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Mutation Carriers (mutation + carrier)
Kinds of Mutation Carriers Selected AbstractsParkinson's disease and LRRK2: Frequency of a common mutation in U.S. movement disorder clinicsMOVEMENT DISORDERS, Issue 4 2006Denise M. Kay PhD Abstract The G2019S mutation in the LRRK2 gene is reportedly a common cause of familial Parkinson's disease (PD) and may also have a significant role in nonfamilial PD. The objective of this study was to assess mutation carrier frequency in PD patients from movement disorder clinics in the United States, stratified by family history, age at onset, and geography; to determine carrier frequency in a large and well-characterized control population; to examine segregation of mutation in families of patients; and to correlate genotype with clinical phenotype. One thousand four hundred twenty-five unrelated PD patients from movement disorder clinics in Oregon, Washington, and New York and 1,647 unrelated controls were studied. The G2019S mutation was detected using a TaqMan assay and verified by sequencing. Eighteen of 1,425 patients and one of 1,647 controls had the mutation. Carrier frequency (± 2SE) in patients was 0.013 ± 0.006 overall, 0.030 ± 0.019 in familial PD, 0.007 ± 0.005 in nonfamilial PD, 0.016 ± 0.013 in early-onset PD, and 0.012 ± 0.007 in late-onset PD. Geographic differences were insignificant. Age at onset of mutation carriers ranged from 28 to 71 years. Mutation carriers were clinically indistinguishable from idiopathic PD. LRRK2 G2019S is the single most common pathogenic mutation linked to neurodegenerative disease to date. © 2005 Movement Disorder Society [source] Screening for the BRCA1-ins6kbEx13 mutation: potential for misdiagnosis,,HUMAN MUTATION, Issue 5 2007Susan J Ramus Abstract Misdiagnosis of a germline mutation associated with an inherited disease syndrome can have serious implications for the clinical management of patients. A false negative diagnosis (mutation missed by genetic screening) limits decision making about intervention strategies within families. More serious is the consequence of a false positive diagnosis (genetic test suggesting a mutation is present when it is not). This could lead to an individual, falsely diagnosed as a mutation carrier, undergoing unnecessary clinical intervention, possibly involving risk-reducing surgery. As part of screening 283 ovarian cancer families for BRCA1 mutations, we used two different methods (mutation specific PCR and multiplex ligation-dependant probe amplification) to screen for a known rearrangement mutation L78833.1:g.44369_50449dup (ins6kbEx13). We found false positive and false negative results in several families. We then tested 61 known carriers or non-carriers from an epidemiological study of BRCA1 and BRCA2 mutation carriers (the EMBRACE study). These data highlight the need for caution when interpreting analyses of the ins6kbEx13 mutation and similar mutations, where characterising the exact sequence alteration for a deleterious mutation is not a part of the routine genetic test. © 2007 Wiley-Liss, Inc. [source] Impact of BRCA mutations on female fertility and offspring sex ratio,AMERICAN JOURNAL OF HUMAN BIOLOGY, Issue 2 2010Roxana Moslehi Positive selection for inherited mutations in breast and ovarian cancer predisposing genes, BRCA1 and BRCA2, may contribute to the high frequency of BRCA mutations among the Ashkenazi Jewish population. Impact of BRCA mutations on fertility has not been generally explored in epidemiologic studies. There are reports of distorted sex ratios in BRCA carrier families but these findings have been attributed to bias. We investigated the effect of BRCA mutations on female fertility and offspring sex ratio in a study of 260 Ashkenazi Jewish women with ovarian cancer and 331 controls, unselected for age or family history of the disease. Pregnancy success was similar for 96 mutation carrier (0.84) and 164 noncarrier cases (0.87) and controls (0.83). After adjusting for covariates, there were no significant differences between BRCA carrier and noncarrier cases and controls with regards to fertility, despite lower pregnancy rates among all cases compared to controls (P = 0.0049). Male/female sex ratios were significantly lower among offspring of carriers (0.71) than offspring of noncarriers (0.95) or those of the controls (0.99). Comparisons among the three groups yielded statistically significant distortion against males among the offspring of known and obligate BRCA carriers compared to noncarriers (OR = 0.74, 95% CI:0.55,0.99) and controls (OR = 0.71, 95% CI:0.54,0.94). In conclusion, we did not find evidence for an effect of BRCA mutations on female fertility. We found a significant excess of females among the offspring of female carriers of BRCA1 and BRCA2 mutations. Potential contribution of observed sex ratio distortions to positive selection for BRCA mutations may warrant further investigation. Am. J. Hum. Biol., 2010. © 2009 Wiley-Liss, Inc. [source] First appraisal of brain pathology owing to A30P mutant alpha-synucleinANNALS OF NEUROLOGY, Issue 5 2010Kay Seidel PhD Familial Parkinson disease (PD) due to the A30P mutation in the SNCA gene encoding alpha-synuclein is clinically associated with PD symptoms. In this first pathoanatomical study of the brain of an A30P mutation carrier, we observed neuronal loss in the substantia nigra, locus coeruleus, and dorsal motor vagal nucleus, as well as widespread occurrence of alpha-synuclein immunopositive Lewy bodies, Lewy neurites, and glial aggregates. Alpha-synuclein aggregates ultrastructurally resembled Lewy bodies, and biochemical analyses disclosed a significant load of insoluble alpha-synuclein, indicating neuropathological similarities between A30P disease patients and idiopathic PD, with a more severe neuropathology in A30P carriers. ANN NEUROL 2010;67:684,689 [source] Heterogeneity in young adult onset diabetes: aetiology alters clinical characteristicsDIABETIC MEDICINE, Issue 9 2002K. R. Owen Abstract Aims To describe the characteristics of hepatocyte nuclear factor (HNF) 1, mutation carriers diagnosed with diabetes after 25 years and compare them with young-onset Type 2 diabetic patients (YT2D) diagnosed at the same age. Subjects and methods We studied 44 (21 male, 23 female) patients