Rohan Taylor

Cost-effectiveness of Population Screening for BRCA Mutations in Ashkenazi Jewish Women Compared With Family History–Based Testing

Background: Population-based testing for BRCA1/2 mutations detects the high proportion of carriers not identified by cancer family history (FH)–based testing. We compared the cost-effectiveness of population-based BRCA testing with the standard FH-based approach in Ashkenazi Jewish (AJ) women. Methods: A decision-analytic model was developed to compare lifetime costs and effects amongst AJ women in the UK of BRCA founder-mutation testing amongst: 1) all women in the population age 30 years or older and 2) just those with a strong FH (≥10% mutation risk). The model assumes that BRCA carriers are offered risk-reducing salpingo-oophorectomy and annual MRI/mammography screening or risk-reducing mastectomy. Model probabilities utilize the Genetic Cancer Prediction through Population Screening trial/published literature to estimate total costs, effects in terms of quality-adjusted life-years (QALYs), cancer incidence, incremental cost-effectiveness ratio (ICER), and population impact. Costs are reported at 2010 prices. Costs/outcomes were discounted at 3.5%. We used deterministic/probabilistic sensitivity analysis (PSA) to evaluate model uncertainty. Results: Compared with FH-based testing, population-screening saved 0.090 more life-years and 0.101 more QALYs resulting in 33 days’ gain in life expectancy. Population screening was found to be cost saving with a baseline-discounted ICER of -£2079/QALY. Population-based screening lowered ovarian and breast cancer incidence by 0.34% and 0.62%. Assuming 71% testing uptake, this leads to 276 fewer ovarian and 508 fewer breast cancer cases. Overall, reduction in treatment costs led to a discounted cost savings of £3.7 million. Deterministic sensitivity analysis and 94% of simulations on PSA (threshold £20000) indicated that population screening is cost-effective, compared with current NHS policy. Conclusion: Population-based screening for BRCA mutations is highly cost-effective compared with an FH-based approach in AJ women age 30 years and older.

CHEK2 variants in susceptibility to breast cancer and evidence of retention of the wild type allele in tumours.

We have recently shown that the CHEK2*1100delC mutation acts as a low penetrance breast cancer susceptibility allele. To investigate if other CHEK2 variants confer an increased risk of breast cancer, we have screened an affected individual with breast cancer from 68 breast cancer families. Five of these individuals were found to harbour germline variants in CHEK2. Three carried the 1100delC variant (4%). One of these three individuals also carried the missense variant, Arg180His. In the other two individuals, missense variants, Arg117Gly and Arg137Gln, were identified. These two missense variants reside within the Forkhead-associated domain of CHEK2, which is important for the function of the expressed protein. None of these missense variants were present in 300 healthy controls. Microdissected tumours with a germline mutation showed loss of the mutant allele suggesting a mechanism for tumorigenesis other than a loss of the wild type allele. This study provides further evidence that sequence variation in CHEK2 is associated with an increased risk of breast cancer, and implies that tumorigenesis in association with CHEK2 mutations does not involve loss of the wild type allele.

Population Testing for Cancer Predisposing BRCA1/BRCA2 Mutations in the Ashkenazi-Jewish Community: A Randomized Controlled Trial

Background: Technological advances raise the possibility of systematic population-based genetic testing for cancer-predisposing mutations, but it is uncertain whether benefits outweigh disadvantages. We directly compared the psychological/quality-of-life consequences of such an approach to family history (FH)–based testing. Methods: In a randomized controlled trial of BRCA1/2 gene-mutation testing in the Ashkenazi Jewish (AJ) population, we compared testing all participants in the population screening (PS) arm with testing those fulfilling standard FH-based clinical criteria (FH arm). Following a targeted community campaign, AJ participants older than 18 years were recruited by self-referral after pretest genetic counseling. The effects of BRCA1/2 genetic testing on acceptability, psychological impact, and quality-of-life measures were assessed by random effects regression analysis. All statistical tests were two-sided. Results: One thousand, one hundred sixty-eight AJ individuals were counseled, 1042 consented, 1034 were randomly assigned (691 women, 343 men), and 1017 were eligible for analysis. Mean age was 54.3 (SD = 14.66) years. Thirteen BRCA1/2 carriers were identified in the PS arm, nine in the FH arm. Five more carriers were detected among FH-negative FH-arm participants following study completion. There were no statistically significant differences between the FH and PS arms at seven days or three months on measures of anxiety, depression, health anxiety, distress, uncertainty, and quality-of-life. Contrast tests indicated that overall anxiety (P = .0001) and uncertainty (P = .005) associated with genetic testing decreased; positive experience scores increased (P = .0001); quality-of-life and health anxiety did not change with time. Overall, 56% of carriers did not fulfill clinical criteria for genetic testing, and the BRCA1/2 prevalence was 2.45%. Conclusion: Compared with FH-based testing, population-based genetic testing in Ashkenazi Jews doesn’t adversely affect short-term psychological/quality-of-life outcomes and may detect 56% additional BRCA carriers.

