Autosomal dominant vasovagal syncope: Clinical features and linkage to chromosome 15q26.
Neurology. 2013 Apr 16;80(16):1485-1493
Authors: Klein KM, Bromhead CJ, Smith KR, O'Callaghan CJ, Corcoran SJ, Heron SE, Iona X, Hodgson BL, McMahon JM, Lawrence KM, Scheffer IE, Dibbens LM, Bahlo M, Berkovic SF
OBJECTIVE: To establish the occurrence of an autosomal dominant form of vasovagal syncope (VVS) by detailed phenotyping of multiplex families and identification of the causative locus. METHODS: Patients with VVS and a family history of syncope were recruited. A standardized questionnaire was administered to all available family members and medical records were reviewed. Of 44 families recruited, 6 were suggestive of autosomal dominant inheritance. Genome-wide linkage was performed in family A using single nucleotide polymorphism genotyping microarrays. Targeted analysis of chromosome 15q26 with microsatellite markers was implemented in 4 families; 1 family was too small for analysis. RESULTS: Family A contained 30 affected individuals over 3 generations with a median onset of 8 to 9 years. The other families comprised 4 to 14 affected individuals. Affected individuals reported typical triggers of VVS (sight of blood, injury, medical procedures, prolonged standing, pain, frightening thoughts). The triggers varied considerably within the families. Significant linkage to chromosome 15q26 (logarithm of odds score 3.28) was found in family A. Linkage to this region was excluded in 2 medium-sized families but not in 2 smaller families. Sequence analysis of the candidate genes SLCO3A1, ST8SIA2, and NR2F2 within the linkage interval did not reveal any mutations. CONCLUSIONS: Familial VVS, inherited in an autosomal dominant manner, may not be rare and has similar features to sporadic VVS. The chromosome 15q26 locus in family A increases the susceptibility to VVS but does not predispose to a particular vasovagal trigger. Linkage analysis in the remaining families established likely genetic heterogeneity.
PMID: 23589636 [PubMed - as supplied by publisher]
The Role of Memory-related Gene WWC1 (KIBRA) in Lifetime Posttraumatic Stress Disorder: Evidence from Two Independent Samples from African Conflict Regions.
Biol Psychiatry. 2013 Apr 10;
Authors: Wilker S, Kolassa S, Vogler C, Lingenfelder B, Elbert T, Papassotiropoulos A, de Quervain DJ, Kolassa IT
BACKGROUND: Posttraumatic stress disorder (PTSD) results from the formation of a strong memory for the sensory-perceptual and affective representations of traumatic experiences, which is detached from the corresponding autobiographical context information. Because WWC1, the gene encoding protein KIBRA, is associated with long-term memory performance, we hypothesized that common WWC1 alleles influence the risk for a lifetime diagnosis of PTSD. METHODS: Traumatic load and diagnosis of current and lifetime PTSD were assessed in two independent African samples of survivors from conflict zones who had faced severe trauma (n = 392, Rwanda, and n = 399, Northern Uganda, respectively). Array-based single nucleotide polymorphism (SNP) genotyping was performed. The influence of WWC1 tagging SNPs and traumatic load on lifetime PTSD was estimated by means of logistic regression models with correction for multiple comparisons in the Rwandan sample. Replication analysis was performed in the independent Ugandan sample. RESULTS: An association of two neighboring SNPs in almost complete linkage disequilibrium, rs10038727 and rs4576167, with lifetime PTSD was discovered in the Rwandan sample. Although each traumatic event added to the probability of lifetime PTSD in a dose-dependent manner in both genotype groups, carriers of the minor allele of both SNPs displayed a diminished risk (p = .007, odds ratio = .29 [95% confidence interval = .15-.54]). This effect was confirmed in the independent Ugandan sample. CONCLUSIONS: This study reveals an association between two WWC1 SNPs and the likelihood of PTSD development, indicating that this memory-related gene might be involved in processes that occur in response to traumatic stress and influence the strengthening of fear memories.
PMID: 23582269 [PubMed - as supplied by publisher]
Low penetrance susceptibility to glioma is caused by the TP53 variant rs78378222.
