PURPOSE: Every year, thousands of Americans pursue prenatal diagnosis of fetal aneuploidy though chorionic villus sampling (CVS) or amniocentesis. Because these procedures are invasive and carry an inherent risk for pregnancy loss, they are selectively offered to women who have an increased risk to have a child with a chromosome condition, such as aneuploidy. In order to identify pregnancies at an increased risk, several non-invasive screening methods have been developed. Although quite useful, these screening methods have limited accuracy and can only be completed during specific gestational age windows. Recent discovery of cell free fetal DNA in maternal circulation has created new and exciting possibilities for prenatal screening and non-invasive prenatal diagnosis. This research study explores shotgun next-generation sequencing of fetal DNA in maternal plasma as a method for non-invasive identification of fetal aneuploidy. METHODS: We carried out shotgun next-generation sequencing on samples of maternal plasma DNA obtained in the first trimester of pregnancies with confirmed aneuploidy and control pregnancies. Three Trisomy 21 samples were compared to four control samples in order to identify any differences in the amount of chromosomal material. RESULTS: We identified a statistically significant increase in chromosome 21 material in the cases of Trisomy 21 as compared to the control cases. IMPLICATIONS: This research demonstrates that shotgun next-generation sequencing of maternal plasma DNA can successfully identify Trisomy 21, showing that it is possible to detect fetal aneuploidy using this noninvasive method. This technology could potentially be used as a method of noninvasive screening for fetal aneuploidy, which is likely to have improved accuracy over other screening methods. Development of a screening test with greater sensitivity and specificity could have significant public health implications. This would not only provide more accurate identification of pregnancies at an increased risk for aneuploidy, but it would also reduce the number of false positives. This in turn would reduce the number of pregnancies that are unnecessarily classified as high risk, preventing avoidable parental anxiety and reducing the number of pregnancies that are put at unnecessary risk of invasive prenatal diagnostic procedures.

BACKGROUND: Cutis laxa (CL) is a group of disorders characterized by loose, inelastic, and redundant skin. The different types of CL are distinguished by clinical features, inheritance, and molecular findings. The objective of this study was to characterize the pulmonary phenotype of the different types of CL based on age of onset (congenital, acquired/late-onset, or unknown) and mutational status. The first aim of this study was to collect clinical data to better define the pulmonary involvement in cutis laxa. The second aim was to determine if heterozygous carriers of recessive types of cutis laxa are susceptible to chronic lung disease. METHODS: Clinical questionnaires, medical histories, and pulmonary function tests (PFTs) were used to collect clinical data on patients with a confirmed or suspected diagnosis of CL and unaffected first-degree relatives with a known mutation (carriers). The clinical data was then compared between the groups categorized by age of onset and between those with known mutations (mutational status). RESULTS: The clinical questionnaires and medical histories of 83 CL patients with 8 acquired/late-onset, 52 congenital, and 23 of unknown etiology and 5 carriers were analyzed. In addition, mutations have been identified in 27 of the 83 patients in ELN, FBLN4, FBLN5, ATP6V0A2, or LTBP4, and the 5 carriers had mutations in either FBLN4 or LTBP4. The most common respiratory responses amongst the patients included pneumonia (24.1%), tachypnea (15.7%), and emphysema (12.0%). The only statistically significant finding was dyspnea in acquired/late-onset patients. Of those with a known mutation, 15 reported pulmonary involvement, with 10 of these individuals having at least one LTBP4 mutation. For the 13 PFTs collected, the 10 CL patients ranged from normal lung function to very severe obstruction, and 3 carriers were deemed to have normal function. An important new finding was the presence of pulmonary obstructive disease in those with ATP6V0A2 mutations. CONCLUSION: These results demonstrate a high prevalence and significant heterogeneity of pulmonary complications in CL. Further research is needed to determine any correlation between specific pulmonary findings and genotypes. PUBLIC HEALTH SIGNIFICANCE: Chronic lung disease is a common cause of morbidity in the general population. Uncovering the genetic basis of chronic lung disease in inherited syndromes has the potential to identify key molecular targets for improved diagnosis and treatment of common respiratory ailments.

