Biomedical subjects
Publications and source records attributed to V Murday.
Neonatal hepatitis and biliary hypoplasia are not recognised features of Williams syndrome. A case of Williams syndrome, presenting with neonatal conjugated hyperbilirubinaemia leading to an initial misdiagnosis is reported.
BACKGROUND: Peutz-Jeghers syndrome (PJS) is a rare, autosomal dominant cancer predisposition syndrome characterised by oro-facial pigmentation and hamartomatous polyposis of the gastrointestinal tract. A causal germline mutation in STK11 can be identified in 30% to 80% of PJS patients. METHODS: Here we report the comprehensive mutational analysis of STK11 in 38 PJS probands applying conventional PCR based mutation detection methods and the recently introduced MLPA (multiplex ligation dependent probe amplification) technique developed for the identification of exonic deletions/duplications. RESULTS: Nineteen of 38 probands (50%) had detectable point mutations or small scale deletions/insertions and six probands (16%) had genomic deletions encompassing one or more STK11 exons. CONCLUSIONS: These findings demonstrate that exonic STK11 deletions are a common cause of PJS and provide a strong rationale for conducting a primary screen for such mutations in patients.
BACKGROUND: CHARGE syndrome has an estimated prevalence of 1/10,000. Most cases are sporadic which led to hypotheses of a non-genetic aetiology. However, there was also evidence for a genetic cause with reports of multiplex families with presumed autosomal dominant, possible autosomal recessive inheritance and concordant twin pairs. We identified a monozygotic twin pair with CHARGE syndrome and a de novo balanced chromosome rearrangement t(8;13)(q11.2;q22). METHODS: Fluorescence in situ hybridisation was performed with BAC and PAC probes to characterise the translocation breakpoints. The breakpoint on chromosome 8 was further refined using 10 kb probes we designed and produced using sequence data for clone RP11 33I11, the Primer3 website, and a long range PCR kit. RESULTS: BAC and PAC probe hybridisation redefined the breakpoints to 8q12.2 and 13q31.1. Probe RP11 33I11 spanned the breakpoint on chromosome 8. Using our 10 kb probes we demonstrated that the chromodomain gene CHD7 was disrupted by the translocation between exons 3 and 8. DISCUSSION: Identifying that the translocation breakpoint in our patients occurred between exons 3 and 8 of CHD7 suggests that disruption of this gene is the cause of CHARGE syndrome in the twins and independently confirms the role of CHD7 in CHARGE syndrome.
Despite there being an increasing literature on the impact of cancer genetic counseling on risk perception and mental health, there is a lack of data describing impact on risk management. Genetic counseling and testing for cancer predisposition genes aims to improve the future health of those at high risk through appropriate surveillance and screening. However, management of breast cancer risk in women with a family history of this disease is an area of controversy. Counseling services may recommend specific risk management options to women, who then rely on their local screening service to make provision. This study investigated the impact of genetic counseling on management of breast cancer risk in women attending Cancer Family Clinics. A total of 293 women attending four genetic clinics were enrolled. Rates of breast self-examination, clinical breast examination, mammography, biopsy, detected cancers, and other screenings were documented. Participants' perceived benefits and barriers to mammography were assessed along with cancer worry. Results show that rates of mammography, clinical breast examination, and breast self-examination were increased following clinic attendance (p < 0.001). Women in the under 35 age-group had limited access to screening. Rates for biopsy and detected cancers were low. Women reported positive attitudes to mammography, with few reported barriers. Contrary to previous studies, there was no evidence that anxiety about breast cancer impedes uptake of health surveillance methods. Genetic counseling had a positive impact on management of breast cancer risk. Whether this translates into future health gains remains to be established.
The aim of the study was to compare psychosocial outcomes for 50 new clinic attendees, referred for cancer genetic counselling to five UK centres. The centres represented England, Scotland and Wales, and were randomly selected from groups ranked by different levels of clinical activity in cancer genetics practice. Questionnaires assessed demographic data, risk perception, mental health and use of health services pre-consultation and at 1 and 12 months follow-up. Satisfaction was measured for attendees and referring doctors at follow-up. A total of 256 unaffected adults fulfilled the study criteria. The five centres varied widely with respect to service organisation and activity, but all had a greater proportion of unaffected attendees with a breast cancer risk (61-91%) than either a bowel cancer risk (0-33%) or ovarian cancer risk (3-25%). There were no significant differences in the psychosocial data between centres pre-counselling. No significant change over time occurred for any of the centres for risk perception or general psychological distress. There were significant differences between centres in reduction of cancer worry from baseline to 12 months and with the number of women who were recommended to have mammographic surveillance who had not received this. Overall, one-third of women for whom mammography had been recommended had not been screened within 1 year of follow-up. Subsequent attendance at the GP, but not at a hospital, was associated with risk level, but differences between centres could not be analysed. Satisfaction differed significantly between centres for 4 : 14 aspects of service provision and with 3 : 17 items concerning communication; satisfaction was high overall. Over 90% of referring doctors were moderately/very satisfied with the service, but 23% were dissatisfied with waiting times and 19% with access to preventive treatment. Results differed significantly between centres for doctor's satisfaction with the provision of referral criteria and prescribing information. In conclusion, there were relatively few significant differences in psychosocial outcomes between centres, considering the wide variation in service organisation and activity. These significant differences were not consistent across the centres, therefore, differences could not be linked to specific aspects of service provision.