Br J Cancer. 2013 Apr 9;
Authors: Enciso-Mora V, Hosking FJ, Stefano AL, Zelenika D, Shete S, Broderick P, Idbaih A, Delattre JY, Hoang-Xuan K, Marie Y, Labussière M, Alentorn A, Ciccarino P, Rossetto M, Armstrong G, Liu Y, Gousias K, Schramm J, Lau C, Hepworth SJ, Schoemaker M, Strauch K, Müller-Nurasyid M, Schreiber S, Franke A, Moebus S, Eisele L, Swerdlow A, Simon M, Bondy M, Lathrop M, Sanson M, Houlston RS
Background:Most of the heritable risk of glioma is presently unaccounted for by mutations in known genes. In addition to rare inactivating germline mutations in TP53 causing glioma in the context of the Li-Fraumeni syndrome, polymorphic variation in TP53 may also contribute to the risk of developing glioma.Methods:To comprehensively evaluate the impact of variation in TP53 on risk, we analysed 23 tagSNPs and imputed 2377 unobserved genotypes in four series totaling 4147 glioma cases and 7435 controls.Results:The strongest validated association signal was shown by the imputed single-nucleotide polymorphism (SNP) rs78378222 (P=6.86 × 10(-24), minor allele frequency ∼0.013). Confirmatory genotyping confirmed the high quality of the imputation. The association between rs78378222 and risk was seen for both glioblastoma multiforme (GBM) and non-GBM tumours. We comprehensively examined the relationship between rs78378222 and overall survival in two of the case series totaling 1699 individuals. Despite employing statistical tests sensitive to the detection of differences in early survival, no association was shown.Conclusion:Our data provided strong validation of rs78378222 as a risk factor for glioma but do not support the tenet that the polymorphism being a clinically useful prognostic marker. Acquired TP53 inactivation is a common feature of glioma. As rs78378222 changes the polyadenylation signal of TP53 leading to impaired 3'-end processing of TP53 mRNA, the SNP has strong plausibility for being directly functional contributing to the aetiological basis of glioma.British Journal of Cancer advance online publication, 9 April 2013; doi:10.1038/bjc.2013.155 www.bjcancer.com.
PMID: 23571737 [PubMed - as supplied by publisher]
High-Quality and -Quantity DNA Extraction from Frozen Archival Blood Clots for Genotyping of Single-Nucleotide Polymorphisms.
Genet Test Mol Biomarkers. 2013 Apr 10;
Authors: Bank S, Nexø BA, Andersen V, Vogel U, Andersen PS
Background: The recovery of biological samples for genetic epidemiological studies can be cumbersome. Blood clots are routinely collected for serological examinations. However, the extraction of DNA from blood clots can be difficult and often results in low yields. Aim: The aim was to compare the efficiency of commercial purification kits for extracting DNA from long-term frozen clotted blood. Methods: Serum tubes with clotted blood were stored at -20°C for 1 to 2.5 years before DNA extraction. DNA was extracted from 10 blood clot samples using PureGene (Qiagen) with and without glycogen, the QIAamp DNA Micro kit (Qiagen), and the Nucleospin 96 Blood kit (Macherey-Nagel). Furthermore, blood clots from 1055 inflammatory bowel disease patients were purified using the Maxwell 16 Blood purification kit (Promega). The DNA was extracted according to the manufacturers` instructions and real-time PCR and the A260/A280 ratio were used to evaluate the quality of the extracted DNA. Results: The highest DNA yield was obtained by the Maxwell 16 Blood purification kit (Promega) with a median of 4.90 μg (range 0.8-25 μg) pr 300 μL total blood. PureGene with glycogen (Qiagen) had the second highest yield with a median of 0.65 μg (range 0.5-2.6 μg) pr 300 μL total blood. Conclusion: The yield obtained by the different commercial kits varied considerably. Our work demonstrates that high-quality and -quantity DNA can be extracted with the Maxwell 16 Blood purification kit (Promega) from cryopreserved blood clots, even after prolonged storage. The recovered DNA served as a reliable PCR template for single-nucleotide polymorphism assays.
PMID: 23574531 [PubMed - as supplied by publisher]