Browsing by Author "Kotze, M. J."
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- ItemApplication of advanced molecular technology in the diagnosis and management of genetic disorders in South Africa(Health & Medical Publishing Group, 2016) Kotze, M. J.Background. Genetic testing has evolved from a niche speciality for diagnosis of rare disorders and carrier screening to subtyping of complex medical conditions for targeted treatment. Genes causing monogenic disorders are well characterised, but risk management of multifactorial and polygenic disorders guided from the genetic background remains a challenge. Objective. This study describes the use of a pathology-supported genetic testing (PSGT) strategy designed to facilitate the move from single- to multi-gene testing and next-generation sequencing (NGS). Methods. In contrast to direct-to-consumer genetic testing, PSGT requires preselection of patients and data integration to determine current and future risk implications. To enable this process, a genomics database resource generated at the interface between the laboratory and clinic is available for clinical interpretation. Results. The PSGT approach led to the development of testing algorithms for improved clinical management of patients with cancer and other complex disorders with a genetic component. Local evidence is presented to demonstrate the application of PSGT for assessment of clinical relevance in patients with rare germline variants and functional polymorphisms underlying shared disease pathways. Conclusion. PSGT is ideally suited to serve as a screening step for microarray analysis and whole genome/exome sequencing as the next frontier in personalised medicine. Use of these advanced molecular technologies to match genotype with phenotype provides a resource for diagnosis and discovery over a lifetime.
- ItemA DNA polymorphism in the human low-density lipoprotein receptor gene(Health and Medical Publishing Group -- HMPG, 1986-07) Kotze, M. J.; Retief, A. E.; Brink, P. A.; Weich, H. F. H.A new restriction fragment length polymorphism (RFLP) in the low-density lipoprotein receptor gene is described using the Stu I restriction endonuclease and a cDNA probe. The frequency of the two RFLP alleles was determined in 60 unrelated white subjects and 11,70/6 of them were found to be heterozygous for the polymorphism. Mendelian segregation of the RFLP was found in 3 informative families. The possible use of the RFLP in the diagnosis of familial nypercholesterolaemia in South Africa is discussed.
- ItemInherited colon cancers(Health & Medical Publishing Group, 2000) Goldberg, P. A.; Madden, M. V.; Harocopos, C.; Grobbelaar, J. J.; Kotze, M. J.; Marx, M. P.; De Jong, G.Grobbelaar et al.' and Ramesar et al.' (in this issue) have identified germline mutations in certain families with h"o different types of inherited colorectal cancers. This means that blood tests are now available in South Africa for clinical use in these particular families. Within the families these DNA-based tests can separate individuals with the mutation that causes cancer from those who do not have it. Those with a mutation may pass the family-specific mutation to their children.
- ItemMolecular characterisation of a low-frequency mutation in exon 8 of the human low-density lipoprotein receptor gene(Health & Medical Publishing Group, 1989) Kotze, M. J.; Langenhoven, E.; Warnich, Louise; Marx, M. P.; Retief, A. E.The prevalence of familial hypercholesterolaemia (FH), an autosomal dominant disease characterised by raised low-density lipoprotein (LDL) cholesterol levels, is at least five times higher in the white Afrikaner population than in most other population groups in the world. A founder gene effect has been suggested to explain this abnormally high frequency. Detection of a polymorphic Stu I site in the 5' region of the LDL receptor gene and association of both restriction fragment length polymorphism alleles with FH in Afrikaners, indicated the existence of at least two founder members of the disease in this population. DNA from a hetero-allelic FH homozygote from this South African group has been analysed through genomic cloning and sequencing. The DNA polymorphic site is caused by a single guanine to adenine transition within exon 8 of the LDL receptor gene and can be used in the determination of haplotype-associated defects.
- ItemNon-alcoholic fatty liver disease (NAFLD) in the Western Cape : a descriptive analysis(Health and Medical Publishing Group (HMPG), 2010) Kruger, F. C.; Daniels, C.; Kidd, M.; Swart, G.; Brundyn, K.; Van Rensburg, C.; Kotze, M. J.Background. Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease in Western countries, but the disease profile has not yet been described in South Africa. NAFLD affects all spheres of society, especially the poorest and least educated. Aim. To investigate the demographics and clinical and biochemical features of South African patients diagnosed with non-alcoholic fatty liver and non-alcoholic steatohepatitis (NASH) in the Western Cape, South Africa. Design/method. Overweight/obese subjects were screened by ultrasound and those with fatty liver/hepatomegaly were included. Liver biochemistry, insulin resistance (using the insulin resistance homeostasis model assessment method for insulin resistance, HOMA-IR) and body mass index were assessed and liver biopsies were performed on patients older than 45 years with persistently abnormal liver function and/ or hepatomegaly. Results. We screened 233 patients: 69% coloured, 25% Caucasian, 5% black and 1% Asian. The majority (73%) were female. NAFLD was confirmed histologically in 111 patients, of whom 36% had NASH and 17% advanced liver fibrosis. No black patient had advanced fibrosis. Subjects with NASH had higher mean triglyceride (p=0.03) and cholesterol (p=0.01) levels than subjects with NAFL. All patients were insulin resistant/diabetic. HOMA-IR and not the degree of obesity was strongly associated with advanced fibrosis (p=0.09). Conclusion. This study is the first to describe the clinical characteristics of NAFLD in South Africa, albeit only in the Western Cape population. Insulin resistance was the universal factor present. The degree of obesity was not associated with severity of disease. The role of genetic risk factors in disease development and severity remains to be defined.
