Reflex testing for Lynch syndrome: if we build it, will they come? Lessons learned from the uptake of clinical genetics services by individuals with newly diagnosed colorectal cancer (CRC).

The aim of this qualitative study was to examine the experience of individuals facing a choice about genetic counselling/testing in the context of newly diagnosed colorectal cancer (CRC). Nineteen individuals with newly diagnosed CRC, including 12 individuals who accepted genetic counselling ("acceptors") and 7 individuals who declined genetic counselling ("refusers"), were interviewed using a standardized questionnaire guide which focused on motivations and barriers experienced in the decision process. Data were analyzed using Karlsson's Empirical Phenomenological method of data analysis (Karlsson in Psychological qualitative research from a phenomenological perspective. Almgvist and Wiksell International, Stockholm, 1993). Three major themes were identified: facing challenges in health literacy; mapping an unknown territory; and adjusting to cancer. The study participants' testimonies provided novel insights into potential reasons for patient non-engagement in pilot studies of reflex testing for Lynch syndrome, and allowed us to formulate several recommendations for enhancing patient engagement. Our study findings suggest that patient engagement in clinical cancer genetics services, including reflex testing for Lynch syndrome, can only be achieved by addressing current health literacy issues, by deconstructing current misconceptions related to potential abuses of genetic information, by emphasizing the clinical utility of genetic assessment, and by adapting genetics practices to the specific context of cancer care.

Family history tools in primary care: does one size fit all?

Family health history (FHH) has potential value in many health care settings. This review discusses the potential uses of FHH information in primary care and the need for tools to be designed accordingly. We developed a framework in which the attributes of FHH tools are mapped against these different purposes. It contains 7 attributes mapped against 5 purposes. In considering different FHH tool purposes, it is apparent that different attributes become more or less important, and that tools for different purposes require different implementation and evaluation strategies. The context in which a tool is used is also relevant to its effectiveness. For FHH tools, it is unlikely that 'one size fits all', although appreciation of different purposes, users and contexts should facilitate the development of different applications from single FHH platforms.

Consent for newborn screening: the attitudes of health care providers.

BACKGROUND: As newborn screening (NBS) expands to meet a broader definition of benefit, the scope of parental consent warrants reconsideration. METHODS: We conducted a mixed methods study of health care provider attitudes toward consent for NBS, including a survey (n = 1,615) and semi-structured interviews (n = 36). RESULTS: Consent practices and attitudes varied by provider but the majority supported mandatory screening (63.4%) and only 36.6% supported some form of parental discretion. Few health care providers (18.6%) supported seeking explicit consent for screening condition-by-condition, but a larger minority (39.6%) supported seeking consent for the disclosure of incidentally generated sickle cell carrier results. Qualitative findings illuminate these preferences: respondents who favored consent emphasized its ease while dissenters saw consent as highly complex. CONCLUSION: Few providers supported explicit consent for NBS. Further, those who supported consent viewed it as a simple process. Arguably, these attitudes reflect the public health emergency NBS once was, rather than the public health service it has become. The complexity of NBS panels may have to be aligned with providers' capacity to implement screening appropriately, or providers will need sufficient resources to engage in a more nuanced approach to consent for expanded NBS.

Identifying mental health services in clinical genetic settings.

The purpose of this study was to examine the mental health needs of individuals at risk for adult onset hereditary disorder (AOHD) from the perspective of their genetic service providers, as it is unknown to what extent psychosocial services are required and being met. A mail-out survey was sent to 281 providers on the membership lists of the Canadian Association of Genetic Counsellors and the Canadian College of Medical Geneticists. The survey assessed psychosocial issues that were most commonly observed by geneticists, genetic counsellors (GCs), and nurses as well as availability and types of psychosocial services offered. Of the 129 respondents, half of genetic service providers reported observing signs of depression and anxiety, while 44% noted patients' concerns regarding relationships with family and friends. In terms of providing counselling to patients, as the level of psychological risk increased, confidence in dealing with these issues decreased. In addition, significantly more GCs reported that further training in psychosocial issues would be most beneficial to them if resources were available. As a feature of patient care, it is recommended that gene-based predictive testing include an integrative model of psychosocial services as well as training for genetic service providers in specific areas of AOHD mental health.

Clinical obligations and public health programmes: healthcare provider reasoning about managing the incidental results of newborn screening.

