize the study by analyzing present ethical challenges and evaluating the role of genomics on the current healthcare expenditures. Recent changes in the healthcare approach for the screening, diagnostics, and treatment of the disorder will also be taken into consideration to develop a detailed guideline on clinician education. One of the fundamental ethical issues related to Down Syndrome is the practice of prenatal screening and diagnostics of the fetuses for the identification of chromosomal abnormalities. As explained by Stapleton (2017), though recent advances in non-invasive prenatal testing (NIPT) allow couples to make more reasonable reproductive choices, the nature of the diagnostics raises a number of ethical inquiries. On the one hand, some experts argue that there is little purpose in offering NIPT for congenital non-preventable disorders (Griffin, Edwards, Chitty, & Lewis, 2018). On the other hand, there is a tendency to believe that parents may be more prepared for the upbringing of a child with special needs, once they are informed promptly. According to Stapleton (2017), the major concern refers to the prediction that fear of positive results in NIPT will lead to a lower level of tolerance and support for newborns diagnosed with Trisomy 21. Therefore, it is critical for healthcare professionals to follow the established ethical guidelines, wherein practitioners hold a neutral position, allowing couples to make independent reproductive decisions based on their values. Despite the aforementioned ethical dilemmas in the field, genetics and genomics can improve the quality of healthcare while reducing governmental expenditures. Christensen, Dukhovny, Siebert, and Green (2015) elaborated that genome sequencing of individuals at birth can help practitioners to diagnose hereditary diseases at an early stage and select proper treatment. The major benefit of such practice lies in the ability to minimize the toxic barrier caused by redundant diagnostics methods and inaccurate prescriptions. Over recent years, there has been a reported tendency for the decreased monetary spending on genetics-based procedures. For instance, as stated by Christensen et al. (2015), in 2007, it cost the US healthcare system nearly ten million dollars to perform the whole genome sequencing. In the nearest future, the estimated price for the same practice is estimated to be only one thousand dollars, signifying the high likelihood of its incorporation into the healthcare routine (Christensen et al., 2015). Possible outcomes for the industry include improved medical care, a higher level of patients’ awareness on the issue, and implications for the clinician education, orientated on the inclusion of people with Down Syndrome. Both from the perspective of recent ethical challenges and genomics advancements, healthcare providers shifted their focus from a generalized approach to patient-centered care. As noted by Karmiloff-Smith et al. (2016), the updated clinical guidelines specify that the presence of a genetic abnormality in patients with Down Syndrome should be balanced with individual differences. Contemporary research on “induced pluripotent stem cells” suggests that, on the contrary to the previous beliefs, there exist notable differences in the cell composition and brain chemicals in people with Trisomy 21 (Karmiloff-Smith et al., 2016, p. 2). Therefore, in terms of the clinical approach to care, such a study warrants the need for thorough diagnostics of all healthcare systems for the selection of a suitable model of treatment. Moreover, now, pregnant women are given a choice for both invasive and non-invasive prenatal testing, which highlights the significance of the personal reproductive choice, which was not widely spread several decades ago. While dealing with a non-preventable genetic disease involves physical and psychological challenges for patients, parents, and healthcare providers, specific guidelines on clinician education may ease the process of adjustment. As mentioned by Kazemi, Salehi, and Kheirollahi (2016), practitioners should inform parents whose child was diagnosed with Down Syndrome on the risks and complications related to the inherited disorder. During the pregnancy, women should be educated about the available laboratory methods for prenatal screening and diagnostics of the disease. For better integration in society, patients with Trisomy 21 should be involved in art, speech, and physical therapies. It is equally essential for healthcare professionals to take advantage of the multiple online