A specific RAD51 haplotype increases breast cancer risk in Jewish non-Ashkenazi high-risk women

While the precise genes involved in determining familial breast cancer risk in addition to BRCA1/2 are mostly unknown, one strong candidate is RAD51. Jewish non-Ashkenazi women at high-risk for breast/ovarian cancer and ethnically matched controls were genotyped using four single nucleotide polymorphisms spanning the RAD51 genomic region, and the resulting haplotypes were constructed using the GERBIL algorithm. A total of 314 individuals were genotyped: 184 non-Ashkenazi high-risk women (119 with breast cancer), and 130 unaffected, average-risk ethnically matched controls. Using GEBRIL, three frequent haplotypes were constructed. One of the haplotypes (TGTA -coined haplotype 3) was present in 7.3% (19/260 haplotypes) of controls (n = 130) and in 16.8% (40/238 haplotypes) of high-risk breast cancer patients (n = 119, P = 0.001). A specific RAD51 haplotype is more prevalent among non-Ashkenazi Jewish high-risk women than in average-risk population

Ataxia-telangiectasia: Linkage analysis in highly inbred Arab and Druze families and differentiation from an ataxia-microcephaly-cataract syndrome

Ataxia-telangiectasia (A-T) is a progressive autosomal recessive disease featuring neurodegeneration, immunodeficiency, chromosomal instability, radiation sensitivity and a highly increased proneness to cancer. A-T is ethnically widespread and genetically heterogeneous, as indicated by the existence of four complementation groups in this disease. Several "A-T-like" genetic diseases share various clinical and cellular characteristics with A-T. By using linkage analysis to study North American and Turkish A-O families, the ATA (A-T, complementation group A) gene has been mapped to chromosome 11q23. A number of Israeli Arab A-T patients coming from large, highly inbred families were assigned to group A In one of these families, an additional autosomal recessive disease was identified, characterized by ataxia, hypotonia, microcephaly and bilateral congenital cataracts. In two patients with this syndrome, normal levels of serum immunoglobulins and alpha-fetoprotein, chromosomal stability in peripheral blood lymphocytes and skin fibroblasts, and normal cellular response to treatments with X-rays and the radiomimetic drug neocarzinostatin indicated that this disease does not share, with A-T, any additional features other than ataxia. These tests also showed that another patient in this family, who is also mentally retarded, is affected with both disorders. This conclusion was further supported by linkage analysis with 11q23 markers. Lod scores between A-O and these markers, cumulated over three large Arab families, were significant and confirmed the localization of the ATA gene to aq23. However, another Druze family unassigned to a specific complementation group, showed several recombinants between A-T and the same markers, leaving the localization of the A-T gene in this family open

EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy

Vici syndrome is a progressive neurodevelopmental multisystem disorder due to recessive mutations in the key autophagy gene EPG5. We report genetic, clinical, neuroradiological, and neuropathological features of 50 children from 30 families, as well as the neuronal phenotype of EPG5 knock-down in Drosophila melanogaster. We identified 39 different EPG5 mutations, most of them truncating and predicted to result in reduced EPG5 protein. Most mutations were private, but three recurrent mutations (p.Met2242Cysfs*5, p.Arg417*, and p.Gln336Arg) indicated possible founder effects. Presentation was mainly neonatal, with marked hypotonia and feeding difficulties. In addition to the five principal features (callosal agenesis, cataracts, hypopigmentation, cardiomyopathy, and immune dysfunction), we identified three equally consistent features (profound developmental delay, progressive microcephaly, and failure to thrive). The manifestation of all eight of these features has a specificity of 97%, and a sensitivity of 89% for the presence of an EPG5 mutation and will allow informed decisions about genetic testing. Clinical progression was relentless and many children died in infancy. Survival analysis demonstrated a median survival time of 24 months (95% confidence interval 0–49 months), with only a 10th of patients surviving to 5 years of age. Survival outcomes were significantly better in patients with compound heterozygous mutations (P = 0.046), as well as in patients with the recurrent p.Gln336Arg mutation. Acquired microcephaly and regression of skills in long-term survivors suggests a neurodegenerative component superimposed on the principal neurodevelopmental defect. Two-thirds of patients had a severe seizure disorder, placing EPG5 within the rapidly expanding group of genes associated with early-onset epileptic encephalopathies. Consistent neuroradiological features comprised structural abnormalities, in particular callosal agenesis and pontine hypoplasia, delayed myelination and, less frequently, thalamic signal intensity changes evolving over time. Typical muscle biopsy features included fibre size variability, central/internal nuclei, abnormal glycogen storage, presence of autophagic vacuoles and secondary mitochondrial abnormalities. Nerve biopsy performed in one case revealed subtotal absence of myelinated axons. Post-mortem examinations in three patients confirmed neurodevelopmental and neurodegenerative features and multisystem involvement. Finally, downregulation of epg5 (CG14299) in Drosophila resulted in autophagic abnormalities and progressive neurodegeneration. We conclude that EPG5-related Vici syndrome defines a novel group of neurodevelopmental disorders that should be considered in patients with suggestive features in whom mitochondrial, glycogen, or lysosomal storage disorders have been excluded. Neurological progression over time indicates an intriguing link between neurodevelopment and neurodegeneration, also supported by neurodegenerative features in epg5-deficient Drosophila, and recent implication of other autophagy regulators in late-onset neurodegenerative disease

