Wessex Clinical Genetics Service
Wessex Clinical Genetics Service
Killick E.,Institute of Cancer Research |
Morgan R.,University of Surrey |
Launchbury F.,University of Surrey |
Bancroft E.,Royal Marsden NHS Foundation Trust |
And 23 more authors.
Scientific Reports | Year: 2013
Controversy surrounds the use of PSA as a biomarker for prostate cancer detection, leaving an unmet need for a novel biomarker in this setting; urinary EN2 may identify individuals with clinically relevant prostate cancer. Male BRCA1 and BRCA2 mutation carriers are at increased risk of clinically significant prostate cancer and may benefit from screening. Urine samples from 413BRCA1 and BRCA2 mutation carriers and controls were evaluated. Subjects underwent annual PSA screening with diagnostic biopsy triggered by PSA > 3.0 ng/ml; 21 men were diagnosed with prostate cancer. Urinary EN2 levels were measured by ELISA and had a sensitivity of 66.7% and specificity of 89.3% for cancer detection. There was no statistically significant difference in EN2 levels according to genetic status or Gleason score. Urinary EN2 may be useful as a non-invasive early biomarker for prostate cancer detection in genetically high-risk individuals.
PubMed | Belfast City Hospital, University of Edinburgh, James Cook University, Auckland Hospital and 13 more.
Type: Journal Article | Journal: American journal of medical genetics. Part A | Year: 2016
KBG syndrome is characterized by short stature, distinctive facial features, and developmental/cognitive delay and is caused by mutations in ANKRD11, one of the ankyrin repeat-containing cofactors. We describe 32 KBG patients aged 2-47 years from 27 families ascertained via two pathways: targeted ANKRD11 sequencing (TS) in a group who had a clinical diagnosis of KBG and whole exome sequencing (ES) in a second group in whom the diagnosis was unknown. Speech delay and learning difficulties were almost universal and variable behavioral problems frequent. Macrodontia of permanent upper central incisors was seen in 85%. Other clinical features included short stature, conductive hearing loss, recurrent middle ear infection, palatal abnormalities, and feeding difficulties. We recognized a new feature of a wide anterior fontanelle with delayed closure in 22%. The subtle facial features of KBG syndrome were recognizable in half the patients. We identified 20 ANKRD11 mutations (18 novel: all truncating) confirmed by Sanger sequencing in 32 patients. Comparison of the two ascertainment groups demonstrated that facial/other typical features were more subtle in the ES group. There were no conclusive phenotype-genotype correlations. Our findings suggest that mutation of ANKRD11 is a common Mendelian cause of developmental delay. Affected patients may not show the characteristic KBG phenotype and the diagnosis is therefore easily missed. We propose updated diagnostic criteria/clinical recommendations for KBG syndrome and suggest that inclusion of ANKRD11 will increase the utility of gene panels designed to investigate developmental delay. 2016 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc.
Heliovaara E.,University of Helsinki |
Tuupanen S.,University of Helsinki |
Ahlsten M.,University of Helsinki |
Hodgson S.,St George's, University of London |
And 11 more authors.
Journal of Molecular Endocrinology | Year: 2011
Pituitary adenomas are common in the general population. Although most of them are sporadic, some occur in a familial setting. In familial pituitary adenoma patients it is common that no germline defects are found after screening of aryl hydrocarbon receptor interacting protein (AIP) and other genes known to underlie the condition, suggesting the existence of yet unknown predisposition genes. Recently, the RET proto-oncogene was found to be a novel in vivo interaction partner of AIP in the pituitary gland. Here, we have screened patients from 16 AIP mutation negative (AIPmut-) pituitary adenoma families for RET germline mutations to assess whether RET could play a role in pituitary adenoma predisposition, similar to AIP. We found five novel germline RET changes: one in RET Exon 4 and the rest in noncoding regions of RET. Two changes, c.1560*G>A and -1285G>A, were segregated in affected family members. We also analyzed the RET region with enhancer element locator (EEL) to identify RET regulatory elements, and to see whether the changes resided in these. None of the variants mapped to the regions predicted by EEL. Expression of RET was examined in ten AIPmut- and seven AIP mutation positive (AIPmut+) somatotropinomas by immunohistochemistry, with a trend showing reduced expression in the latter (P=0.05). We conclude that the RET variants are presumably not related to pituitary adenoma predisposition, although reduced RET expression may play a role in AIP-related genesis of somatotropinomas. © 2011 Society for Endocrinology.