- ItemPredominance of a 6 bp deletion in exon 2 of the LDL receptor gene in Africans with familial hypercholesterolaemia(BMJ Publishing Group Ltd., 2000-02) Thiart, R.; Scholtz, C. L.; Vergotine, J.; Hoogendijk, C. F.; De Villiers, J. N. P.; Nissen, H.; Brusgaard, K.; Gaffney, D.; Hoffs, M. S.; Vermaak, W. J.; Kotze, M. J.In South Africa, the high prevalence of familial hypercholesterolaemia (FH) among Afrikaners, Jews, and Indians as a result of founder genes is in striking contrast to its reported virtual absence in the black population in general. In this study, the molecular basis of primary hypercholesterolaemia was studied in 16 Africans diagnosed with FH. DNA analysis using three screening methods resulted in the identification of seven different mutations in the coding region of the low density lipoprotein (LDLR) gene in 10 of the patients analysed. These included a 6 bp deletion (GCGATG) accounting for 28% of defective alleles, and six point mutations (D151H, R232W, R385Q, E387K, P678L, and R793Q) detected in single families. The Sotho patient with missense mutation R232W was also heterozygous for a de novo splicing defect 313+1G→A. Several silent mutations/polymorphisms were detected in the LDLR and apolipoprotein B genes, including a base change (g→t) at nucleotide position −175 in the FP2 LDLR regulatory element. This promoter variant was detected at a significantly higher (p<0.05) frequency in FH patients compared to controls and occurred in cis with mutation E387K in one family. Analysis of four intragenicLDLR gene polymorphisms showed that the same chromosomal background was identified at this locus in the four FH patients with the 6 bp deletion. Detection of the 6 bp deletion in Xhosa, Pedi, and Tswana FH patients suggests that it is an ancient mutation predating tribal separation approximately 3000 years ago.
- ItemRecurrent LDL-receptor mutation causes familial hypercholesterolaemia in South African coloureds and Afrikaners(Health & Medical Publishing Group, 1995) Kotze, M. J.; Langenhoven, E.; Theart, L.; Loubser, O.; Micklem, A.; Oosthuizen, C. J. J.Three low-density lipoprotein receptor (LDLR) gene mutations were previously shown to cause familial hypercholesterolaemia (FH) in up to 90% of affected Afrikaners. Association of each mutation with a single chromosomal background provided molecular genetic evidence that the proposed 'founder gene effect' was responsible for the high prevalence of FH among white Afrikaners. In this study we report the identification of the FH Afrikaner-2 (FH2) mutation, Val408 to Met, in the so-called coloured population of South Africa, a people of mixed ancestry, with rapid non-radioactive methods for mutation detection. Haplotype analysis with polymorphisms on both sides of the FH2 mutation indicated that the identical LDLR gene mutations found in two different South African population groups were caused by independent events at a potential CpG mutational 'hot spot'. The allelic variation giving rise to the different chromosomal backgrounds of the FH2 mutation does not affect the properties of the abnormal LDLR protein product which causes FH in these subjects. This mutation is thus expected to cause the same severe form of FH in affected coloureds as was previously demonstrated in Afrikaners. Detection of mutant LDLR gene alleles in polymerase chain reaction products, directly after gel electrophoresis, now allows accurate presymptomatic diagnosis of the FH2 mutation in FH patients from two different South African population groups.
- ItemThe UMD-LDLR database: Additions to the software and 490 new entries to the database(WILEY-LISS, DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, USA, NJ, 07030, 2002) Vill�ger, L.; Abifadel, M.; Allard, D.; Rab�s, J-P.; Thiart, R.; Kotze, M. J.; B�roud, C.; Junien, C.; Boileau, C.; Varret, M.
- ItemThe use of DNA markers in the pre-clinical diagnosis of familial adenomatous polyposis in families in South Africa(Health & Medical Publishing Group, 1995) Grobbelaar, J. J.; Oosthuizen, C. J. J.; Madden, M. V.; Bailey, S. E.; Retief, A. E.; Kotze, M. J.Haplotype association studies were performed in 10 unrelated South African families and 1 German immigrant family with familial adenomatous polyposis (FAP). Three DNA probes, recognising five restriction fragment length polymorphisms (RFLPs) around the gene locus for FAP on chromosome 5q, were used. The RFLP analysis was informative or partially informative in all the families studied. Five haplotypes were found to segregate with the disease locus. The predominant association of two of these haplotypes with FAP in the South African families suggests that two mutations may cause the disease in about 70% of families in this population. Meiotic recombination events were detected between the FAP gene and probe M4 (D5S6), but not probes Pi227 (D5S37) and C11p11 (D5S71). Haplotype analysis allowed the preclinical diagnosis of FAP in 5 subjects.