Germline mutations in the LKB1/STK11 tumour suppressor gene cause Peutz-Jeghers syndrome (PJS), a rare dominant disorder. In addition to typical hamartomatous gastrointestinal polyps and pigmented perioral lesions, PJS is associated with an increased risk of tumours at multiple sites. Follow-up information on carriers is limited and genetic heterogeneity makes counselling and management in PJS difficult. Here we report the analysis of the LKB1/STK11 locus in a series of 33 PJS families, and estimation of cancer risks in carriers and noncarriers. Germline mutations of LKB1/STK11 were identified in 52% of cases. This observation reinforces the hypothesis of a second PJS locus. In carriers of LKB1/STK11 mutations, the risk of cancer was markedly elevated. The risk of developing any cancer in carriers by age 65 years was 47% (95% CI: 27-73%) with elevated risks of both gastrointestinal and breast cancer. PJS with germline mutations in LKB1/STK11 are at a very high relative and absolute risk of multiple gastrointestinal and nongastrointestinal cancers. To obtain precise estimates of risk associated with PJS requires further studies of genotype-phenotype especially with respect to LKB1/STK11 negative cases, as this group is likely to be heterogeneous.
Using data obtained during a retrospective interview study of 30 women who had undergone genetic testing-BRCA1/2 mutation searching-this paper describes how women, previously diagnosed with breast/ovarian cancer, perceive their role in generating genetic information about themselves and their families. It observes that when describing their motivations for undergoing DNA testing and their experiences of disclosing genetic information within the family these women provide care based ethical justifications for their actions. Finally, it argues that generating genetic information and disclosing this information to kin raise different types of ethical issues. The implications of these findings for ethical debates about informed choice in the context of genetic testing are discussed.
This study sought to investigate the impact of BRCA1 and BRCA2 mutation searching on women previously diagnosed with breast or ovarian cancer. In-depth interviews were undertaken with 30 women who had undergone a BRCA1 and BRCA2 mutation search within the clinical setting. The main reasons reported for undergoing mutation searching were: to provide genetic information for other family members, general altruism, curiosity about the aetiology of cancer, and to provide information to facilitate risk management decisions. In the main, the process of undergoing genetic testing was not experienced as anxiety provoking. The benefit of receiving a result confirming the presence of a genetic mutation was seen as an end to uncertainty, whereas the costs included difficulties in disclosing information to kin and potentially increased anxiety about one's own or others' cancer risks. Women receiving an inconclusive test result reported a range of emotional reactions. There was evidence that some women misunderstood the meaning of this result, interpreting it as definitive confirmation that a cancer-predisposing mutation was not present within the family. It is concluded that women with cancer who participate in BRCA1 and BRCA2 testing need to receive clear information about the meaning and implications of the different types of test results. Some recommendations for clinical practice are discussed.
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The Li-Fraumeni syndrome (LFS) is a dominant disease whose hallmark is an increased risk of breast cancers, brain tumours, sarcomas, leukaemia and adrenal carcinoma. Some, but not all LFS and Li-Fraumeni-like (LFL) families are caused by TP53 mutations. Bcl10 is a recently identified tumour suppressor reported to be commonly mutated in a wide range of cancers. To investigate the possibility that Bcl10 is a susceptibility gene for LFS and LFL we have analysed 27 LFS/LFL families. No mutations were observed. This indicates that Bcl10 is unlikely to act as a susceptibility gene for LFS and LFL.
