Ethical issues in genetic testing for insurance.
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Genetic Testing↗
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Genetic testing of the family with a Carney-complex member leads to successful early removal of an asymptomatic atrial myxoma in the mother of the patient.
Carney complex is a rare cardiocutaneous syndrome with an autosomal-dominant inheritance pattern. Apart from its cutaneous manifestations of multiple blue naevi and lentigines, it can involve multiple other organ systems, particularly the heart, where myxoma tumours commonly develop and can potentially lead to serious complications such as cerebrovascular accidents and myocardial infarction. Recently, a specific mutation in the gene encoding the R1-alpha regulatory subunit of cyclic adenosine monophosphate-dependent protein kinase A (PRKAR1alpha) has been discovered and found to be associated with a high risk of developing cardiac myxomas. We report the case of a Carney-complex family member who displayed no observable clinical or cardiac features of the disease but who was found to be positive for the PRKAR1alpha gene mutation on genetic testing. Further evaluation of this patient subsequently led to the discovery of a 3-cm atrial myxoma that had previously been undetected on cardiac assessment. This case highlights the potential benefits of using genetic screening for this disease.
Abnormalities, Multiple↗
Conversion technology and its role in genetic testing of inherited diseases.
Identification of germline mutations in a sensitive and specific manner presents a continuing challenge. A major contributing factor to this is that humans are diploid and therefore mutations in one allele are often masked by the normal sequence present on the other copy of the chromosome. Mutation analysis on haploid templates (one copy of a chromosome), rather than on diploid templates (both copies of a chromosome), overcomes this problem and obscured mutations are unmasked. Conversion technology converts a sample from diploid to haploid state by isolating individual alleles in somatic cell hybrids. From each sample, a series of stable hybrids is generated that contains the human chromosome complement in the haploid state. This article describes conversion technology and its applications. The utility of this technique in increasing the sensitivity of genetic testing has been demonstrated for the predisposition to hereditary nonpolyposis colorectal cancer and it is proposed that a similar approach may be applicable to many different diseases.
Animals↗
Predictive genetic testing to control coronary heart disease and hyperlipidemia.
The contribution of genes to the etiology of coronary heart disease (CHD) is highly significant even when monogenic hyperlipidemias are excluded. Previous studies in the area of quantitative genetics and of disease or risk factor association with random genetic markers have, in recent years, been supplemented with studies focused on "candidate genes"--genes whose products are known or suspected to be involved in the atherogenic process, the thrombogenic process, lipid metabolism, or apolipoprotein (apo) structure or function. In 1974, the candidate gene approach led to the detection of a strong association between genetically determined Lp(a) lipoprotein and premature CHD and, in 1976, also led to the detection, in several populations, of the association between lipid levels and genetic types in the normal low density lipoprotein (LDL) polymorphism referred to as the Ag(x) variation. Restriction fragment length polymorphisms in DNA have been uncovered in the genes for several functionally important proteins including apos. Some of these DNA variants have been reported to be associated with CHD or lipid level. Such variants should become useful tools in predictive genetic testing for CHD risk. Most studies on the genetics of risk factors have focused on risk factor level. Because an individual's propensity to develop atherosclerosis could depend not only on absolute lipid levels but also on lipid responses to atherogenic stimuli, we have developed a method to examine if "variability genes" exist. To detect the latter class of genes, we examine within-pair differences in quantitative parameters between monozygotic (MZ) twin pairs possessing and MZ twin pairs lacking the gene under study.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Some public health issues in the current state of genetic testing for breast cancer in Australia.
Two genes associated with a high breast cancer risk (BRCA1 and BRCA2) have been discovered recently from study of large breast-cancer-dense kindreds. It is problematic to make inferences from these atypical families to the general population. Nevertheless, it appears that about 1 to 2 per cent of all breast cancer may be due to rare deleterious mutations in BRCA1 or BRCA2. The majority of breast cancer families with fewer than four cases are likely to have cancers not attributable to these genes. There may be more common mutations in other genes (such as ATM, HRAS1) that confer a moderate risk of breast cancer, and may account for 5 to 15 per cent of cases. At this early stage of cancer genetics, the risks associated with particular mutations are not known, there are no proven and acceptable strategies for women with an inherited susceptibility to ameliorate risk or improve prognosis, and risk estimates appropriate for Australian women with a family history of breast cancer are not established, although data from the United States may overestimate risk. Information is needed from population-based studies, such as the Australian Breast Cancer Family Study (Hopper et al. Breast 1994; 3: 79-86), but 100 per cent mutation detection in large cancer genes is difficult and expensive. Development of a systematic, research-oriented, evidence-based approach to genetic testing in Australia is recommended. Australia could lead the world in having common protocols used in breast cancer clinics across the country, linked to a national research consortium and database.