Blood levels of kynurenines, interleukin-23 and soluble human leucocyte antigen-G at different stages of Huntington's disease.

J. Neurochem. (2010) 112, 112–122.

FLT4/VEGFR3 and Milroy disease: novel mutations, a review of published variants and database update.

Milroy disease (MD) is an autosomal dominantly inherited primary lymphedema. In 1998, the gene locus for MD was mapped to 5q35.3 and variants in the VEGFR3 (FLT4) gene, encoding vascular endothelial growth factor receptor 3 (VEGFR3), were identified as being responsible for the majority of MD cases. Several reports have since been published detailing pathogenic FLT4 mutations. To date, a total of 58 different variants in FLT4, 20 of which are unpublished, have been observed in 95 families with MD. A review of published mutations is presented in this update. Furthermore, the unpublished variants are presented including clinical data. Comparison of clinical features in patients and their families with the same mutations reveals incomplete penetrance and variable expression, making genotype–phenotype correlations difficult. Most mutations are missense, but a few deletions and one splicing variant have also been reported. Several animal models have confirmed the role of VEGFR3 in lymphangiogenesis and studies show mutant VEGFR3 receptors are not phosphorylated. Here, an MD patient with the same p.Ile1053Phe change as seen in the Chy mouse is presented for the first time. This finding confirms that this mouse lineage is an excellent model for MD. All the data reviewed here has been submitted to a database based on the Leiden Open (source) Variation Database (LOVD) and is accessible online at www.lovd.nl/flt4.

Distal venous arterialisation for salvage of critically ischaemic inoperable limbs

BACKGROUND Amputation remains the only option in patients with extensive arterial disease in whom conventional bypass operations are not feasible. Up to 10000 amputations for vascular disease are estimated to be done annually. We investigated the use of venous perfusion as an alternative method of limb salvage. METHODS Over 28 months, 18 patients with critical-limb ischaemia underwent bypass procedures to the venous bed of the foot with vein, synthetic graft, or a combination of these as the conduit. Various methods were used to destroy the valves of the venous system. We followed up patients for a mean of 17 months. FINDINGS Three grafts failed immediately after surgery and necessitated major amputation, with one death. One late failure did not necessitate amputation. 15 patients had relief of symptoms and retained a useful pain-free limb with healing of ulcers and gangrene. Two patients with functioning grafts died at 5 months and 13 months, respectively. Three patients had successful further radiological intervention. The overall limb-salvage rate was 83% and the 1-year limb-salvage rate was 75%. INTERPRETATION Distal venous arterialisation is a unique procedure that has exciting possibilities for limb salvage and merits further investigation. Increased use of this procedure may help to lower the number of limbs amputated for vascular disease.

Absence of linkage of Noonan syndrome to the neurofibromatosis type 1 locus.

Eleven families with Noonan syndrome in either two or three generations have been identified. Following the reports of subjects with features of both Noonan syndrome and neurofibromatosis type 1, these pedigrees have been studied using a number of probes at the neurofibromatosis type 1 locus (17q11). A significantly negative lod score was obtained with the intragenic probe NF1-C2, suggesting that the genes for Noonan syndrome and neurofibromatosis type 1 are not contiguous.