The present study investigated: (1) perception of genetic risk and, (2) the psychological effects of genetic counselling in women with a family history of breast cancer. Using a prospective design, with assessment pre- and post-genetic counselling at clinics and by postal follow-up at 1, 6 and 12 months, attenders at four South London genetic clinics were assessed. Participants included 282 women with a family history of breast cancer. Outcome was measured in terms of mental health, cancer-specific distress and risk perception. High levels of cancer-specific distress were found pre-genetic counselling, with 28% of participants reporting that they worried about breast cancer 'frequently or constantly' and 18% that worry about breast cancer was 'a severe or definite problem'. Following genetic counselling, levels of cancer-specific distress were unchanged. General mental health remained unchanged over time (33% psychiatric cases detected pre-genetic counselling, 27% at 12 months after genetic counselling). Prior to their genetics consultation, participants showed poor knowledge of their lifetime risk of breast cancer since there was no association between their perceived lifetime risk (when they were asked to express this as a 1 in x odds ratio) and their actual risk, when the latter was calculated by the geneticist at the clinic using the CASH model. In contrast, women were more accurate about their risk of breast cancer pre-genetic counselling when this was assessed in broad categorical terms (i.e. very much lower/very much higher than the average woman) with a significant association between this rating and the subsequently calculated CASH risk figure (P = 0.001). Genetic counselling produced a modest shift in the accuracy of perceived lifetime risk, expressed as an odds ratio, which was maintained at 12 months' follow-up. A significant minority failed to benefit from genetic counselling; 77 women continued to over-estimate their risk and maintain high levels of cancer-related worry. Most clinic attenders were inaccurate in their estimates of the population risk of breast cancer with only 24% able to give the correct figure prior to genetic counselling and 36% over-estimating this risk. There was some improvement following genetic counselling with 62% able to give the correct figure, but this information was poorly retained and this figure had dropped to 34% by the 1-year follow-up. The study showed that women attending for genetic counselling are worried about breast cancer, with 34% indicating that they had initiated the referral to the genetic clinic themselves. This anxiety is not alleviated by genetic counselling, although women reported that it was less of a problem at follow-up. Women who continue to over-estimate their risk and worry about breast cancer are likely to go on seeking unnecessary screening if they are not reassured.
Individuals at risk of familial colorectal cancer may be identified from their pedigree but screening guidelines are limited. We wished to assess the opinion of consultants in the region of the value of screening for familial colorectal cancer. All consultant general surgeons and consultant gastroenterologists in South (West) Thames received a questionnaire. This considered the current screening practice of the consultant for colorectal cancer, their opinion of screening patients with a positive family history, and their screening regimen for particular family history scenarios. Seventy-one (62.8%) of consultants replied. Forty-two consultants regularly performed screening colonoscopy (72%) with a median of 15 patients each year (range 2-130). Of these, 23 said that the number screened was limited by resources. Three percent thought regular screening of individual at increased risk of developing colorectal cancer should be yearly, 42% 3 yearly, and 42% 5 yearly. Regarding the risk of dying from colorectal cancer, 14% would screen for a risk of greater than 1 in 6, 45% 1 in 10, 18% 1 in 20, and 10% 1 in 50. Only half of the consultants agreed with published guidelines regarding the age of an index case of colorectal cancer below which they would screen 1st degree relatives. There was substantial variation in suggested screening regimens for the sample family pedigrees. There is wide variation in indications for and clinical practice of screening for familial colorectal cancer and evidence-based refinement of guidelines and increased specialist referral could rationalise resources.
Solitary juvenile polyps are quite frequent in children, but juvenile polyposis (JP) is a rare autosomal dominant trait characterised by the occurrence of numerous polyps in the gastrointestinal tract. Extracolonic phenotypic abnormalities are well documented in patients with familial adenomatous polyposis and Peutz-Jeghers syndrome and can allow a clinical diagnosis to be made before the bowel pathology becomes available. Though described, characteristic extracolonic abnormalities have not been clearly defined in juvenile polyposis. We sought to determine whether there are consistent extracolonic phenotypic abnormalities in JP patients and how frequently this would allow diagnosis of one of the genetic syndromes known to be associated with juvenile polyposis. Twenty-two JP patients underwent clinical examination and data from one patient were obtained from case notes. Those consenting to further investigations had x rays of the skull, chest, and hands and an echocardiogram if clinically indicated. Significant extracolonic phenotypic abnormalities were present in 18 patients (14 male and four female), and included dermatological (13), skeletal (16), neurological (5), cardiopulmonary (4), gastrointestinal (3), genitourinary (4), and ocular (1) features. In five patients the diagnosis of a genetic syndrome was possible: two had Bannayan-Riley-Ruvalcaba syndrome, two had Gorlin syndrome, and one had hereditary haemorrhagic telangiectasia (HHT, also known as Osler-Rendu-Weber syndrome). Other patients had some features of these conditions and of Cowden and Simpson-Golabi-Behmel syndromes, but these were not sufficient to allow a definitive diagnosis.