Dolk H.,University of Ulster |
Armstrong B.,London School of Hygiene and Tropical Medicine |
Lachowycz K.,London School of Hygiene and Tropical Medicine |
Vrijheid M.,London School of Hygiene and Tropical Medicine |
And 5 more authors.
Occupational and Environmental Medicine | Year: 2010
Objectives To investigate whether there is an association between risk of congenital anomaly and annual ward level exposure to air pollution in England during the 1990s. Methods A geographical study was conducted across four regions of England using population-based congenital anomaly registers, 1991-1999. Exposure was measured as 1996 annual mean background sulphur dioxide (SO 2), nitrogen dioxide (NO2) and particulate matter (PM 10) concentrations at census ward level (n=1474). Poisson regression, controlling for maternal age, area socioeconomic deprivation and hospital catchment area, was used to estimate relative risk for an increase in pollution from the 10th to the 90th centile. Results For non-chromosomal anomalies combined, relative risks were 0.99 (95% CI 0.93 to 1.05) for SO2, 0.97 (95% CI 0.84 to 1.11) for NO2 and 0.89 (95% CI 0.75to 1.07) for PM10. For chromosomal anomalies, relative risks were 1.06 (95% CI 0.98 to 1.15) for SO2, 1.11 (95% CI 0.95 to 1.30) for NO2 and 1.18 (95% CI 0.97 to 1.42) for PM10. Raised risks were found for tetralogy of Fallot and SO2 (RR=1.38, 95% CI 1.07 to 1.79), NO 2 (RR=1.44, 95% CI 0.71 to 2.93) and PM10 (RR=1.48, 95% CI 0.57 to 3.84), which is of interest in light of previously reported associations between this cardiac anomaly and other air pollutants. Conclusions While air pollution in the 1990s did not lead to sustained geographical differences in the overall congenital anomaly rate in England, further research regarding specific anomalies is indicated.
Edwards E.,Wessex Clinical Genetics Service |
Lucassen A.,Wessex Clinical Genetics Service
Familial Cancer | Year: 2011
Regional cancer genetics services in the UK base many of their risk assessments on the careful evaluation of a family history of disease. The pathological details of cancers in relatives can help refine this risk assessment and alter subsequent management. By analysing a variety of medical records, we surveyed how often a reported family history was discrepant from that recorded in the records, and how often this impacted on surveillance recommendations. Our survey analysed pathology confirmation and risk assessment in families over a 7-month period of referrals. 839 cancers were reported and 476 were independently confirmed. The accuracy of a reported family history differed depending on the reported site of a cancer and on the degree of relationship to the patient. Whilst the majority of reported cancers (84%) were confirmed, a change in risk assessment through pathology confirmation resulted in altered management in 20% of all referrals. © 2010 Springer Science+Business Media B.V.
PubMed | Wessex Clinical Genetics Service
Type: Journal Article | Journal: Familial cancer | Year: 2011
Regional cancer genetics services in the UK base many of their risk assessments on the careful evaluation of a family history of disease. The pathological details of cancers in relatives can help refine this risk assessment and alter subsequent management. By analysing a variety of medical records, we surveyed how often a reported family history was discrepant from that recorded in the records, and how often this impacted on surveillance recommendations. Our survey analysed pathology confirmation and risk assessment in families over a 7-month period of referrals. 839 cancers were reported and 476 were independently confirmed. The accuracy of a reported family history differed depending on the reported site of a cancer and on the degree of relationship to the patient. Whilst the majority of reported cancers (84%) were confirmed, a change in risk assessment through pathology confirmation resulted in altered management in 20% of all referrals.