Australia↗
Changes in health-related behaviours following BRCA 1/2 genetic testing: the case of hormone replacement therapy.
OBJECTIVE: To determine hormone replacement therapy (HRT)use among women at high risk for breast cancer and ovarian cancer, before genetic testing for the cancer susceptibility genes BRCA1 and BRCA2, and 1 year following disclosure of the test results. METHODS: Participants were 209 French-Canadian women (from 67 high-risk families) who were tested for BRCA1/2 mutations as part of the multidisciplinary research program INHERIT BRCAs (INterdisciplinary HEalth Research International Team on BReast CAncer susceptibility). Use of HRT was recorded at the first genetic counselling session and through a self-administered questionnaire 1 year after result disclosure. RESULTS: At the genetic counselling session, approximately 15% of women (31/209) reported using HRT, a proportion that is significantly lower than the 25% observed among similarly aged women from the general Quebec population (P < .001). Further analyses, based on the generalized estimating equations models, were carried out to evaluate variations in HRT use from the first genetic counselling session up to 1 year post-disclosure of BRCA1/2 test results. These analyses indicated a trend toward decreased HRT use among BRCA1/2 mutation carriers (P = .08). CONCLUSIONS: Women at high risk for breast cancer and ovarian cancer tend to avoid HRT when BRCA1/2 mutations are either suspected or confirmed. Further studies are needed to assess the actual risk of HRT use among women at high risk of breast cancer, and to develop clinical guidelines regarding its use in this population of women.
Adult↗
Predictors of participation in psychosocial telephone counseling following genetic testing for BRCA1 and BRCA2 mutations.
Although adjunctive educational and psychosocial programs are now being developed for BRCA1 and BRCA2 (BRCA1/2) mutation carriers, limited information is available about whether mutation carriers will want to receive such programs or about the characteristics of individuals who participate. The goals of the present study were to describe rates of completing a psychosocial telephone counseling (PTC) intervention that was offered to female BRCA1/2 mutation carriers and to identify sociodemographic and psychological factors associated with decisions to complete the intervention. Subjects were 66 BRCA1/2 mutation carriers who were randomized to receive a PTC intervention following receipt of genetic test results. Sociodemographic and psychological factors were evaluated before notification of assignment to the PTC intervention. Completion of the intervention was determined from study records. Overall, 75.8% of subjects completed the PTC intervention. Compared to unaffected subjects, those affected with breast and/or ovarian cancer were 76% less likely to complete the intervention [odds ratio (OR) = 0.24, 95% confidence interval (CI) = 0.06, 0.98, P = 0.05]. In addition, subjects with higher levels of cancer-specific distress [OR = 4.74, 95% CI = 1.02, 22.03, P = 0.05] and those with greater perceptions of social support [OR = 5.81, 95% CI = 1.29, 26.16, P = 0.02] were also most likely to complete the intervention. The results of this study suggest that while most BRCA1/2 mutation carriers are likely to complete an adjunctive psycho-educational program, personal history of cancer, cancer-specific distress, and perceptions of social support are likely to influence participation.
Adolescent↗
Genetic testing for women previously diagnosed with breast/ovarian cancer: examining the impact of BRCA1 and BRCA2 mutation searching.
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.
Adult↗
Molecular and clinical study of familial adenomatous polyposis for genetic testing and management.
Familial adenomatous polyposis (FAP) is an inherited predisposition to colorectal cancer characterized by the development of numerous adenomatous polyps, predominantly in the colorectal region. Germline mutations of the adenomatous polyposis coli (APC) gene are responsible for familial adenomatous polyposis. We examined germline mutations of the APC gene and clinical features among eighty-seven individuals who consisted of thirty-nine FAP-patients, thirty-seven of their family members with a 1 in 2 risk of predisposition to this disease, and eleven normal persons. We accurately identified nine heterozygotes, among individuals with a 1 in 2 risk by genetic testing, without the uncertainty of the recurrence risk calculated by Bayes' theorem. Six of the nine heterozygotes were confirmed to have colorectal polyps by colonoscopic examination. Since they were diagnosed at 12.7 years-of-age on average, and were no more than 20 years old, they could be treated to prevent colorectal cancer. Based on the genotype-phenotype correlation, we concluded that the germline mutations responsible for the sparse polyps phenotype of FAP-patients tend to locate from codon 1055 in the proximal region of the APC gene, while those for the profuse type locate from codon 1102 in the distal region. Among the thirty-nine FAP-patients, we found that those with the germline mutations within codon 1055 and codon 1262 had colorectal carcinomas of an advanced stage, at a high rate (71.4%). Special attention and aggressive intervention is needed in these patients and relatives at risk. With reasonable and appropriate management, it should be possible to prolong and improve the quality of life of those family members both affected and at risk.
