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Familial hypercholesterolemia (FH) and familial defective apolipoprotein B-100 (FDB) are relatively common lipid disorders caused by mutations in the low-density lipoprotein receptor (LDLR) and apolipoprotein B (apo B) genes, respectively. Molecular analysis at these loci was performed in eight New Zealand subjects with clinical features of heterozygous FH. Utilization of an in vitrolymphocyte receptor assay demonstrated normal receptor function in four patients, three of whom screened positive for the founder-type apo B mutation, R3500Q, causing FDB. Four patients with reduced LDLR function, consistent with heterozygous FH, revealed three previously documented mutations in exons 3 (W66X), 6 (C292Y) and 7 (G322S) of the LDLR gene and, a novel 2-bp deletion (TC or CT) after nucleotide 1204 (or 1205) in exon 9. The remaining patient was found to be FH/FDB negative after extensive mutation screening using both denaturing gradient gel electrophoresis and heteroduplex-single strand conformation polymorphism analysis. Haplotype analysis at the LDLR and apo B loci finally excluded the likelihood that mutations in these two genes underlie the FH phenotype in the molecularly uncharacterized New Zealand family originating from the United Kingdom. This family represents a valuable source of material for future genetic dissection of autosomal dominant hypercholesterolemia (ADH), shown to be a heterogeneous disease through molecular analysis.

Most of the low-density lipoprotein receptor (LDLR) gene mutations causing familial hypercholesterolemia (FH) have been identified in the coding region of the gene. We have screened 180 patients for disease-related gene defects and report the identification of three previously described (IVS3+1G→A, IVS9−1G→A and IVS16−2A→G) and two novel mutations (IVS2+1G→A and IVS14+1G→T) at splice junctions. Approximately 9% (38/404) of LDLR gene point mutations identified to date in FH patients occur in introns and may affect splicing. The severe consequences of these mutations make them an important target for the molecular analysis of FH.

AbstractDefects in the BRCA tumor suppressor genes contribute significantly to the development of breast cancer in South Africa. Additive genetic effects and lifestyle risk factors underlie variable expression patterns in affected families, while also increasing breast cancer risk in the general population. Modifiable environmental factors could determine whether individuals with genetic risk factors develop cancer or fail to respond to treatment. Consequently, there is an increasing demand for genetic testing not only in patients with familial breast cancer, but also in healthy women and patients with sporadic cancer. Today, genetic testing in breast health extends from single-gene diagnostic tests to multi-gene treatment- based tests. For women in whom established breast cancer risk reduction approaches such as surgery and pharmaceuticals are not acceptable or inappropriate, treatment is based on molecular-genetic targets for individualised medical, nutrition and lifestyle intervention. Genetic testing as part of a holistic approach to breast health management translates into individual needs-based risk reduction interventions.

AbstractAssessment and treatment of cardiovascular disease (CVD) risk factors as a preventable cause of cognitive decline, morbidity and mortality is an important clinical goal. The apolipoprotein E (Apo E) gene provides a genetic link between CVD and the development of Alzheimer's disease (AD). The E4 allele increases the risk of coronary heart disease by more than 40% and contributes to the development of late-onset AD in more than 50% of affected patients. Disease expression in the presence of this allele is triggered by interaction with modifiable risk factors such as smoking, alcohol intake and high-calorie diets. It also displays differential therapeutic responses with use of cholesterol-lowering statins and acetylcholinesterase inhibitors. Apo E genotyping as part of a comprehensive evaluation of multiple CVD risk factors, performed in conjunction with nutrition and cognitive assessments, provides the opportunity to optimise treatment to the needs of the individual.

AbstractPhysiological changes in coagulation factors during pregnancy are important to minimise blood loss during gestation and delivery, but may also lead to a 4–6 fold increased risk of venous thromboembolism during pregnancy and after delivery. Approximately 25% of maternal mortality can be ascribed to thromboembolism if untreated, while this figure is reduced to less than 1% when diagnosed on time. Clinical diagnosis is complicated by the fact that the symptoms associated with venous thrombosis are relatively common complaints of pregnant women. A rapid genetic test has been developed for simultaneous detection of the most common genetic risk factors associated with thrombophilia, the factor V 1691GA (Leiden) and prothrombin 20210GA mutations. Mutation 677CT in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, which increases homocysteine levels by 15–25% when two copies of the T-allele is present, is also included as part of this “prenatal care genetic test”. Hyperhomocysteinaemia has been associated with an increased risk of thrombosis and neural tube defects. The importance of multi-gene testing is emphasised by the low predictive value of any single inherited marker and the significant increase in the probability of thrombosis when more than one risk factor is identified.

AbstractOverwhelming evidence indicates that diet is a key environmental factor affecting the incidence of many chronic diseases treated by medical practitioners on a daily basis. Information available in public gene databases, combined with advanced molecular technologies and nutrition research, provides the opportunity for the development of a new set of treatment and prevention strategies based partly on nutritional genomics. Nutrigenetics has been used for decades to prevent rare monogenic disorders such as phenylketonuria. Gene-diet interaction can now also be targeted to prevent or reduce the risk of many chronic conditions long before clinical manifestation. This multidisciplinary approach unites conventional medicine with genetics and lifestyle intervention for optimal health management.

AbstractThe rapid discovery of several iron-related genes in the last 10 years has led to the development of cost-effective genetic assays for early diagnosis of hereditary haemochromatosis (HH). A genetic predisposition for this relatively common autosomal recessive disease has been identified in approximately 1 in 100 South Africans of European descent.If left untreated, this condition may lead to organ damage presenting as cirrhosis, liver cancer, diabetes, arthritis, impotence, sterility and/or cardiac disease. Due to the fact that serum iron parameters are frequently affected by factors such as liver disease and inflammation, direct mutation detection has become the method of choice for accurate diagnosis of inherited iron overload in patients with elevated iron stores. Haemochromatosis can be prevented by regular blood donation or phlebotomy and therefore detection of a genetic predisposition at an early age, before irreversible damage to cardiac, hepatic and endocrine tissue occurs, represents an important clinical goal.