Vascular Behcet and Mutations in Thrombogenic Genes: Methylene Tetrahydrofolate Reductase, Factor V, and Prothrombin

Vasculitis, thrombophlebitis, arterial aneurysms, and occlusions occur in about 25% of patients with Behcet's disease (BD). The common inherited gene defects, factor V (FV) 1691A (Leiden), methylene tetrahydrofolate reductase (MTHFR) 677T, and prothrombin 20210A, are known risk factors for thrombosis. The aim of the study was to evaluate the contribution of these mutations to thrombosis in Israeli patients with BD. Fifty-four patients with BD (n = 54; 27 men and 27 women) underwent clinical and genetic evaluation. Most patients (n = 43; 79.6%) were of Arab descent (31 sporadic and 12 familial cases from 4 families), and 11 patients (20.4%) were of Jewish descent (all sporadic cases). The FV Leiden mutation was identified in five patients (9.2%), and eight patients were MTHFR 677TT homozygotes (14.8%). None had the 20210A mutant prothrombin allele. No statistical differences between carriers and noncarriers with regards to demographic and disease manifestations were calculated. Arabs were diagnosed earlier than Jewish patients (25.8 +/- 11.6 compared with 37.2 +/- 10.7, p = 0.01, respectively), but Jewish patients had, respectively, more events of deep vein thrombosis (DVT) compared with Arabs (3 of 11, 27.3% and 3 of 43, 7%, p = 0.09). Thrombotic events in our patients with BD were not associated with variations in thrombophilic genes

Direct Word Sense Matching for Lexical Substitution

This paper investigates conceptually and empirically the novel sense matching task, which requires to recognize whether the senses of two synonymous words match in context. We suggest direct approaches to the problem, which avoid the intermediate step of explicit word sense disambiguation, and demonstrate their appealing advantages and stimulating potential for future research

Exploring Alzheimer’s Disease Molecular Variability via Calculation of Personalized Transcriptional Signatures

Despite huge investments and major efforts to develop remedies for Alzheimer’s disease (AD) in the past decades, AD remains incurable. While evidence for molecular and phenotypic variability in AD have been accumulating, AD research still heavily relies on the search for AD-specific genetic/protein biomarkers that are expected to exhibit repetitive patterns throughout all patients. Thus, the classification of AD patients to different categories is expected to set the basis for the development of therapies that will be beneficial for subpopulations of patients. Here we explore the molecular heterogeneity among a large cohort of AD and non-demented brain samples, aiming to address the question whether AD-specific molecular biomarkers can progress our understanding of the disease and advance the development of anti-AD therapeutics. We studied 951 brain samples, obtained from up to 17 brain regions of 85 AD patients and 22 non-demented subjects. Utilizing an information-theoretic approach, we deciphered the brain sample-specific structures of altered transcriptional networks. Our in-depth analysis revealed that 7 subnetworks were repetitive in the 737 diseased and 214 non-demented brain samples. Each sample was characterized by a subset consisting of ~1–3 subnetworks out of 7, generating 52 distinct altered transcriptional signatures that characterized the 951 samples. We show that 30 different altered transcriptional signatures characterized solely AD samples and were not found in any of the non-demented samples. In contrast, the rest of the signatures characterized different subsets of sample types, demonstrating the high molecular variability and complexity of gene expression in AD. Importantly, different AD patients exhibiting similar expression levels of AD biomarkers harbored distinct altered transcriptional networks. Our results emphasize the need to expand the biomarker-based stratification to patient-specific transcriptional signature identification for improved AD diagnosis and for the development of subclass-specific future treatment

Privacy and utility of genetic testing in families with hereditary cancer syndromes living in three countries: the international cascade genetic screening experience

Background: Hereditary breast and ovarian cancer and Lynch syndrome are associated with increased lifetime risk for common cancers. Offering cascade genetic testing to cancer-free relatives of individuals with HBOC or LS is a public health intervention for cancer prevention. Yet, little is known about the utility and value of information gained from cascade testing. This paper discusses ELSI encountered during the implementation of cascade testing in three countries with national healthcare systems: Switzerland, Korea, and Israel.Methods: A workshop presented at the 5th International ELSI Congress discussed implementation of cascade testing in the three countries based on exchange of data and experiences from the international CASCADE cohort.Results: Analyses focused on models of accessing genetic services (clinic-based versus population-based screening), and models of initiating cascade testing (patient-mediated dissemination versus provider-mediated dissemination of testing results to relatives). The legal framework of each country, organization of the healthcare system, and socio-cultural norms determined the utility and value of genetic information gained from cascade testing.Conclusion: The juxtaposition of individual versus public health interests generates significant ELSI controversies associated with cascade testing, which compromise access to genetic services and the utility and value of genetic information, despite national healthcare/universal coverage