The exon 13 duplication in the BRCA1 gene is a founder mutation present in geographicaly diverse populations

Recently, a 6-kb duplication of exon 13, which creates a frameshift in the coding sequence of the BRCA1 gene, has been described in three unrelated U.S. families of European ancestry and in one Portuguese family. Here, our goal was to estimate the frequency and geographic diversity of carriers of this duplication. To do this, a collaborative screening study was set up that involved 39 institutions from 19 countries and included 3,580 unrelated individuals with a family history of the disease and 934 early-onset breast and/or ovarian cancer cases. A total of 11 additional families carrying this mutation were identified in Australia (1), Belgium (1), Canada (1), Great Britain (6), and the United States (2). Haplotyping showed that they are likely to derive from a common ancestor, possibly of northern British origin. Our results demonstrate that it is strongly advisable, for laboratories carrying out screening either in English-speaking countries or in countries with historical links with Britain, to include within their BRCA1 screening protocols the polymerase chain reaction-based assay described in this report

Innate pro-B cell progenitors protect against type 1 diabetes by regulating autoimmune effector T cells.

International audienc

Agreement for depression diagnosis between DSM-IV-TR criteria, three validated scales, oncologist assessment, and psychiatric clinical interview in elderly patients with advanced ovarian cancer

International audienceBACKGROUND: Depression, a major outcome in cancer patients, is often evaluated by physicians relying on their clinical impressions rather than patient self-report. Our aim was to assess agreement between patient self-reported depression, oncologist assessment (OA), and psychiatric clinical interview (PCI) in elderly patients with advanced ovarian cancer (AOC). METHODS: This analysis was a secondary endpoint of the Elderly Women AOC Trial 3 (EWOT3), designed to assess the impact of geriatric covariates, notably depression, on survival in patients older than 70 years of age. Depression was assessed using the Geriatric Depression Scale-30 (GDS), the Hospital Anxiety Depression Scale, the distress thermometer, the mood thermometer, and OA. The interview guide for PCI was constructed from three validated scales: the GDS, the Hamilton Depression Rating Scale, and the Montgomery Asberg Depression Rating Scale (MADRS). The Diagnostic and Statistical Manual of Mental Disorders, fourth edition, revised (DSM) criteria for depression were used as a gold standard. RESULTS: Out of 109 patients enrolled at 21 centers, 99 (91%) completed all the assessments. Patient characteristics were: mean age 78, performance status \textgreater/=2: 47 (47%). Thirty six patients (36%) were identified as depressed by the PCI versus 15 (15%) identified by DSM. We found moderate agreement for depression identification between DSM and GDS (kappa=0.508) and PCI (kappa=0.431) and high agreement with MADRS (kappa=0.663). We found low or no agreement between DSM with the other assessment strategies, including OA (kappa=-0.043). Identification according to OA (yes/no) resulted in a false-negative rate of 87%. As a screening tool, GDS had the best sensitivity and specificity (94% and 80%, respectively). CONCLUSION: The use of validated tools, such as GDS, and collaboration between psychologists and oncologists are warranted to better identify emotional disorders in elderly women with AOC

Variants in USP48 encoding ubiquitin hydrolase are associated with autosomal dominant non-syndromic hereditary hearing loss.

Non-Syndromic Hereditary Hearing Loss (NSHHL) is a genetically heterogeneous sensory disorder with about 120 genes already associated. Through exome sequencing (ES) and data aggregation, we identified a family with six affected individuals and one unrelated NSHHL patient with predicted-to-be deleterious missense variants in USP48. We also uncovered an eighth patient presenting unilateral cochlear nerve aplasia and a de novo splice variant in the same gene. USP48 encodes a ubiquitin carboxyl-terminal hydrolase under evolutionary constraint. Pathogenicity of the variants is supported by in vitro assays that showed that the mutated proteins are unable to hydrolyze tetra-ubiquitin. Correspondingly, three-dimensional representation of the protein containing the familial missense variant is situated in a loop that might influence the binding to ubiquitin. Consistent with a contribution of USP48 to auditory function, immunohistology showed that the encoded protein is expressed in the developing human inner ear, specifically in the spiral ganglion neurons, outer sulcus, interdental cells of the spiral limbus, stria vascularis, Reissner's membrane and in the transient Kolliker's organ that is essential for auditory development. Engineered zebrafish knocked-down for usp48, the USP48 ortholog, presented with a delayed development of primary motor neurons, less developed statoacoustic neurons innervating the ears, decreased swimming velocity and circling swimming behavior indicative of vestibular dysfunction and hearing impairment. Corroboratingly, acoustic startle response assays revealed a significant decrease of auditory response of zebrafish lacking usp48 at 600 and 800 Hz wavelengths. In conclusion, we describe a novel autosomal dominant NSHHL gene through a multipronged approach combining ES, animal modeling, immunohistology and molecular assays