with HNF-1, mutations diagnosed with diabetes at ages 25,45 years and 44 YT2D subjects matched for sex and age of diagnosis. Results Median age of onset of diabetes was 35 years in both groups. The HNF-1, group demonstrated: lower body mass index (25.1 vs. 30.7 kg/m2; P < 0.001) and lower fasting triglycerides (1.37 vs. 2.96 mmol/l; P = 0.001) with similar fasting cholesterol level. They had lower glycated haemoglobin A1c (7.3 vs. 8.5%; P = 0.015) despite greater duration of diabetes (24 vs. 16 years; P = 0.02) and less frequent treatment with insulin (21% vs. 55%; P = 0.002). They were less likely to be treated for hypertension (13.3% vs. 56.3%; P = 0.009). Importantly, no difference was observed in reported parental history of diabetes between the two groups (65.9% vs. 63.6%; P = 0.92). Logistic regression showed that triglyceride levels and presence of anti-hypertensive treatment were the most important independent variables. Conclusions Patients with HNF-1, mutations may present with diabetes as young adults between the ages of 25,45 years. In this age range a wide differential diagnosis of diabetes is observed. Conventional criteria of age of onset and family history will not differentiate HNF-1, mutation carriers from YT2D subjects in this age range, but features of the metabolic syndrome, in particular fasting triglycerides and hypertension, are helpful. In patients diagnosed before 45 years without features of insulin resistance the diagnosis of HNF-1, should be considered. [source] Autonomic symptoms in patients and pre-manifest mutation carriers of Huntington's diseaseEUROPEAN JOURNAL OF NEUROLOGY, Issue 8 2010N. A. Aziz Background and purpose:, Although autonomic function tests have revealed abnormalities of the autonomic nervous system in Huntington's disease (HD), autonomic symptoms and their association with other symptoms and signs of HD have not yet been assessed in large groups of patients or pre-manifest mutation carriers. Therefore, we aimed at delineating the characteristics and correlates of autonomic symptoms in HD. Methods:, Using the scales for outcomes in Parkinson's disease-autonomic symptoms (SCOPA-AUT) and Beck Depression Inventory questionnaires, autonomic symptoms and depressed mood were assessed in 63 patients with HD, 21 pre-manifest mutation carriers, and 85 controls. The Unified Huntington's Disease Rating Scale was used to assess other HD symptoms and signs. Results:, Relative to controls, patients with HD experienced significantly more gastrointestinal, urinary, cardiovascular and, in men, sexual problems. The most prevalent symptoms were swallowing difficulties, erection and ejaculation problems, dysphagia, sialorrhea, early abdominal fullness, straining for defecation, fecal and urinary incontinence, urgency, incomplete bladder emptying, and light-headedness whilst standing. Pre-manifest mutation carriers experienced significantly more swallowing difficulties and light-headedness on standing up compared with controls. In patients with HD, autonomic symptoms were associated with a greater degree of functional disability, more severe depression, and antidepressant drugs use. However, depression was the only independent predictor of autonomic dysfunction. Conclusions:, Autonomic symptoms are highly prevalent in patients with HD and may even precede the onset of motor signs. Moreover, autonomic dysfunction is related to functional disability and depression in HD. [source] Erratum: Genomic alterations in histopathologically normal breast tissue from BRCA1 mutation carriers may be caused by BRCA1 haploinsufficiencyGENES, CHROMOSOMES AND CANCER, Issue 8 2010Karin Rennstam No abstract is available for this article. [source] ERBB2, TBX2, RPS6KB1, and MYC alterations in breast tissues of BRCA1 and BRCA2 mutation carriersGENES, CHROMOSOMES AND CANCER, Issue 1 2004Camilo Adem Breast cancer risk is greatly increased in women who carry mutations in the BRCA1 or BRCA2 genes. Because breast cancer initiation is different between BRCA1/2 mutation carriers and women who do not carry mutations, it is possible that the mechanism of breast cancer progression is also different. Histopathologic and genetic studies have supported this hypothesis. To test this hypothesis further, we utilized a large cohort of women who underwent therapeutic mastectomy (TM) and contralateral prophylactic mastectomy (PM). From this cohort, we developed case groups of women with a family history of breast cancer with BRCA1/2 deleterious mutations, with unclassified variant alterations, and with no detected mutation and matched these cases with sporadic controls from the same TM and PM cohort. Fluorescence in situ hybridization was performed on paraffin sections by use of dual-color probes for ERBB2/CEP17, MYC/CEP8, TBX2/CEP17, and RPS6KB1/CEP17. All malignant and benign lesions, including putative precursor lesions, were studied. The invasive cancers from deleterious mutation carriers had a higher prevalence of duplication of MYC (P = 0.006) and TBX2 (P = 0.0008) compared to controls and a lower prevalence of ERBB2 amplification (P = 0.011). Coduplication of MYC and TBX2 was common in the in situ and invasive lesions from the deleterious mutation carriers. The odds ratio of having a BRCA1/2 mutation is 31.4 (95% CI = 1.7,569) when MYC and TBX2 are coduplicated but ERBB2 is normal. Unclassified variant carriers/no mutation detected and sporadic controls had a similar prevalence of alterations, suggesting that hereditary patients with no deleterious mutations follow a progression pathway similar to that of sporadic cases. With the exception of one atypical ductal hyperplasia lesion, no putative precursor lesion showed any detectable alteration of the probes tested. There was no significant intratumoral heterogeneity of genetic alterations. Our data confirm that a specific pattern of genomic instability characterizes BRCA1/2 -related cancers and that this pattern has implications for the biology of these cancers. Moreover, our current and previous results emphasize the interaction between phenotype and genotype in BRCA1/2 -related breast cancers and that a combination of morphologic features and alterations of ERBB2, MYC, and TBX2 may better define mechanisms of tumor progression, as well as determine which patients are more likely to carry