Adenomatous Polyposis Coli↗
Genetic testing for familial cancer. A clinician's perspective.
Molecular genetics researchers have recently identified several genes (and mutations) that result in family cancers. This has prompted the development of molecular diagnostic tests to identify individuals at risk, making it possible to prevent certain types of cancer. However, detection and prevention of certain malignancies are impeded because few medical practitioners know of these tests, and because patients fear the emotional consequences of testing. To highlight some of these issues, we describe a patient who chose to be tested for the RET gene mutation. The mutation was identified, additional family members were tested, and several were found to be at risk. The RET gene mutation is 100% predictive for the ultimate development of medullary thyroid cancer. Testing and counseling provided this patient and her family with information not only about the thyroid cancer in their family, but also about multiple endocrine neoplasia, a syndrome resulting from mutation of this particular gene. Familial cancer clinics are being established to assist patients and physicians who face questions about familial diseases and the value of genetic testing. We include in this report information about the familial cancer clinics in Minnesota and list the services and testing opportunities available at these clinics.
Adolescent↗
Redefining race: can genetic testing provide biological proof of Indian ethnicity?
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Cultural Characteristics↗
Genetic testing: for whose benefit is it provided?
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Commerce↗
Epileptogenic brain malformations: clinical presentation, malformative patterns and indications for genetic testing.
We review here those malformations of the cerebral cortex which are most often observed in epilepsy patients, for which a genetic basis has been elucidated or is suspected and give indications for genetic testing. There are three forms of lissencephaly (agyria-pachygyria) resulting from mutations of known genes, which can be distinguished because of their distinctive imaging features. They account for about 85% of all licence-phalies. Lissencephaly with posteriorly predominant gyral abnormality is caused by mutations of the LIS1 gene on chromosome 17. Anteriorly predominant lissencephaly in hemizygous males and subcortical band heterotopia (SBH) in heterozygous females are caused by mutations of the XLIS (or DCX) gene. Mutations of the coding region of XLIS were found in all reported pedigrees, and in most sporadic female patients with SBH. Missense mutations of both LIS1 and XLIS genes have been observed in some of the rare male patients with SBH. Autosomal recessive lissencephaly with cerebellar hypoplasia has been associated with mutations of the reelin gene. With few exceptions, children with lissencephaly have severe developmental delay and infantile spasms early in life. Patients with SBH have a mild to severe mental retardation with epilepsy of variable severity and type. X-linked bilateral periventricular nodular heterotopia (BPNH) consists of typical BPNH with focal epilepsy in females and prenatal lethality in males. About 88% of patients have focal epilepsy. Filamin A (FLNA) mutations have been reported in some families and in sporadic patients. Additional, possibly autosomal recessive gene(s) are likely to be involved in causing BPNH non-linked to FLN1. Tuberous sclerosis (TS) is a dominant disorder caused by mutations in at lest two genes, TSC1 and TSC2. 75% of cases are sporadic. Most patients with TS have epilepsy. Infantile spasms are a frequent early manifestation of TS. Schizencephaly (cleft brain) has a wide anatomo-clinical spectrum, including focal epilepsy in most patients. Familial occurrence is rare. Heterozygous mutations in the EMX2 gene have been reported in some patients. However, at present, there is no clear indication on the possible pattern of inheritance and on the practical usefulness that mutation detection in an individual with schizencephaly would carry in terms of genetic counselling. Amongst several syndromes featuring polymicrogyria, bilateral perisylvian polymicrogyria had familial occurrence on several occasions. Genetic heterogeneity is likely, including autosomal recessive, X-linked dominant, X-linked recessive inheritance and association to 22q11.2 deletions. FISH analysis for 22q11.2 is advisable in all patients with perisylvian polymicrogyria. Parents of an affected child with normal karyotype should be given up to a 25% recurrence risk.
1-Alkyl-2-acetylglycerophosphocholine Esterase↗
Genetic testing and breast cancer: the women's point of view.
Breast cancer is the most common cancer among women in Western countries (130,000 cases per year in Europe) and accounts for 20-25% of all malignancies in European women. In the past few years medical journals have focused greater attention on the quality and quantity of information provided to consumers; there is a general consensus amongst physicians on the importance of having better informed consumers. This change in attitude is influencing greatly the physician-patient relationship and political decisions. Breast cancer associations, like the National Breast Cancer Coalition in the USA or EUROPA DONNA, the European Breast Cancer Coalition in Europe, have pushed for involvement in the discussion of any phase of illness, and have a particular interest in preventive medicine. The identification of high-risk women by genetic testing for BRCA1 and BRCA2 mutations is largely debated, in particular regarding patient counseling, and psychosocial and legislative support. This article reports the different points of view raised by women's movements, so that useful suggestions may be provided to improve breast cancer prevention modalities.
