3. Electronic Theses and Dissertations (ETDs) - All submissions
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Item Cystic fibrosis genetic counselling: an audit of counsellees and their at-risk relatives(2009-02-11T11:14:54Z) Macaulay, ShelleyABSTRACT Cystic fibrosis (CF) is an autosomal recessive disorder that occurs in all ethnic groups. Mutations in the cystic fibrosis transmembrane regulator (CFTR) gene are responsible for pulmonary obstruction, chronic lung infections, pancreatic insufficiency, meconium ileus, failure to thrive and infertility. Genetic testing for CF at the DNA level is available. A diagnosis of CF in an individual has implications for other family members and so genetic counselling should form part of CF management. Genetic counselling has been offered by the Clinical Unit of the Division of Human Genetics, National Health Laboratory Service and the University of the Witwatersrand, Johannesburg, for many years. At the beginning of 2006, genetic services were introduced into the CF Clinics of Johannesburg Hospital by way of specialist Genetic Counselling Clinics. The study aimed to determine who utilises the CF genetic counselling services and why, to estimate the number of at-risk relatives per family, and how many of them had mutation testing and genetic counselling. Finally, the study explored what impact the specialist Genetic Counselling Clinics had on the overall service of genetic counselling. The files of 153 families seen for CF genetic counselling from 1990 to 2006 were analysed. The majority of counsellees (93%) were white. Most counsellees were parents of CF probands (35%). Relatives with carrier risks of 67% (siblings) and 50% formed only 7% and 6% of all counsellees respectively. Most individuals attended genetic counselling in order to gather information. On average, 5.9 ± 3.45 families were seen for CF genetic counselling per year from 1990 to 2005, whereas in 2006, 58 families were seen. Paediatrician, physician and nurse referrals increased notably during 2006 compared to prior years. In 140 unrelated CF-affected families, 1991 at-risk relatives, with carrier risks above 25%, were identified. Only 11% of these relatives had mutation testing and only 8% attended genetic counselling. Uptake of genetic counselling is greater when the service is integrated into CF treatment clinics than when it is offered externally. The low uptake of mutation testing and genetic counselling by at-risk relatives suggests that new methods of educating individuals for cascade screening and testing are required.Item Molecular profiling of the CFTR gene in black and coloured South African cystic fibrosis patients(2008-09-23T08:23:23Z) De Carvalho, Candice LeeABSTRACT INTRODUCTION: Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the CFTR gene. The gene mutation profile is extremely heterogeneous and mutations show a variable distribution among population groups. In SA the 3120+1G->A splice site mutation has been found predominantly in Black and Coloured patients. It occurs in Black CF patients at an estimated frequency of 46%. The CF carrier frequency is estimated at 1/34 in Black and 1/55 in Coloured populations, and based on these rates, it is clear that a significant number of Black and Coloured patients remain undiagnosed. Point mutations account for the majority of the mutations that have been found in the CFTR gene. Copy number mutations are, however, increasingly being detected in CF patients through the use of gene dosage-dependant assays. These mutations have been found to occur in the CFTR gene in various African American families and exon rearrangements are thought to account for 1.3% of all CF chromosomes across all populations. AIMS: To use haplotypes to analyse the origin(s) of the 3120+1G->A mutation and the likely frequencies of the remaining unknown mutations. To increase mutation detection in the SA Black and Coloured groups by searching for CFTR gene exons for copy number mutations. METHODS: In patients with at least one copy of the 3120+1G>A mutation haplotype studies will be used to elucidate the origin(s) of this mutation in SA Black and Coloured CF patients, by analyzing pyrosequencing SNP genotype data. In patients with at least one unknown mutation, haplotype studies will reveal the likely relative frequencies of the unknown mutations in these populations. In Black and Coloured CF patients with at least one unknown mutation, a multiplex ligation dependant probe amplification (MLPA) CF kit will be used for the detection of exon copy number mutations. RESULTS: The results of the haplotype data show that there is a G-G-C-G-T-A haplotype, for markers MetD-KM19-J44-T854T-Tub18-J32, associated with the 3120+1G->A mutation in both Black and Coloured patients. Unknown mutation-associated haplotypes indicate that there are two relatively common unknown mutations in each of these populations. MLPA results show that one patient is a carrier of an exon 2 deletion. CONCLUSION: A single origin for the 3120+1G>A mutation in Black and Coloured CF patients is supported by the data. Exon copy number changes in the CFTR gene are not a major mutational mechanism leading to CF in SA Black and Coloured patients.