The current study has two aims: (1) to look at people's recall of risk information after genetic counselling and (2) to determine the impact of receiving an audiotape of the genetic consultation on level of recall, cancer related worry, and women's uptake of risk management methods. Using a prospective randomised controlled design, subjects receiving an audiotape were compared with a standard consultation group. Participants were drawn from attenders at the genetic clinics of two London hospitals and included 115 women with a family history of breast cancer. Assessment of perceived genetic risk, mental health, cancer worry, and health behaviour was made before counselling at the clinic (baseline) and by postal follow up. Usefulness of audiotapes and satisfaction with the clinical service was assessed by study specific measures. The data indicate that cancer worry is reduced by provision of an audiotape of the genetic consultation. Recall of the genetic risk figure, however, is not affected by provision of an audiotape and neither is it related to women's overall perception of being more or less at risk of breast cancer than the average woman. Forty-one percent of women accurately recalled their personal risk of breast cancer at one month follow up; however, 25% overestimated, 11% underestimated, and 23% could not remember or did not know their breast cancer risk. Recall of the risk figure is more accurate when the clinical geneticist has given this to the woman as an odds ratio rather than in other formats. Subsequent health behaviour is unaffected by whether women have an audiotape record of their genetic consultation. Results suggest that having a precise risk figure may be less important than women taking away from the consultation an impression that something can be offered to help them manage that risk. Provision of an audiotape of the consultation is of limited usefulness. The need for psychological care to be better integrated into genetic counselling at cancer family clinics was highlighted by the study. The results are discussed in terms of future service development.
A 38-yr-old man with an unusual type of Ehlers-Danlos syndrome presented for elective abdominal aortic aneurysm repair. During surgery he developed acute myocardial ischaemia, resulting in abandonment of the procedure. He was shown subsequently to have severe triple vessel coronary artery disease. Silent ischaemia associated with severe coronary artery disease, although rare, may be associated with the syndrome and is difficult to recognize as other cardiac abnormalities are frequently present.
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One hundred and thirty-four families or individuals with auditory-pigmentary syndromes such as Waardenburg syndrome (WS) or probable neurocristopathies were screened for mutations in the PAX3 and MITF genes. PAX3 mutations were found in 20/25 families with definite Type 1 WS and 1/2 with Type 3 WS, but in none of 23 with definite Type 2 WS or 36 with other neurocristopathies. The PAX3 mutations included substitutions of conserved amino acids in the paired domain or the homeodomain, splice-site mutations, nonsense mutations and frame-shifting insertions or deletions. No phenotype-genotype correlations were noted within WS1 families. With MITF, mutations likely to affect protein function were found in seven families, five of which had definite Type 2 WS. We conclude that Type 1 and Type 3 WS are allelic and are normally caused by loss of function mutations in PAX3; that Type 2 WS is heterogeneous, with about 20% of cases caused by mutations in MITF, and that individuals with auditory, pigmentary or neural crest syndromes which do not fit stringent definitions of Waardenburg syndrome are unlikely to have mutations in either the PAX3 or MITF genes. The molecular pathology of MITF/microphthalmia mutations appears to be different in humans and mice, with gene dosage having more significant effects in humans than in the mouse.
OBJECTIVES: To determine the frequency and mode of inheritance of familial dilated cardiomyopathy in the United Kingdom. BACKGROUND: Two recent prospective studies have suggested that familial forms of dilated cardiomyopathy are common but have been limited by selective screening methods, inadequate diagnostic criteria, and low rates of ascertainment. METHODS: Prospective screening study of 236 relatives from 40 families of patients with dilated cardiomyopathy. Screening consisted of clinical examination, 12 lead electrocardiogram, and two-dimensional Doppler echocardiography. Relatives with systemic hypertension and other cardiac diseases were excluded from the study. All echocardiograms were performed by an experienced echocardiographer who was blinded to clinical information. Relatives were classified as having dilated cardiomyopathy, left ventricular enlargement (method of Henry), depressed fractional shortening, or as being normal. Relatives with abnormal investigations underwent further evaluation as appropriate. RESULTS: Twenty five cases of dilated cardiomyopathy were identified and came from 10 (25%) of the 40 families screened. Pedigree analysis was most consistent with autosomal dominant inheritance and variable penetrance (65-95%). Of the remaining apparently healthy relatives, 37 (18%) were found to have left ventricular enlargement and nine (4%) depressed fractional shortening; these values were significantly higher than those observed in 239 healthy controls (24 (10%), P = 0.02 and one (0.4%), P = 0.01, respectively). CONCLUSIONS: Patients with dilated cardiomyopathy commonly have an affected family member and a high proportion of apparently healthy relatives with minor echocardiographic abnormalities. Segregation analysis suggests that familial dilated cardiomyopathy is the result of the transmission of a rare autosomal dominant gene. Further studies are currently underway to characterise the molecular basis of familial dilated cardiomyopathy and identify early disease within these families.