BRCA1 Protein↗
Impact of HFE genetic testing on clinical presentation of hereditary hemochromatosis: new epidemiological data.
BACKGROUND: Hereditary hemochromatosis (HH) is a common inherited disorder of iron metabolism in Northern European populations. The discovery of a candidate gene in 1996 (HFE), and of its main mutation (C282Y), has radically altered the way to diagnose this disease. The aim of this study was to assess the impact of the HFE gene discovery on the clinical presentation and epidemiology of HH. METHODS: We studied our cohort of 415 patients homozygous for the C282Y allele and included in a phlebotomy program in a blood centre in western Brittany, France. RESULTS: In this cohort, 56.9% of the patients were male and 21.9% began their phlebotomy program before the implementation of the genetic test. A significant decrease in the sex ratio was noticed following implementation of this DNA test, from 3.79 to 1.03 (p < 10(-5)), meaning that the proportion of diagnosed females relatives to males greatly increased. The profile of HH patients at diagnosis changed after the DNA test became available. Serum ferritin and iron values were lower and there was a reduced frequency of clinical signs displayed at diagnosis, particularly skin pigmentation (20.1 vs. 40.4%, OR = 0.37, p < 0.001) and hepatomegaly (11.0 vs. 22.7%, OR = 0.42, p = 0.006). In contrast, fatigue became a more common symptom at diagnosis (68.0 vs. 51.2%, OR = 2.03, p = 0.004). CONCLUSION: This study highlights the importance of the HFE gene discovery, which has simplified the diagnosis of HH and modified its clinical presentation and epidemiology. This study precisely measures these changes. Enhanced diagnosis of HFE-related HH at an early stage and implementation of phlebotomy treatment are anticipated to maintain normal life expectancy for these patients.
Adolescent↗
The impact of diagnostic error on testing genetic association in case-control studies.
In case-control studies, subjects in the case group may be recruited from suspected patients who are diagnosed positively with disease. While many statistical methods have been developed for measurement error or misclassification of exposure variables in epidemiological studies, no studies have been reported on the effect of errors in diagnosing disease on testing genetic association in case-control studies. We study the impact of using the original Cochran-Armitage trend test assuming no diagnostic error when, in fact, cases and controls may be clinically diagnosed by an imperfect gold standard or a reference test. The type I error, sample size and asymptotic power of trend tests are examined under a family of genetic models in the presence of diagnostic error. The empirical powers of the trend tests are also compared by simulation studies under various genetic models.
Case-Control Studies↗
Genetic Testing Unveils a Novel Thrombospondin-1 Domain Containing Protein 1 Gene Variant as the Cause of Chronic Edema in a 79-Year-Old Woman.
Edema requires management tailored to its underlying etiology; however, in some cases the cause remains elusive. We describe a 79-year-old woman with lifelong unexplained peripheral edema. Comprehensive evaluation excluded common etiologies such as heart failure, renal dysfunction, and venous thrombosis. Whole-genome sequencing identified a novel homozygous splice-site variant (NM_018676.4:c.58+2T>G) in the thrombospondin-1 domain-containing protein 1 (THSD1) gene, which has previously been associated with non-immune hydrops fetalis (NIHF). This report describes, to our knowledge, the first elderly patient with chronic peripheral edema harboring a likely pathogenic THSD1 variant, suggesting that THSD1-related disease may, in rare instances, persist beyond the perinatal period and present into late adulthood. Although causality cannot be established definitively from a single case, the findings highlight the potential utility of genetic testing in adults with chronic unexplained edema.
chronic edema↗
[Genetic study of plasmid integration into yeast chromosomes. III. Selection for a phenotype of Saccharomyces cerevisiae (Meyen ex Hansen) clones which lost the 2-micron DNA and their genetic testing].
We used the coloured adeI (cir+) haploid strain containing an episomal plasmid integrated into the chromosome I for visual detection and genetic testing of Saccharomyces cerevisiae clones having lost 2 microns DNA. During incubation, colonies of this strain were covered with numerous papillae of the same genotype. Stable clones which did not generate such papillae were isolated. Hybrids of these clones with (cir0) partner were not shown to exhibit destabilization of the chimeric chromosome. The stable clones isolated proved to lack 2 microns DNA, as shown by colony hybridization technique. We conclude therefore that the loss of the cryptic yeast plasmid may be phenotypically detected.
Chromosome Deletion↗