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Thesis (M.S.)--University of Wisconsin--Madison, 1983. / Typescript. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 124-129).

Introduction: Fetal medicine practitioners (FMPs) are responsible for making decisions about the appropriateness of a late termination of pregnancy (LTOP) based on their assessment of the severity of the prenatal diagnosis while also taking into account the practical, legal and ethical aspects. This study aimed to investigate the views and experiences of FMPs involved in LTOP decision-making in the Western Cape and how these views may guide decisions to offer LTOP. Specifically, the research questions guiding this study aimed to investigate FMPs views on the Choice on Termination of Pregnancy Act (CTOPA), No. 92 of 1996, as well as their attitudes towards the provision and ethics of LTOP. Methodology: A total of six semi-structured, individual face-to-face interviews were conducted between February and March 2020 in the privacy of the participant's office. All interviews were audio-recorded and transcribed. Interpretive phenomenological analysis was used as a framework to analyse the data and transcripts were managed using NVivo 12 software. Results and Discussion: Participants believed that the CTOPA is based on the principle of gradualism and that while women have reproductive choice, TOP becomes progressively restricted as gestation advances to protect the fetus. However, they felt that the specified cut-offs in the CTOPA are arbitrary and open to interpretation and believed there is a need for further documentation to guide practitioners as to which conditions should be considered for LTOP. When making a decision to offer LTOP, participants considered various factors including fetal age, whether a feticide was required and the prognosis. Participants considered that conditions which qualified as severe were untreatable and would have a significant, long-term negative impact on the individual's functioning and quality of life. When considering acceptability of LTOP, participants felt that LTOP was justified to prevent suffering for both the future child and for the parents. However, participants did not believe that LTOP was justified to prevent all disability. Lastly, participants valued societal consensus when making morally demanding decisions and believed that decisions around LTOP needed to be made by multidisciplinary teams to ensure objectivity, as well as to share the moral burden.

The present study explored the interactional dynamics of intercultural Genetic Counselling sessions in clinics in Johannesburg. Genetic Counselling is a relatively young profession and although extensive research is available on the process there is a paucity of literature on what occurs in the interactions and even less is available on intercultural encounters. The selected methodology for the study was discourse analysis which concentrates on analysing what the discussions do rather than what they are about. The data comprised of 17 video recorded prenatal genetic counselling sessions with women who were at an increased risk of having a baby with a chromosome abnormality due to advanced maternal age. The sessions were conducted in English by six genetic counsellors. The video recordings were transcribed and the transcripts and recordings were analysed based on Principles of Discourse Analysis. It was apparent during the initial phases of the analysis that there was a distinct order to the interactions with six specific phases being identified. Certain phases appeared significant, and as a result openings, decision-making and counselling phases were analysed further. Counsellor dominance in the interactions manifested in the number of strategies they had developed to guide the women through the counselling session. In their active participation, the counsellors identified the agenda and they controlled it throughout the interaction. During decision making, they used active strategies to assist the women to make a decision regarding having an amniocentesis performed. Even in the counselling segments where the counsellors and the women discussed issues related the women’s life, the initiation and development were controlled by the counsellors. In contrast to the counsellors’ dominance of interactional space, the women shared issues relating to their life world during the counselling segments. This apparent contrast seemed to create tension in the counsellors’ role as they had to either ‘educate’ or ‘counsel’. Tension was further created by the counsellors’ perceived obligations to practise in a particular way. Adhering to firmly embedded principles of the profession seemed to limit the counsellors’ practices and simultaneously prevented the achievement of these principles. The emerging tensions is thought to be related to the health care setting in which patients, as a result of social and political reason, have not been active participants in their healthcare decisions. The interactions were shaped by the health care system as it influenced the setting of the agenda, the order in the interactions and the counselling techniques used. The emerging phenomena could not be labelled as cultural and it was rather found that culture was inherent to the individuals and the setting in these interactions. The findings have implications for genetic counselling practice in South Africa as existing models of training and practice necessitate adapting to incorporate the insights gained. The contextual influences require consideration and the patients need to be made the focus of the sessions. A culturally sensitive model of genetic counselling as proposed in the study is thought to advance the profession towards true patient-centered Genetic Counselling practices.