BRCA1/2 mutations. © 2004 Wiley-Liss, Inc. [source] Optimal designs for estimating penetrance of rare mutations of a disease-susceptibility geneGENETIC EPIDEMIOLOGY, Issue 3 2003Gail Gong Abstract Many clinical decisions require accurate estimates of disease risks associated with mutations of known disease-susceptibility genes. Such risk estimation is difficult when the mutations are rare. We used computer simulations to compare the performance of estimates obtained from two types of designs based on family data. In the first (clinic-based designs), families are ascertained because they meet certain criteria concerning multiple disease occurrences among family members. In the second (population-based designs), families are sampled through a population-based registry of affected individuals called probands, with oversampling of probands whose families are more likely to segregate mutations. We generated family structures, genotypes, and phenotypes using models that reflect the frequencies and penetrances of mutations of the BRCA1/2 genes. We studied the effects of risk heterogeneity due to unmeasured, shared risk factors by including risk variation due to unmeasured genotypes of another gene. The simulations were chosen to mimic the ascertainment and selection processes commonly used in the two types of designs. We found that penetrance estimates from both designs are nearly unbiased in the absence of unmeasured shared risk factors, but are biased upward in the presence of such factors. The bias increases with increasing variation in risks across genotypes of the second gene. However, it is small compared to the standard error of the estimates. Standard errors from population-based designs are roughly twice those from clinic-based designs with the same number of families. Using the root-mean-square error as a measure of performance, we found that in all instances, the clinic-based designs gave more accurate estimates than did the population-based designs with the same numbers of families. Rough variance calculations suggest that clinic-based designs give more accurate estimates because they include more identified mutation carriers. Genet Epidemiol 24:173,180, 2003. © 2003 Wiley-Liss, Inc. [source] G-substrate gene promoter SNP (,1323T>C) modifies plasma total cholesterol and triglyceride phenotype in familial hypercholesterolemia: Intra-familial association study in an eight-generation hyperlipidemic kindredGERIATRICS & GERONTOLOGY INTERNATIONAL, Issue 2 2004Yukiko Nobe Background: Plasma lipid and lipoprotein generally reflect the complex influences of multiple genetic loci, for instance, even familial hypercholesterolemia (FH), a representative example of monogenic hyperlipidemia, often presents with phenotypic heterogeneity. Methods: In the course of investigating familial coronary artery disease in Utah, we studied 160 members of an eight-generation extended family of FH, to examine possible genetic modification of lipoprotein phenotype by ,modifier locus'. G-substrate (GSBS) is an endogenous substrate for cGMP-dependent protein kinase. We carried out an intrafamilial correlation analysis of modifier effect of ,1323T>C substitution in the GSBS gene among 85 LDLR-mutation carriers and 75 non-carriers. Results: In the LDLR - mutation carriers, the plasma cholesterol levels were highest among ,1323C homozygotes (mean ± SD = 454 ± 101 mg/dL), lowest among ,1323T homozygotes (mean ± SD, 307 ± 72 mg/dL) and intermediate among ,1323T/C heterozygotes (mean ± SD, 314 ± 62 mg/dL; P = 0.015). Similarly, in the LDLR-mutation carriers, the plasma triglyceride levels were highest among ,1323C homozygotes (mean ± SD, 371 ± 381 mg/dL), lowest among ,323T homozygotes (mean ± SD, 171 ± 94 mg/dL), and intermediate among ,1323T/C heterozygotes (mean ± SD, 218 ± 130 mg/dL; P = 0.003). No such gene-interactive effect was observed among non-carriers of the LDLR-mutation. Conclusion: These results indicate a significant modification of the phenotype of FH with defective LDLR allele, by GSBS-1323C allele in the kindred studied. [source] Triple negative tumours: a critical reviewHISTOPATHOLOGY, Issue 1 2008J S Reis-Filho Breast cancer is a heterogeneous disease that encompasses several distinct entities with remarkably different biological characteristics and clinical behaviour. Currently, breast cancer patients are managed according to algorithms based on a constellation of clinical and histopathological parameters in conjunction with assessment of hormone receptor (oestrogen and progesterone receptor) status and HER2 overexpression/gene amplification. Although effective tailored therapies have been developed for patients with hormone receptor-positive or HER2+ disease, chemotherapy is the only modality of systemic therapy for patients with breast cancers lacking the expression of these markers (triple-negative cancers). Recent microarray expression profiling analyses have demonstrated that breast cancers can be systematically characterized into biologically and clinically meaningful groups. These studies have led to the re-discovery of basal-like breast cancers, which preferentially show a triple-negative phenotype. Both triple-negative and basal-like cancers preferentially affect young and African-American women, are of high histological grade and have more aggressive clinical behaviour. Furthermore, a significant overlap between the biological and clinical characteristics of sporadic triple-negative and basal-like cancers and breast carcinomas arising in BRCA1 mutation carriers has been repeatedly demonstrated. In this review, we critically address the characteristics of basal-like and triple-negative cancers, their similarities and differences, their response to chemotherapy as well as strategies for the development of novel therapeutic targets for these aggressive types of breast cancer. In addition, the possible mechanisms are discussed leading to BRCA1 pathway dysfunction in sporadic triple-negative and basal-like cancers and animal models for these tumour types. [source] Histopathological features of breast cancer in carriers of ATM gene variantsHISTOPATHOLOGY, Issue 5 2006R L Balleine Aims:, Germline variants in the ataxia telangiectasia mutated (ATM) gene have been implicated in increased breast cancer risk. The aim of this study was to determine