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Hoischen A.,Radboud University Nijmegen | Van Bon B.W.M.,Radboud University Nijmegen | Rodriguez-Santiago B.,Radboud University Nijmegen | Rodriguez-Santiago B.,University Pompeu Fabra | And 21 more authors.
Nature Genetics | Year: 2011

Bohring-Opitz syndrome is characterized by severe intellectual disability, distinctive facial features and multiple congenital malformations. We sequenced the exomes of three individuals with Bohring-Opitz syndrome and in each identified heterozygous de novo nonsense mutations in ASXL1, which is required for maintenance of both activation and silencing of Hox genes. In total, 7 out of 13 subjects with a Bohring-Opitz phenotype had de novo ASXL1 mutations, suggesting that the syndrome is genetically heterogeneous. © 2011 Nature America, Inc. All rights reserved.

PubMed | University of Cologne, University of Turin, Vilnius University, Erasmus Medical Center and 133 more.
Type: Journal Article | Journal: JAMA | Year: 2015

Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists.To identify mutation-specific cancer risks for carriers of BRCA1/2.Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19,581 carriers of BRCA1 mutations and 11,900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents. We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position. We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk.Mutations of BRCA1 or BRCA2.Breast and ovarian cancer risks.Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR=1.46; 95% CI, 1.22-1.74; P=210(-6)), c.4328 to c.4945 (BCCR2; RHR=1.34; 95% CI, 1.01-1.78; P=.04), and c. 5261 to c.5563 (BCCR2, RHR=1.38; 95% CI, 1.22-1.55; P=610(-9)). We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR=0.62 (95% CI, 0.56-0.70; P=910(-17)). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR=1.71; 95% CI, 1.06-2.78; P=.03), c.772 to c.1806 (BCCR1; RHR=1.63; 95% CI, 1.10-2.40; P=.01), and c.7394 to c.8904 (BCCR2; RHR=2.31; 95% CI, 1.69-3.16; P=.00002). We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR=0.51; 95% CI, 0.44-0.60; P=610(-17)). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR=0.57; 95% CI, 0.41-0.80; P=.001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers.Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations.

PubMed | Institute of Oncology, University of Cologne, St George's, University of London, University Of Clermont Ferrand and 116 more.
Type: | Journal: Breast cancer research : BCR | Year: 2015

Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production. Individuals with different mitochondrial haplogroups differ in their metabolism and sensitivity to oxidative stress. Variability in mitochondrial genetic background can alter reactive oxygen species production, leading to cancer risk. In the present study, we tested the hypothesis that mitochondrial haplogroups modify breast cancer risk in BRCA1/2 mutation carriers.We genotyped 22,214 (11,421 affected, 10,793 unaffected) mutation carriers belonging to the Consortium of Investigators of Modifiers of BRCA1/2 for 129 mitochondrial polymorphisms using the iCOGS array. Haplogroup inference and association detection were performed using a phylogenetic approach. ALTree was applied to explore the reference mitochondrial evolutionary tree and detect subclades enriched in affected or unaffected individuals.We discovered that subclade T1a1 was depleted in affected BRCA2 mutation carriers compared with the rest of clade T (hazard ratio (HR) = 0.55; 95% confidence interval (CI), 0.34 to 0.88; P = 0.01). Compared with the most frequent haplogroup in the general population (that is, H and T clades), the T1a1 haplogroup has a HR of 0.62 (95% CI, 0.40 to 0.95; P = 0.03). We also identified three potential susceptibility loci, including G13708A/rs28359178, which has demonstrated an inverse association with familial breast cancer risk.This study illustrates how original approaches such as the phylogeny-based method we used can empower classical molecular epidemiological studies aimed at identifying association or risk modification effects.

Banka S.,University of Manchester | Howard E.,University of Manchester | Bunstone S.,University of Manchester | Chandler K.E.,University of Manchester | And 7 more authors.
Clinical Genetics | Year: 2013

Kabuki syndrome (KS) is a rare multi-system disorder that can result in a variety of congenital malformations, typical dysmorphism and variable learning disability. It is caused by MLL2 point mutations in the majority of the cases and, rarely by deletions involving KDM6A. Nearly one third of cases remain unsolved. Here, we expand the known genetic basis of KS by presenting five typical patients with the condition, all of whom have novel MLL2 mutation types- two patients with mosaic small deletions, one with a mosaic whole-gene deletion, one with a multi-exon deletion and one with an intragenic multi-exon duplication. We recommend MLL2 dosage studies for all patients with typical KS, where traditional Sanger sequencing fails to identify mutations. The prevalence of such MLL2 mutations in KS may be comparable with deletions involving KDM6A. These findings may be helpful in understanding the mutational mechanism of MLL2 and the disease mechanism of KS. © 2012 John Wiley & Sons A/S.