Cytosine methylation confers instability on the cardiac troponin T gene in hypertrophic cardiomyopathy

Editor—Hypertrophic cardiomyopathy (HCM) is an inherited disease (MIM 192600, 115195) of the heart muscle, characterised by unexplained left ventricular hypertrophy. HCM is also one of the major causes of sudden cardiac death,1sometimes occurring in young asymptomatic people.2-4Although sporadic forms do rarely occur,5 generally HCM has an autosomal dominant pattern of inheritance caused by mutations of the genes coding for proteins of the cardiac sarcomere. Subjects with HCM caused by mutations in the cardiac troponin T ( cTNT ) gene have been clinically shown to be at increased risk of sudden death,6 which may occur even in the absence of marked morphological abnormalities.7Since incomplete penetrance of the clinical phenotype, measured by ECG and echocardiographic parameters, is one of the hallmarks of “troponin” disease, the identification of cTNT mutation in probands would facilitate identification of “at risk” relatives who may not fulfil clinical diagnostic criteria. In the course of a study undertaken to characterise the cTNT mutation profile in HCM patients, we identified a cluster of mutations in exons 8 and 9. Five out of the 11 mutations published to date in this gene have been found in exons 88 and 9.7-10 We report here a novel Arg94Cys de novo mutation in a female patient presenting with HCM bringing the total of cTNT mutations to 12. Four of the mutations found in exon 9, Arg92Trp, Arg92Gln, Arg94Cys, and Ala104Val, involve C→T transitions (or G→A transitions in the opposite strand) within CpG dinucleotides. Approximately 70% of the cytosines within CpG dinucleotides in the mammalian genome contain highly mutable 5-methyl-cytosine (5mC) residues. These residues are not randomly distributed and the majority of the genome is CpG depleted.11 Although some CpG dinucleotides are found within coding regions, most CpG residues are in CpG islands, …

A PvuII polymorphism in the 5′ flanking region of the apolipoprotein AIV gene: its use to study genetic variation determining serum lipid and apolipoprotein concentration

SummaryWe have used a 1.05-kb unique genomic fragment from the 5′ end of the apolipoprotein (apo) CIII gene to identify a restriction fragment length polymorphism (RFLP) detected with the restriction enzyme PvuII, in the apoCIII-apoAIV intergenic region. In a sample of 220 normolipidaemic individuals from the UK population, the frequency of the rare allele, VB2 is 0.054. The PvuII polymorphism is in apparent linkage equilibrium with three other RFLPs of this gene cluster, detected with the restriction enzymes XmnI, PstI and SstI, but in linkage disequilibrium with an RFLP in the apoCIII gene also detected with PvuII. Taken together, these five RFLPs have a PIC (polymorphism information content) value of 0.8, and therefore are informative for genetic studies. Individuals with the genotype VB1VB2 had lower mean concentrations of apoAI, and HDL-cholesterol than individuals with the genotype VB1VB1. However these differences were not statistically significant.

Novel Mutations in the Duplicated Region of the Polycystic Kidney Disease 1 (PKD1) Gene Provides Supporting Evidence for Gene Conversion

Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common human single-gene disorders, and is the most common inherited form of cystic kidney disease. It is estimated that approximately 85% of ADPKD is due to mutations in the PKD1 gene, which is located on chromosome 16p13.3. Mutation analysis in this gene is difficult, because more than two-thirds of reiterated several times at 16p13.1. In this study, mutation screening in 90 ADPKD patients was carried out on exons in the duplicated region of the PKD1 gene (23-34), using genomic long-range PCR followed by nested PCR and single-strand conformation polymorphism (SSCP), and finally cycle sequencing. Two nonconservative missense mutations were detected in exons 25 and 31, and two conservative mutations were found in exons 24 and 29. A novel splicing mutation, which is expected to cause skipping of exon 30, was detected in one case. Moreover, six intronic variants, three silent variants, and one polymorphic variant were detected in this study. Comparison between some of these changes and published sequences from the homologous genes on 16p13.1, revealed supporting evidence for the gene conversion theory as a mechanism responsible for some of the mutations in the PKD1 gene. Factors likely to facilitate gene conversion in this region of the PKD1 gene are discussed.