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Mccauley J.,Molecular Genetics DNA Laboratory | Masand N.,Kings College London | Mcgowan R.,Ferguson Smith Center for Clinical Genetics | Rajagopalan S.,Liverpool Hospital | And 7 more authors.
American Journal of Medical Genetics, Part A | Year: 2011

X-linked VACTERL-hydrocephalus syndrome (X-linked VACTERL-H) is a rare disorder caused by mutations in the gene FANCB which underlies Fanconi Anemia (FA) complementation group B. Cells from affected males have increased chromosome breakage on exposure to DNA cross-linking agents. Only five FANCB mutations found in six affected males, including an affected uncle and nephew, have been reported. We have identified FANCB mutations in a further four affected families. The VACTERL-H phenotype segregates as an X-linked recessive trait in three of these. Each mutation is predicted to truncate the FANCB open reading frame and results in highly skewed X-inactivation in unaffected carrier females. Phenotypic data were available on six affected males. Comparison of the clinical findings in our patients with published clinical data (total 12 patients) shows that ventriculomegaly, bilateral absent thumbs and radii, vertebral defects, renal agenesis, and growth retardation are the major phenotypic signs in affected males. Less frequent are brain, pituitary, ear and eye malformations, gastrointestinal atresias (esophageal, duodenal and anal), tracheoesophageal fistula, lung segmentation defects, and small genitalia. Three of six of our patients survived the perinatal period. One boy lived up to 2 years 10 months but developed aplastic anemia and died of renal failure. These data show that loss-of-function FANCB mutations result in a recognizable, multiple malformation phenotype in hemizygous males for which we propose clinical criteria to aid diagnosis. © 2011 Wiley-Liss, Inc. Source


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. Source


Davidson D.F.,University Hospital Crosshouse | Bradshaw N.,Ferguson Smith Center for Clinical Genetics | Perry C.G.,University of Glasgow | Lindsay R.,University of Glasgow | Freel E.M.,University of Glasgow
Annals of Clinical Biochemistry | Year: 2012

Background: Catecholamine-producing neuroendocrine tumours are found in chromaffin cells of the adrenal medulla (phaeochromocytoma) or extra-adrenal paraganglia (paraganglioma), known collectively as PPGLs. In approximately a quarter or more of cases of PPGL, these rare tumours arise as a result of germline mutations of several tumour susceptibility genes. At the Crosshouse laboratory, urine tests include free metadrenalines (fMAs) (also known as free metanephrines) which demonstrate superior sensitivity over that obtained by urinary vanillyl mandelic acid, catecholamines or plasma catecholamines in the diagnosis of PPGL. This retrospective audit was to determine if urinary fMAs offered discrimination among the hereditary forms of PPGL. Methods: Retrospective biochemical and genetic data were gathered from 1997 to 2011. The identified urine specimens were those obtained at the time of first diagnosis or recurrence of PPGL. Results of catecholamines and metabolites were standardized as multiples of their respective relevant upper reference limits (URLs). Results: Results were available for 29 affected patients (15 females and 14 males), median age 26 (range 9-63) years, comprising three mutation groups: succinate dehydrogenase subunit B or D ([SDHB/D] 16 patients), multiple endocrine neoplasia type 2 ([MEN 2] 6 patients) and von Hippel-Lindau disease ([VHL] 7 patients). The parent catecholamines exhibited increased values for noradrenaline (NA) and/or adrenaline (AD) for 25/29 (86.2%) patients. Either or both free normetadrenaline (fNMA) and fMA were elevated in 29/29 (100%) patients. Conclusions: The ratio of the multiples of URL for fMA/fNMA displayed a clearer separation of MEN 2 patients from those with SDHB/D or VHL than did the equivalent AD/NA ratio. Source


Hilton-Jones D.,West Wing | Bowler M.,Myotonic Dystrophy Support Group | Lochmueller H.,Institute of Genetic Medicine | Longman C.,Ferguson Smith Center for Clinical Genetics | And 5 more authors.
Neuromuscular Disorders | Year: 2012

Excessive daytime sleepiness (EDS), of very similar pattern to that seen in narcolepsy syndrome, is extremely common in myotonic dystrophy type 1 (DM1). In a significant minority it has a profound disabling effect on employment, social functioning and activities of daily living. Limited published studies have shown inconsistent results from use of the psychostimulant drug modafinil. A recent European Medicines Agency (EMA) review concluded that on current evidence regarding safety and efficacy, modafinil's use should be restricted to the treatment of narcolepsy. In other conditions (although DM1 was not specifically considered) it was concluded that there was insufficient evidence of benefit to outweigh potentially serious side-effects, including severe skin reactions and cardiac arrhythmia. Clinicians with extensive experience in the management of DM1 have found modafinil to be extremely effective in appropriately selected patients with a very low incidence of serious side-effects. Given the recent EMA review, patients have expressed concern about the potential restriction of the use of modafinil in DM1. This brief review is an audit of the experience of a large group of patients and their clinicians concerning EDS and DM1 and concludes that despite the limited literature there is strong evidence to support the use of modafinil in carefully selected patients. © 2012 Elsevier B.V. Source


Morales F.,United Medical Systems | Couto J.M.,United Medical Systems | Higham C.F.,United Medical Systems | Higham C.F.,University of Glasgow | And 11 more authors.
Human Molecular Genetics | Year: 2012

Deciphering the contribution of genetic instability in somatic cells is critical to our understanding of many human disorders. Myotonic dystrophy type 1 (DM1) is one such disorder that is caused by the expansion of a CTG repeat that shows extremely high levels of somatic instability. This somatic instability has compromised attempts to measure intergenerational repeat dynamics and infer genotype-phenotype relationships. Using single-molecule PCR, we have characterized more than 17 000 de novo somatic mutations from a large cohort of DM1 patients. These data reveal that the estimated progenitor allele length is the major modifier of age of onset. We find no evidence for a threshold above which repeat length does not contribute toward age at onset, suggesting pathogenesis is not constrained to a simple molecular switch such as nuclear retention of the DMPK transcript or haploinsufficiency for DMPK and/or SIX5. Importantly, we also show that age at onset is further modified by the level of somatic instability; patients in whom the repeat expands more rapidly, develop the symptoms earlier. These data establish a primary role for somatic instability in DM1 severity, further highlighting it as a therapeutic target. In addition, we show that the level of instability is highly heritable, implying a role for individual-specific trans-acting genetic modifiers. Identifying these trans-acting genetic modifiers will facilitate the formulation of novel therapies that curtail the accumulation of somatic expansions and may provide clues to the role these factors play in the development of cancer, aging and inherited disease in the general population. © The Author 2012. Published by Oxford University Press. All rights reserved. Source

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