resources with the utmost updated information on the illness to improve their knowledge. Relevant examples include the Huddersfield Down Syndrome Support Group, National Association for Down Syndrome, and National Down Syndrome Society. Apart from self-education, supervisors should conduct regular training and meetings with their subordinates to increase their theoretical background on the matter. Ultimately, the practice of treating Down Syndrome involves a number of ethical challenges which has influenced the traditional approach to healthcare, shifting the focus from a generalized protocol to a patient-centered approach. In the aforementioned situation, genetics did not only improve the medical outcomes of the patients but also decreased overall expenditures. While Trisomy 21 remains an incurable and non-preventable illness, recent scientific advancements leave hope for a better prognosis. References Al-Biltagi, M. (2015). Down syndrome from epidemiologic point of view. Ecronicon Paediatrics, 2(1), 82-91. Web. Ambreen, A., Ashok, K., Srinivasan, M., Shalu, J., & Sarita, A. (2015). Down syndrome: An insight of the disease. Journal of Biomedical Science, 22(41), 1-9. Web. Antonarakis, S. (2016). Down syndrome and the complexity of genome dosage imbalance [Abstract]. Nature Reviews Genetics, 18(3), 147-163. Web. Chitty, L. S., Wright, D., Hill, M., Verhoef, T., I., Daley, R., Lewis, C., … Morris, S. (2016). Uptake, outcomes, and costs of implementing non-invasive prenatal testing for Down’s syndrome into NHS maternity care: Prospective cohort study in eight diverse maternity units. BMJ, 354(i3424), 1-11. Web. Christensen, K. D., Dukhovny, D., Siebert, U., & Green, R. C. (2015). Assessing the costs and cost-effectiveness of genomic sequencing. Journal of Personalized Medicine, 5(4), 470–486. Web. Gardiner, K. J. (2015). Pharmacological approaches to improving cognitive function in Down syndrome: Current status and considerations. Drug Design, Development and Therapy, 9, 103-125. Web. Griffin, B., Edwards, S., Chitty L. S., & Lewis C. (2018). Clinical, social and ethical issues associated with non-invasive prenatal testing for aneuploidy. Journal of Psychosomatic Obstetrics & Gynecology, 39(1), 11-18. Web. Huiracocha, L., Almeida, C., Huiracocha, K., Arteaga, J., Arteaga, A., & Blume, S. (2017). Parenting children with Down syndrome: Societal influences. Journal of Child Health Care, 21(4), 488–497. Web. Israni, A. V., & Mandal, A. (2017). De Novo Robertsonian Translocation t (21; 21) in a child with Down syndrome. Journal of Naepal Paediatric Society, 37(1), 92-94. Web. Karmiloff-Smith, A., Al-Janabi, T., D’Souza, H., Groet, J., Massand, E., Mok, K., … Strydom, A. (2016). The importance of understanding individual differences in Down syndrome. F1000Research, 5(389), 1-10. Web. Kazemi, M., Salehi, M., & Kheirollahi, M. (2016). Down syndrome: Current status, challenges, and future perspectives. International Journal of Molecular and Cellular Medicine, 5(3), 125-133. Lewanda, A. F., Gallegos, M. F., & Summar, M. (2018). Patterns of dietary supplement use in children with Down Syndrome. The Journal of Pediatrics, 201, 100-105. Web. Majumder, P., Bhaumik, P., Ghosh, P., Bhattacharya, M., & Ghosh, S. (2015). Recent advances in research on Down syndrome. In S. K. Dey (Ed.), Health problems in Down syndrome (pp. 87-100). Web. Mazurek, D., & Wyka, J. (2015). Down Syndrome – Genetic and nutritional aspects of accompanying disorders. Roczniki Panstwowego Zakladu Higieny, 66(3), 189-194. Plaiasu, V. (2017). Down syndrome – Genetics and cardiogenetics. Maedica (Buchar), 12(3), 208-213. Web. Proceedings and debate of the 116th congress, first session. (2019). Congressional Record, 165(44), 2649-2682. Web. Ptorney, L. T., & Wittenbrook, W. (2015). Position of the Academy of Nutrition and Dietetics: Nutrition services for individuals with intellectual and developmental disabilities and special health care need. Journal of the Academy of Nutrition and Dietetics, 115(4), 593-608. Web. Sarata, A. K. (2015). Genetic testing: Background and policy issues (CRS Report No. RL33832). Web. Stapleton, G. (2017). Qualifying choice: Ethical reflection on the scope of prenatal screening. Medicine, Health Care, and Philosophy, 20(2), 195–205. Web. Zhao, W-W., Wu, M., Chen, F., Jiang, S., Su, H., Liang, J., … Yu, S. (2015). Robertsonian translocations: An overview of 872 Robertsonian translocations identified in a diagnostic laboratory in China. PLOS One, 10(5), 1-14. Web.

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