Mavaddat N.,Center for Cancer Genetic Epidemiology | Peock S.,Center for Cancer Genetic Epidemiology | Frost D.,Center for Cancer Genetic Epidemiology | Ellis S.,Center for Cancer Genetic Epidemiology | And 31 more authors.
Journal of the National Cancer Institute | Year: 2013

Background Reliable estimates of cancer risk are critical for guiding management of BRCA1 and BRCA2 mutation carriers. The aims of this study were to derive penetrance estimates for breast cancer, ovarian cancer, and contralateral breast cancer in a prospective series of mutation carriers and to assess how these risks are modified by common breast cancer susceptibility alleles. Methods Prospective cancer risks were estimated using a cohort of 978 BRCA1 and 909 BRCA2 carriers from the United Kingdom. Nine hundred eighty-eight women had no breast or ovarian cancer diagnosis at baseline, 1509 women were unaffected by ovarian cancer, and 651 had been diagnosed with unilateral breast cancer. Cumulative risks were obtained using Kaplan-Meier estimates. Associations between cancer risk and covariables of interest were evaluated using Cox regression. All statistical tests were two-sided. Results The average cumulative risks by age 70 years for BRCA1 carriers were estimated to be 60% (95% confidence interval [CI] = 44% to 75%) for breast cancer, 59% (95% CI = 43% to 76%) for ovarian cancer, and 83% (95% CI = 69% to 94%) for contralateral breast cancer. For BRCA2 carriers, the corresponding risks were 55% (95% CI = 41% to 70%) for breast cancer, 16.5% (95% CI = 7.5% to 34%) for ovarian cancer, and 62% (95% CI = 44% to 79.5%) for contralateral breast cancer. BRCA2 carriers in the highest tertile of risk, defined by the joint genotype distribution of seven single nucleotide polymorphisms associated with breast cancer risk, were at statistically significantly higher risk of developing breast cancer than those in the lowest tertile (hazard ratio = 4.1, 95% CI = 1.2 to 14.5; P =. 02). Conclusions Prospective risk estimates confirm that BRCA1 and BRCA2 carriers are at high risk of developing breast, ovarian, and contralateral breast cancer. Our results confirm findings from retrospective studies that common breast cancer susceptibility alleles in combination are predictive of breast cancer risk for BRCA2 carriers. © 2013 The Author.

Wright C.M.,Yorkhill Hospitals | Stone D.H.,Yorkhill Hospitals | Parkinson K.N.,Newcastle University
Archives of Disease in Childhood | Year: 2010

Objective: During a study of weight faltering it was observed that infants from a minority Haredi (ultra-Orthodox Jewish) religious group showed very different growth patterns from the rest of the cohort. The authors thus set out to explore the characteristics of the community that may explain these differences. Setting and subjects: Gateshead Millennium Study cohort, UK. Design: Prospective population-based cohort study of 961 term infants (of whom 33 were from the Haredi community) recruited shortly after birth and followed by postal questionnaires and measurement at age 13 months. Results: At birth Haredi children had similar weights to the rest of the cohort, but by the age of a year the Haredi babies were significantly lighter (mean difference -1.06; p<0.001) and shorter even after allowing for parental heights (length z score mean difference -0.5; p=0.02). They were much more likely to have had weight faltering at some point: Haredi 48%, remainder 11%; RR=4.36; p<0.001. The Haredi families were much larger (54% had 5-12 siblings) were breast fed for longer (67% >4 months vs 15% of remainder; p<0.01) and started solids later (mean difference (CI) 7.5 (5.3 to 9.8) weeks; p<0.001) and these factors largely explained the differences in weight gain. Conclusions: The extreme growth patterns seen in these children seem to relate to large family size and delayed and inadequate introduction of complementary solids, which are known risk factors for malnutrition in less affluent societies.

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