whether the histopathology of breast cancers occurring in ATM variant carriers is distinctive or resembles the described BRCA1 mutation-associated phenotype. Methods:, The histopathological features of breast cancers occurring in ATM variant carriers from multiple-case breast cancer families were compared with matched controls. The test group included 21 cases of in situ and/or invasive cancer from carriers of either the IVS10-6T,G, 2424V,G or 1420L,F ATM variants in the absence of BRCA1 or BRCA2 mutations. An additional four invasive cancers from carriers of a pathogenic BRCA1 mutation in the context of a familial ATM variant were also examined. Results:, The histopathology of breast cancers in ATM variant-only carriers was not significantly different from controls and known features of BRCA1 mutation-associated cancer were rarely seen. In contrast, these features were prominent in the small group of cases with a pathogenic BRCA1 mutation. Conclusions:, Breast cancer occurring in carriers of ATM variants is not associated with distinctive histopathological features and does not resemble the tumour phenotype commonly observed in BRCA1 mutation carriers. [source] Deletions removing the last exon of TACSTD1 constitute a distinct class of mutations predisposing to Lynch syndrome,HUMAN MUTATION, Issue 2 2009Marietta E. Kovacs Abstract Several different genetic alterations in the etiology of Lynch syndrome (hereditary nonpolyposis colorectal cancer [HNPCC]) are known, mostly point mutations and genomic rearrangements in 1 of at least 3 mismatch-repair (MMR) genes. However, no susceptibility factor has yet been identified in a significant part (30,50%) of clinicopathologically well-defined HNPCC families, suggesting the presence of other predisposing mechanisms. In a set of probands from 27 Lynch syndrome families who lacked evidence of a germline mutation in either the MSH2 or MLH1 gene, we performed genomic deletion screening with the use of multiplex ligation-dependent probe amplification (MLPA) and sequencing. We used immunohistochemistry (IHC) and microsatellite instability (MSI) analyses on samples of the probands of all families. Comparative analysis of mRNA transcripts was performed on blood leukocyte,derived samples from mutation carriers and noncarrier controls. We report that large germline deletions encompassing the last exons of the TACSTD1 gene, upstream of MSH2, cosegregate with the HNPCC phenotype in 19% (5/27) of families tested. The tumors of the carriers show high-level MSI and MSH2 protein loss. We show that these deletions, by removing the transcriptional termination sequences of the upstream gene, give rise to multiple TACSTD1/MSH2 fusion transcripts. Our results provide evidence that deletions removing the last exon of TACSTD1 constitute a distinct class of mutations predisposing to Lynch syndrome. Thus, analysis of the 3, region of the TACSTD1 gene should be included in the routine mutation screening protocols for HNPCC. Hum Mutat 30, 197,203, 2009. © 2009 Wiley-Liss, Inc. [source] Molecular characterization of novel progranulin (GRN) mutations in frontotemporal dementia,HUMAN MUTATION, Issue 4 2008Odity Mukherjee Abstract Frontotemporal dementia (FTD) is a clinical term encompassing dementia characterized by the presence of two major phenotypes: 1) behavioral and personality disorder, and 2) language disorder, which includes primary progressive aphasia and semantic dementia. Recently, the gene for familial frontotemporal lobar degeneration (FTLD) with ubiquitin-positive, tau-negative inclusions (FTLD-U) linked to chromosome 17 was cloned. In the present study, 62 unrelated patients from the Washington University Alzheimer's Disease Research Center and the Midwest Consortium for FTD with clinically diagnosed FTD and/or neuropathologically characterized cases of FTLD-U with or without motor neuron disease (MND) were screened for mutations in the progranulin gene (GRN; also PGRN). We discovered two pathogenic mutations in four families: 1) a single-base substitution within the 3, splice acceptor site of intron 6/exon 7 (g.5913A>G [IVS6,2A>G]) causing skipping of exon 7 and premature termination of the coding sequence (PTC); and 2) a missense mutation in exon 1 (g.4068C>A) introducing a charged amino acid in the hydrophobic core of the signal peptide at residue 9 (p.A9D). Functional analysis in mutation carriers for the splice acceptor site mutation revealed a 50% decrease in GRN mRNA and protein levels, supporting haploinsufficiency. In contrast, there was no significant difference in the total GRN mRNA between cases and controls carrying the p.A9D mutation. Further, subcellular fractionation and confocal microscopy indicate that although the mutant protein is expressed, it is not secreted, and appears to be trapped within an intracellular compartment, possibly resulting in a functional haploinsufficiency. Hum Mutat 29(4), 512,521, 2008. © 2008 Wiley-Liss, Inc. [source] Screening for the BRCA1-ins6kbEx13 mutation: potential for misdiagnosis,,HUMAN MUTATION, Issue 5 2007Susan J Ramus Abstract Misdiagnosis of a germline mutation associated with an inherited disease syndrome can have serious implications for the clinical management of patients. A false negative diagnosis (mutation missed by genetic screening) limits decision making about intervention strategies within families. More serious is the consequence of a false positive diagnosis (genetic test suggesting a mutation is present when it is not). This could lead to an individual, falsely diagnosed as a mutation carrier, undergoing unnecessary clinical intervention, possibly involving risk-reducing surgery. As part of screening 283 ovarian cancer families for BRCA1 mutations, we used two different methods (mutation specific PCR and multiplex ligation-dependant probe amplification) to screen for a known rearrangement mutation L78833.1:g.44369_50449dup (ins6kbEx13). We found false positive and false negative results in several families. We then tested 61 known carriers or non-carriers from an epidemiological study of BRCA1 and BRCA2 mutation carriers (the EMBRACE study). These data highlight the need for caution when interpreting analyses of the ins6kbEx13 mutation and similar mutations, where characterising the exact sequence alteration for a deleterious mutation is