Screening of male breast cancer and of breast-ovarian cancer families for BRCA2 mutations using large bifluorescent amplicons

41 breast cancer or breast-ovarian cancer families, including 12 families with at least one affected first-degree male relative, were screened for mutations in the BRCA2 gene. Mutations had not been found in the BRCA1 gene of these families. Chemical cleavage of Mismatch was used to identify nucleotide changes within large PCR products (average size 1.2 kb) that carried strand-specific fluorescent end-labels. 15 amplicons were sufficient to scan 18 exons, including the large exon 11. The remaining 9 small exons were examined by Denaturing Gradient Gel Electrophoresis. The high sensitivity of this approach was documented by the detection, in these 41 patients, of all 9 exonic single nucleotide polymorphisms reported with heterozygosity >0.1. Truncating BRCA2 mutations were found in 7 of the 41 families. 3 of them were in the group of 12 families comprising cases of male breast cancer. Since the methods used here have no bias for particular types of mutations, these data confirm the high proportion of frameshifts among mutations in BRCA2. However, relevant single nucleotide substitutions were also found: one resulting in a stop codon and another one, present in a male patient, was the previously reported change Asp2723His, that affects a highly conserved region of the BRCA2 protein. This study indicates a BRCA2 contribution of 10% (95% CI 2.5–17.5) to our original cohort of 59 breast-ovarian cancer families, whereas the contribution of BRCA1 had been estimated at 46% (95% CI 33–59). © 2001 Cancer Research Campaign http://www.bjcancer.co

Attempts to detect retrotransposition and de novo deletion of Alus and other dispersed repeats at specific loci in the human genome

Dispersed repeat elements contribute to genome instability by de novo insertion and unequal recombination between repeats. To study the dynamics of these processes, we have developed single DNA molecule approaches to detect de novo insertions at a single locus and Alu-mediated deletions at two different loci in human genomic DNA. Validation experiments showed these approaches could detect insertions and deletions at frequencies below 10(-6) per cell. However, bulk analysis of germline (sperm) and somatic DNA showed no evidence for genuine mutant molecules, placing an upper limit of insertion and deletion rates of 2 x 10(-7) and 3 x 10(-7), respectively, in the individuals tested. Such re-arrangements at these loci therefore occur at a rate lower than that detectable by the most sensitive methods currently available

S100B is not a reliable prognostic index in paediatric TBI.

Pediatr Neurosurg. 2007;43(4):258-64

Increased risk of breast cancer among female relatives of patients with ataxia-telangiectasia: a causal relationship?

International audienc

Risk estimation as a decision-making tool for genetic analysis of the breast cancer susceptibility genes. EC Demonstration Project on Familial Breast Cancer.

For genetic counselling of a woman on familial breast cancer, an accurate evaluation of the probability that she carries a germ-line mutation is needed to assist in making decisions about genetic-testing. We used data from eight collaborating centres comprising 618 families (346 breast cancer only, 239 breast or ovarian cancer) recruited as research families or counselled for familial breast cancer, representing a broad range of family structures. Screening was performed in affected women from 618 families for germ-line mutations in BRCA1 and in 176 families for BRCA2 mutations, using different methods including SSCP, CSGE, DGGE, FAMA and PTT analysis followed by direct sequencing. Germ-line BRCA1 mutations were detected in 132 families and BRCA2 mutations in 16 families. The probability of being a carrier of a dominant breast cancer gene was calculated for the screened individual under the established genetic model for breast cancer susceptibility, first, with parameters for age-specific penetrances for breast cancer only [7] and, second, with age-specific penetrances for ovarian cancer in addition [20]. Our results indicate that the estimated probability of carrying a dominant breast cancer gene gives a direct measure of the likelihood of detecting mutations in BRCA1 and BRCA2. For breast/ovarian cancer families, the genetic model according to Narod et al. [20] is preferable for calculating the proband's genetic risk, and gives detection rates that indicate a 50% sensitivity of the gene test. Due to the incomplete BRCA2 screening of the families, we cannot yet draw any conclusions with respect to the breast cancer only families

Stability data, irregular connections and tropical curves

We study a class of meromorphic connections nabla(Z) on P^1, parametrised by the central charge Z of a stability condition, with values in a Lie algebra of formal vector fields on a torus. Their definition is motivated by the work of Gaiotto, Moore and Neitzke on wall-crossing and three-dimensional field theories. Our main results concern two limits of the families nabla(Z) as we rescale the central charge Z to RZ. In the R to 0 ``conformal limit'' we recover a version of the connections introduced by Bridgeland and Toledano Laredo (and so the Joyce holomorphic generating functions for enumerative invariants), although with a different construction yielding new explicit formulae. In the R to infty ``large complex structure" limit the connections nabla(Z) make contact with the Gross-Pandharipande-Siebert approach to wall-crossing based on tropical geometry. Their flat sections display tropical behaviour, and also encode certain tropical/relative Gromov-Witten invariants

Forward and backward digit span difficulties in children with specific learning disorder

This study examined performance in the forward and backward digit span task of the Wechsler Intelligence Scale for Children–Fourth Edition (WISC–IV) in a large group of children with specific learning disorder (SLD) as compared with a group of typically developing children matched for age and sex. Our results further support the hypothesis that the intellectual difficulties of children with SLD involve working memory in the forward digit span task to a greater extent than in the backward digit span task. The correlation of the two spans with a General Ability Index (GAI) was similar in SLD, and smaller in magnitude than in typically developing children. Despite a GAI within normal range, children with SLD had difficulty with both digit span tasks, but more so for forward span. This pattern was similar for different SLD profiles with clinical diagnoses of dyslexia and mixed disorder, but the impairments were more severe in the latter. Age differences were also investigated, demonstrating larger span impairment in older children with SLD than in younger