Black South African women who have breast cancer have been found in general to be diagnosed at a younger age, have a more aggressive disease and a poorer prognosis in comparison to their Caucasian counterparts. However, there is a paucity of research related to the manner in which breast cancer is inherited in black South African families. It is also not known whether these individuals harbour deleterious mutations in breast cancer predisposition genes. As 5-10% of breast cancers have been shown to be inherited, in white populations, this study aimed to investigate family history and inheritance of breast cancer in black South African women. It also aimed to evaluate the use and consistency of existing risk assessment models in this population. A retrospective, file-based analysis of 45 black South African women who were diagnosed with breast cancer before the age of 50 years was performed. The probands were ascertained from the Genetic Counselling Clinic held weekly at the Breast and Plastic Clinic, Chris Hani Baragwanath Hospital. Information was obtained from the subjects’ genetic counselling files as well as the Oncology database that is housed at the Clinic. Information pertaining to the personal breast disease history of the probands as well as their family histories (three generation pedigrees) was entered into a spreadsheet and analysed. The results of this study indicated that there were very few young black South African women with breast cancer who had a significant family history of cancer (4/45; 9%). Family history is an important factor in assessing an individual’s breast cancer risks. Results also suggested that age at diagnosis may not be an appropriate predictor of inherited breast cancer risk in this population. A significant proportion of black South African women diagnosed with breast cancer younger than 50 years might be proven to have sporadic rather than inherited breast cancers. Three risk assessment tools (The Claus Model, the Tyrer-Cuzick Model and the Manchester Scoring system) were evaluated in this study. They were shown to have some degree of consistency and each had unique advantages and disadvantages of use within this population. The main limitation of these risk assessment tools is that they were designed based on data from Caucasian populations and as such their applicability to a non-Caucasian population has not been validated. Their true validity within this population can only be established once molecular genetic analysis has been performed. This study highlights the necessity of molecular genetic screening in this population in order to further delineate which individuals in this population are truly at an increased risk of developing inherited breast cancer. This information is important because it can inform which individuals would benefit from cancer risk assessments and various cancer prevention and reduction strategies. Information obtained from this study will be useful to direct future research in this population with respect to genetic counselling for inherited breast cancer.

Includes bibliographical references / Sickle Cell Disease (SCD) is an autosomal recessively inherited blood disorder that leads to a debilitating systemic illness. Although the disease was initially found predominantly in tropical and subtropical regions, SCD has now become a global health problem, due to migration of people from various countries with a high burden thereof. Consequently, the incidence of SCD in South Africa has increased dramatically over the last decade. This study, which constitutes a minor dissertation in fulfilment of an MSc (Med) Genetic Counselling degree, aimed to explore the knowledge and understanding of SCD among parents of affected children in Cape Town as well as identify burdens associated with caring for a child with SCD. Furthermore, the study assessed opportunities to improve genetic counselling services available to parents and explored their attitude to preventive policies. A phenomenological approach was used to conduct this research. Seventeen semi-structured interviews were conducted with the biological parent of a child attending the Red Cross War Memorial Children's Hospital Haematology Clinic. Participants were selected using both purposive and convenience sampling methods. Data collected during these interviews were analysed using thematic content analysis. Themes and relevant sub-themes were identified and grouped into three categories: knowledge and understanding; experiences and burdens; and attitude toward preventative policies. While the majority of participants had some knowledge of SCD, several misconceptions were discovered, often relating to participants' prior knowledge of the disease. A number of burdens experienced by participants were revealed, with both practical and psychosocial implications. Finally, it was found that the majority of participants supported all methods of screening for SCD, regardless of whether they would make use of the screening services themselves. Findings of this study provide valuable insights on the subject of experiences of parents of children affected with SCD as well as the potential role of genetic counselling services. This study contributes towards improving understanding and subsequent services provided to individuals raising a child affected with Sickle Cell Disease.

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