not a part of the routine genetic test. © 2007 Wiley-Liss, Inc. [source] Low frequency of AXIN2 mutations and high frequency of MUTYH mutations in patients with multiple polyposis,,HUMAN MUTATION, Issue 10 2006Sophie Lejeune Abstract Familial adenomatous polyposis has been linked to germline mutations in the APC tumor suppressor gene. However, a number of patients with familial adenomatous polyposis (with either classical or attenuated phenotype) have no APC mutation. Recently, germline mutations in the Wnt pathway component gene AXIN2 have been associated with tooth agenesis-colorectal cancer syndrome. Moreover, biallelic mutations in the base excision repair gene MUTYH have been associated with polyposis and early-onset colorectal cancer. The aim of this study was to further assess the contribution of AXIN2 and MUTYH to hereditary colorectal cancer susceptibility. AXIN2 and MUTYH genes were screened for germline mutations by PCR and direct sequencing in 39 unrelated patients with multiple adenomas or colorectal cancer without evidence of APC mutation nor mismatch repair defect. Two novel AXIN2 variants were detected in one patient with multiple adenomas, but no clearly pathogenic mutation. In contrast, nine different MUTYH mutations were detected in eight patients, including four novel mutations. Biallelic MUTYH mutations were only found in patients with multiple adenomatous polyposis (7 out of 22 (32%)). Interestingly, five MUTYH mutation carriers had a family history consistent with dominant inheritance. Moreover, one patient with biallelic MUTYH mutations presented with multiple adenomas and severe tooth agenesis. Therefore, germline mutations are rare in AXIN2 but frequent in MUTYH in patients with multiple adenomas. Our data suggest that genetic testing of MUTYH may be of interest in patients with pedigrees apparently compatible with autosomal recessive as well as dominant inheritance. © 2006 Wiley-Liss, Inc. [source] Mutations of human cationic trypsinogen (PRSS1) and chronic pancreatitis,HUMAN MUTATION, Issue 8 2006Niels Teich Abstract Ten years ago, the groundwork for the discovery of the genetic basis of chronic pancreatitis was laid by linkage analyses of large kindreds with autosomal dominant hereditary chronic pancreatitis. Subsequent candidate gene sequencing of the 7q35 chromosome region revealed a strong association of the c.365G>A (p.R122 H) mutation of the PRSS1 gene encoding cationic trypsinogen with hereditary pancreatitis. In the following years, further mutations of this gene were discovered in patients with hereditary or idiopathic chronic pancreatitis. In vitro the mutations increase autocatalytic conversion of trypsinogen to active trypsin and thus probably cause premature, intrapancreatic trypsinogen activation in vivo. The clinical presentation is highly variable, but most affected mutation carriers have relatively mild disease. In this review, we summarize the current knowledge on trypsinogen mutations and their role in pancreatic diseases. Hum Mutat 27(8), 721,730, 2006. © 2006 Wiley-Liss, Inc. [source] Population-based detection of Lynch syndrome in young colorectal cancer patients using microsatellite instability as the initial testINTERNATIONAL JOURNAL OF CANCER, Issue 5 2009Lyn Schofield Abstract Approximately 1,2% of colorectal cancers (CRC) arise because of germline mutations in DNA mismatch repair genes, referred to as Lynch syndrome. These tumours show microsatellite instability (MSI) and loss of expression of mismatch repair proteins. Pre-symptomatic identification of mutation carriers has been demonstrated to improve survival; however, there is concern that many are not being identified using current practices. We evaluated population-based MSI screening of CRC in young patients as a means of ascertaining mutation carriers. CRC diagnosed in patients aged <60 years were identified from pathology records. No prior information was available on family history of cancer. PCR techniques were used to determine MSI in the BAT-26 mononucleotide repeat and mutation in the BRAF oncogene. Loss of MLH1, MSH2, MSH6 and PMS2 protein expression was evaluated in MSI+ tumours by immunohistochemistry. MSI+ tumours were found in 105/1,344 (7.8%) patients, of which 7 were excluded as possible Lynch syndrome because of BRAF mutation. Of the 98 "red flag" cases that were followed up, 25 were already known as mutation carriers or members of mutation carrier families. Germline test results were obtained for 35 patients and revealed that 22 showed no apparent mutation, 11 showed likely pathogenic mutations and 2 had unclassified variants. The proportion of MSI+ cases in different age groups that were estimated to be mutation carriers was 89% (<30 years), 83% (30,39), 68% (40,49) and 17% (50,59). We recommend MSI as the initial test for population-based screening of Lynch syndrome in younger CRC patients, regardless of family history. © 2008 Wiley-Liss, Inc. [source] Surveillance for endometrial cancer in hereditary nonpolyposis colorectal cancer syndromeINTERNATIONAL JOURNAL OF CANCER, Issue 4 2007Laura Renkonen-Sinisalo Abstract The estimated lifetime risk for endometrial carcinoma (EC) in hereditary nonpolyposis colorectal cancer syndrome (HNPCC) is 32,60%, thus supporting surveillance. The survival rate of EC patients is, however, favourable questioning the need for surveillance. Yet, the effectiveness of gynecological surveillance remains to be shown. The 2 previously published studies were based on transvaginal ultrasound (TVUS) alone. Intrauterine biopsy has not been tested in surveillance for EC in HNPCC families. The effect of gynecological surveillance was evaluated among 175 Finnish mutation carriers. During 759 person years at risk, there were 503 surveillance visits including TVUS and intrauterine biopsy of endometrium at 94% and 74% of the visits, respectively. EC occurred in 14 cases, 11 of which were diagnosed by surveillance, 8 by intrauterine biopsies. TVUS indicated only 4 EC patients but missed 6 other cases. Intrauterine sampling detected 14 additional cases of potentially premalignant hyperplasia. The stage distribution and survival tended to be more favorable in the 14 EC cases of the surveilled group (no deaths) than in the group of 83 symptomatic mutation carriers of whom 6 died of EC, but with no statistical significance. Four cases of ovarian cancer occurred but none was detected by surveillance in TVUS examinations. In conclusion, EC surveillance in HNPCC seems more effective with endometrial biopsies than with TVUS alone. A definite improvement in survival remains to be shown. The detection of early cancer stages and premalignant lesions offers the opportunity to avoid extensive adjuvant treatment. © 2006 Wiley-Liss, Inc. [source] MDM2 SNP309 T>G alone or in combination with the TP53 R72P polymorphism does not appear to influence disease expression and age of diagnosis of colorectal cancer in HNPCC patientsINTERNATIONAL JOURNAL OF CANCER, Issue 3 2007Bente A. Talseth Abstract Disease expression in hereditary nonpolyposis colorectal cancer (HNPCC) cannot be readily explained by mutation site in the respective DNA mismatch repair genes associated with this disorder. One explanation is the role of modifying genes that can either promote or prevent disease development on a background of increased risk. Two single nucleotide polymorphisms in MDM2 and TP53 have been shown to be associated with younger ages of disease onset in HNPCC (TP53) and Li-Fraumeni syndrome (MDM2). In this study 220 HNPCC patients were examined, from Australia and Poland, all characterized at the molecular level to determine the frequency of the MDM2 SNP309 T>G and to assess its influence on disease expression. The results were then pooled with the results of a previous study to assess the combined influence of the MDM2 SNP309 T>G and TP53 SNP R72P. A significant difference was observed between CRC patients and unaffected MMR gene mutation carriers over the age of 45 years (p = 0.01). The unaffected MMR gene mutation carriers over the age of 45 years who carry the G allele have a reduced risk of developing CRC. The results indicate that the MDM2 SNP309, alone or in combination with TP53 R72P, does not influence age of diagnosis of CRC in individuals with HNPCC. In conclusion, the data indicates the G allele of MDM2 SNP309 might have a protective effect on disease development in HNPCC patients and that age of diagnosis of CRC is not associated with MDM2 SNP309 or TP53 R72P either as single SNPs or combined. © 2006 Wiley-Liss, Inc. [source] Germline mutations 657del5 of the NBS1 gene contribute significantly to the incidence of breast cancer in Central PolandINTERNATIONAL JOURNAL OF CANCER, Issue 2 2006Jan Steffen Abstract Recent studies have demonstrated that heterozygous carriers of the NBS1 657del5 mutation have an increased risk for familial and bilateral breast cancer, but similar studies in consecutive breast cancer patients were inconclusive. Here, in a study of 562 nonselected breast cancer patients from Central Poland, we found 11 (1.96%) 657del5 mutation carriers vs. 3.47 expected (OR 3.21, 95%CI: 1.36,7.61, p = 0.0107) and only 9 (1.6%) carriers of the 5382insC mutation of the BRCA1 gene, most frequently found among breast cancer patients in Poland. No carriers of R215W, another pathogenic mutation of the NBS1 gene, were found in the present study. All carriers of the 657del5 mutation had sporadic breast tumors while 5 of 9 5382insC carriers had a family history of breast/ovarian cancer or bilateral breast carcinoma. In the pooled group of patients from the present and our previous study, carried out also in patients from Central Poland, we obtained the following risk estimates (OR) for 657del5 carriers, as related to the age at breast cancer diagnosis: <40 years: 8.36; (95%CI: 2.57,27.27) p = 0.0003; <50 years: 4.27 (95%CI: 1.67,10.89) p = 0.003; ,50 years: 2.40 (95%CI: 0.91,6.35) p = 0.1250; all ages: 3.13 (95% CI: 1.40,7.00) p = 0.0066. These findings demonstrate conclusively that NBS1 657del5 mutation carriers have a significantly, though moderately increased, age-related risk of breast cancer, and imply that in populations with a high 657del5 carrier frequency this mutation may contribute substantially to the overall incidence of breast cancer, particularly in younger age groups. © 2006 Wiley-Liss, Inc. [source] Coffee consumption and breast cancer risk among BRCA1 and BRCA2 mutation carriersINTERNATIONAL JOURNAL OF CANCER, Issue 1 2006André Nkondjock Abstract Although there are several plausible biologic mechanisms whereby coffee consumption might influence the risk of breast cancer, epidemiologic evidence is limited. We assessed the association between coffee consumption and breast cancer risk among high-risk women who carry BRCA mutations. We performed a matched case-control analysis on 1,690 women with a BRCA1 or BRCA2 mutation from 40 centers in 4 countries. Average lifetime coffee consumption was estimated via a self-administered questionnaire. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression. After adjustment for potential confounders, the ORs for breast cancer in BRCA carriers who habitually drank 0, 1,3, 4,5 and 6 or more cups of coffee were 1.00, 0.90 (95% CI 0.72,1.12), 0.75 (95% CI 0.47,1.19) and 0.31 (95% CI 0.13,0.71; p -trend = 0.02). The effect was limited to the consumption of caffeinated coffee. These results suggest that among women with BRCA gene mutation, coffee consumption is unlikely to be harmful and that high levels of consumption may in fact be related to reduced breast cancer risk. © 2005 Wiley-Liss, Inc. [source] Smoking and the risk of breast cancer among carriers of BRCA mutationsINTERNATIONAL JOURNAL OF CANCER, Issue 3 2004Parviz Ghadirian Abstract The effect of cigarette smoking on the risk of breast cancer is controversial, although most studies show little or no effect. It has been suggested that smoking may reduce the risk of developing hereditary breast cancer. We completed a case-control study on 1,097 women with breast cancer who were BRCA1 or BRCA2 mutation carriers and 1,097 age-matched controls with a mutation in the same gene but without breast cancer. There were no statistically significant differences between the cases and controls in terms of the number of current and ex-smokers (41.2% and 40.4%, respectively) or the age at smoking commencement (18.2 years and 18.5 years, respectively). There were no statistically significant differences between cases and controls regarding beginning smoking within 5 years of menarche (OR = 1.03; 95% CI 0.83 to l.28) or before the first pregnancy (OR = 1.09; 95% CI = 0.90 to 1.33). In conclusion, contrary to our previous report, smoking does not appear to be a risk factor for breast cancer among carriers of BRCA mutations. © 2004 Wiley-Liss, Inc. [source] Evidence for an age-related influence of microsatellite instability on colorectal cancer survivalINTERNATIONAL JOURNAL OF CANCER, Issue 6 2002Susan M. Farrington Abstract It is well established that microsatellite instability (MSI), the hallmark of defective DNA mismatch repair (MMR), is associated with prolonged survival in colorectal cancer compared with tumours that are microsatellite stable (MSS). MSI in sporadic colorectal tumours is primarily due to epigenetic silencing of MLH1. However, there are no prospective population-based studies of survival in patients with germline MMR gene mutations who develop cancer. Although MSI is almost universal in tumours from HNPCC family members, there is a potential confounding effect of ascertainment and other biases that could explain the apparent survival benefit in HNPCC families. Resolving whether germline MMR gene mutations impact on survival is important because it potentially undermines the rationale for surveillance of mutation carriers. Here, we report an investigation of the influence of MSI on survival in cohorts of cancer patients (aged < 30 years at diagnosis, n = 118; non-age-selected, n = 181) in the context of clinicopathologic variables. There was a substantial age-related influence of tumour MSI status on survival. In young patients with tumour MSI, 65% of patients with MSI tumours had germline MSH2 or MLH1 mutations. Clinicopathologic variables and tumour MSI of the cohort were studied with respect to survival and compared with control groups. Young patients had excess MSI tumours (p < 0.000001), mucinous tumours (p < 0.01), advanced disease (p , 0.001) and poorer 5-year survival compared with older cases. Cox proportional hazard analysis identified Dukes' stage, age at diagnosis and calendar year of treatment as independent predictors of survival. There was no detectable association between tumour MSI and survival in young patients, although we confirmed previous observations that MSI is associated with better prognosis in later onset cohorts. These findings underscore the rationale for surveillance and early identification of tumours in MMR gene carriers as well as refining understanding of the influence of MSI on cancer progression. © 2002 Wiley-Liss, Inc. [source] Activation Delay and VT Parameters in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy: Toward Improvement of Diagnostic ECG CriteriaJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 8 2008MONIEK G.P.J. COX M.D. Introduction: Desmosomal changes, electrical uncoupling, and surviving myocardial bundles embedded in fibrofatty tissue are hallmarks of activation delay in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). Currently, generally accepted task force criteria (TFC) are used for clinical diagnosis. We propose additional criteria based on activation delay and ventricular tachycardia (VT) to improve identification of affected individuals. Methods and Results: Activation delay and VT-related 12-lead electrocardiographic (ECG) criteria were studied, while off drugs, in 42 patients with proven ARVD/C according to TFC, and 27 controls with idiopathic VT from the RV outflow tract. Two of three measured TFC could only be identified in a small minority of ARVD/C patients. Additional ECG criteria proposed in this study included (a) prolonged terminal activation duration, an indicator of activation delay; (b) VT with LBBB morphology and superior axis; and (c) multiple different VT morphologies. These criteria were met in 30 (71%), 28 (67%), and 37 (88%) ARVD/C patients, respectively, and in one control patient (P < 0.001). Electrophysiologic studies contributed importantly to yield different VT morphologies. Pathogenic plakophilin-2 mutations were identified in 25 (60%) of ARVD/C patients and in none of the controls. In ARVD/C patients, parameters measured were not significantly different between mutation carriers and noncarriers, except for negative T waves in V1,3, occurring more frequently in patients with mutation. Conclusions: The proposed additional criteria are specific for ARVD/C and more sensitive than the current TFC. Therefore, adding the newly proposed criteria to current TFC could improve ARVD/C diagnosis, independent of DNA analysis. [source] MAPK-pathway activity, Lrrk2 G2019S, and Parkinson's diseaseJOURNAL OF NEUROSCIENCE RESEARCH, Issue 6 2007Linda R. White Abstract The 6055G>A mutation in the leucine-rich repeat kinase 2 (LRRK2) gene results in a G2019S substitution in the mixed-lineage kinase domain of Lrrk2, causing autosomal dominant Parkinson's disease (PD). We hypothesized the mutation alters cellular mitogen-activated protein kinase (MAPK) signalling cascades, and might be detectable in tissues other than in the brain. We therefore compared total levels and activation of the signalling proteins Src, HSP27, p38 MAPK, JNK, and ERK, in extracts of leukocytes isolated from patients with PD carrying the G2019S mutation, healthy mutation carriers, patients with idiopathic PD, and healthy controls. Phosphorylation of Src, HSP27, and JNK was reduced significantly in cell extracts from patients with G2019S-associated PD compared to healthy controls. Similarly, phosphorylation was reduced significantly in Src and HSP27 in the group of healthy carriers of the mutation, as well as in patients with idiopathic PD. Significant reductions in total Src were also observed in these three groups compared to the controls. The results of this pilot project therefore indicate significant alterations in key signalling proteins in leukocytes from patients with PD, and were most pronounced in G2019S-associated PD. Changes in MAPK-signalling may thus be common to PD pathophysiology, regardless of aetiology. Such changes may also be shown in blood samples during the preclinical stage of LRRK2 -associated PD, which could be particularly important for the development of neuroprotective strategies to delay onset, or slow progression of PD. © 2007 Wiley-Liss, Inc. [source] Raised serum ferritin predicts non-response to interferon and ribavirin treatment in patients with chronic hepatitis C infectionLIVER INTERNATIONAL, Issue 3 2002S Distante Abstract: Background/Aim: Previous studies have indicated that response to interferon therapy is inversely proportional to the amount of body iron stores. We have studied the relationship between serum ferritin, transferrin saturation, liver iron, presence of HFE-C282Y gene mutation and response to treatment in patients with chronic hepatitis C infection. Methods: Two hundred and fifty-six naive, HCV-RNA positive patients (60% males, median age 38 years, range 21,70) were treated with interferon and ribavirin for 6 months. Iron indices and the presence of the C282Y mutation were measured. In 242 (94%) patients iron deposition were determined by Perls staining method. Patients with negative HCV-RNA at 6 months after the end of treatment were defined as sustained viral responders. Results: Non-responders (n = 127) had significantly higher median s-ferritin values compared with sustained viral responders (130 µg/L vs. 75 µg/L P < 0.001). There was no difference in transferrin saturation among the two response groups. Only 23% (4/7) of patients with Perls grade 1 in liver biopsies responded to treatment vs. 54% (122/225) patients without iron deposition (P = 0.02), however, 10/13-non-responders had HCV genotype one. Two patients (0.8%) were homozygous for the C282Y mutation, 36 patients were heterozygous (14%). Among mutation carriers 26/38 achieved sustained response compared with 102/216 non-carriers (68% vs. 48%, P = 0.02). In a multivariate analysis s-ferritin (P = 0.030) and C282Y carrier status (P = 0.012) remained independent predict of sustained response. Conclusions: Raised s-ferritin values predicate non-response to interferon-ribavirin therapy in hepatitis C patients. Response rate in C282Y mutation carriers seems greater than in non-carriers. [source] "Jerky" dystonia in children: Spectrum of phenotypes and genetic testing,MOVEMENT DISORDERS, Issue 5 2009Friedrich Asmus MD Abstract Hyperkinetic dystonia is characterized by phasic, tremulous, and "jerky" movements in addition to twisting postures. We studied longitudinally 23 index patients with hyperkinetic dystonia from a quaternary pediatric movement disorder clinic in Ireland. Four clinical categories emerged: (1) Eight patients were diagnosed with myoclonus-dystonia, of whom seven carried heterozygous epsilon sarcoglycan (SGCE) mutations, including a novel deletion of exon 10. Gait disorder, unsteadiness, or frequent falls before 18 months were detected in all SGCE mutation carriers, whereas the typical neck-predominant presentation developed only years later. (2) One patient classified as benign hereditary chorea, because jerks were choreiform and continuous rather than action-induced, carried a heterozygous stop mutation of the TITF -1 gene (Y114X, exon 2). (3) Three mutation-negative patients were grouped as "myoclonic dystonia" with jerks only in the body regions affected by dystonia. (4) Eleven patients presented with a novel combination of dystonia and low amplitude poly-mini myoclonus of the upper limbs and pectoral muscles (D-PMM). In early childhood up to 3 years of age, an initial presentation with predominant gait impairment with only subtle jerks should prompt consideration of SGCE mutation analysis in addition to testing for DYT1 mutations. A causative gene for D-PMM remains to be identified. © 2008 Movement Disorder Society [source] Parkinson's disease due to the R1441G mutation in Dardarin: A founder effect in the basquesMOVEMENT DISORDERS, Issue 11 2006Javier Simón-Sánchez BSc Abstract The recent discovery of mutations in Dardarin (LRRK2) have been related to the appearance of Parkinson's disease in several families. Notably, one single mutation in this gene (R1441G) not only appeared in familial, but also in apparently sporadic Parkinson disease (PD) patients of Basque descent. A clinical population was ascertained, and subjects were classified into Basque and non-Basque descent according to their known ancestry. The R1441G mutation was assayed using an allele-specific polymerase chain reaction, and several single nucleotide polymorphisms surrounding this mutation were analyzed by direct sequencing. In addition to 22 members of the original Basque families where R1441G was identified, we observed 17 carriers of the mutation who were apparently related through a common ancestor. From a clinical perspective, the disease observed in mutation carriers is indistinguishable from that in noncarriers. The R1441G mutation causes a form of Parkinson's disease that is equivalent to that observed in idiopathic Parkinson's disease. This mutation appears in 16.4% and 4.0% of familial and sporadic PD in this Basque population, respectively. © 2006 Movement Disorder Society [source] Parkinson's disease and LRRK2: Frequency of a common mutation in U.S. movement disorder clinicsMOVEMENT DISORDERS, Issue 4 2006Denise M. Kay PhD Abstract The G2019S mutation in the LRRK2 gene is reportedly a common cause of familial Parkinson's disease (PD) and may also have a significant role in nonfamilial PD. The objective of this study was to assess mutation carrier frequency in PD patients from movement disorder clinics in the United States, stratified by family history, age at onset, and geography; to determine carrier frequency in a large and well-characterized control population; to examine segregation of mutation in families of patients; and to correlate genotype with clinical phenotype. One thousand four hundred twenty-five unrelated PD patients from movement disorder clinics in Oregon, Washington, and New York and 1,647 unrelated controls were studied. The G2019S mutation was detected using a TaqMan assay and verified by sequencing. Eighteen of 1,425 patients and one of 1,647 controls had the mutation. Carrier frequency (± 2SE) in patients was 0.013 ± 0.006 overall, 0.030 ± 0.019 in familial PD, 0.007 ± 0.005 in nonfamilial PD, 0.016 ± 0.013 in early-onset PD, and 0.012 ± 0.007 in late-onset PD. Geographic differences were insignificant. Age at onset of mutation carriers ranged from 28 to 71 years. Mutation carriers were clinically indistinguishable from idiopathic PD. LRRK2 G2019S is the single most common pathogenic mutation linked to neurodegenerative disease to date. © 2005 Movement Disorder Society [source] | |||||||||||||||||||||||||||||||