BACKGROUND: Expanded newborn screening generates incidental results, notably carrier results. Yet newborn screening programmes typically restrict parental choice regarding receipt of this non-health serving genetic information. Healthcare providers play a key role in educating families or caring for screened infants and have strong beliefs about the management of incidental results. METHODS: To inform policy on disclosure of infant sickle cell disorder (SCD) carrier results, a mixed-methods study of healthcare providers was conducted in Ontario, Canada, to understand attitudes regarding result management using a cross-sectional survey (N = 1615) and semistructured interviews (N = 42). RESULTS: Agreement to reasons favouring disclosure of SCD carrier results was high (65.1%-92.7%) and to reasons opposing disclosure was low (4.1%-18.1%). Genetics professionals expressed less support for arguments favouring disclosure (35.3%-78.8%), and more agreement with arguments opposing disclosure (15.7%-51.9%). A slim majority of genetics professionals (51.9%) agreed that a reason to avoid disclosure was the importance of allowing the child to decide to receive results. Qualitatively, there was a perceived "duty" to disclose, that if the clinician possessed the information, the clinician could not withhold it. DISCUSSION: While a majority of respondents perceived a duty to disclose the incidental results of newborn screening, the policy implications of these attitudes are not obvious. In particular, policy must balance descriptive ethics (ie, what providers believe) and normative ethics (ie, what duty-based principles oblige), address dissenting opinion and consider the relevance of moral principles grounded in clinical obligations for public health initiatives.

Noonan syndrome and neurofibromatosis type I in a family with a novel mutation in NF1.

Noonan syndrome (NS) and neurofibromatosis type I (NF1) belong to a group of clinically related disorders that share a common pathogenesis, dysregulation of the RAS-MAPK pathway. NS is characterized by short stature, heart defect, pectus deformity and facial dysmorphism, whereas skin manifestations, skeletal defects, Lisch nodules and neurofibromas are characteristic of NF1. Both disorders display considerable clinical variability. Features of NS have been observed in individuals with NF1 -a condition known as neurofibromatosis-Noonan syndrome (NFNS). The major gene causing NFNS is NF1. Rarely, a mutation in PTPN11 in addition to an NF1 mutation is present. We present the clinical and molecular characterization of a family displaying features of both NS and NF1, with complete absence of neurofibromas. To investigate the etiology of the phenotype, mutational analysis of NF1 was conducted, revealing a novel missense mutation in exon 24, p.L1390F, affecting the GAP-domain. Additional RAS-MAPK pathway genes were examined, but no additional mutations were identified. We confirm that NF1 mutations are involved in the etiology of NFNS. Furthermore, based on our results and previous studies we suggest that evaluation of the GAP-domain of NF1 should be prioritized in NFNS.

Canada: public health genomics.

Canada has a diverse population of 32 million people and a universal, publicly funded health care system provided through provincial and territorial health insurance plans. Public health activities are resourced at provincial/territorial level with strategic coordination from national bodies. Canada has one of the longest-standing genetics professional specialty organizations and is one of the few countries offering master's level training designed specifically for genetic counselors. Prenatal screening is offered as part of routine clinical prenatal services with variable uptake. Surveillance of the effect of prenatal screening and diagnosis on the birth prevalence of congenital anomalies is limited by gaps and variations in surveillance systems. Newborn screening programs vary between provinces and territories in terms of organization and conditions screened for. The last decade has witnessed a four-fold increase in requests for genetic testing, especially for late onset diseases. Tests are performed in provincial laboratories or outside Canada. There is wide variation in participation in laboratory quality assurance schemes, and there are few regulatory frameworks in Canada that are directly relevant to genetics testing services or population genetics. Health technology assessment in Canada is conducted by a diverse range of organizations, several of which have produced reports related to genetics. Several large-scale population cohort studies are underway or planned, with initiatives to harmonize their conduct and the management of ethical issues, both within Canada and with similar projects in other countries.

Face-brain asymmetry in autism spectrum disorders.

The heterogeneity of autism spectrum disorders (ASDs) confounds attempts to identify causes and pathogenesis. Identifiable endophenotypes and reliable biomarkers within ASDs would help to focus molecular research and uncover genetic causes and developmental mechanisms. We used dense surface-modelling techniques to compare the facial morphology of 72 boys with ASD and 128 first-degree relatives to that of 254 unrelated controls. Pattern-matching algorithms were able to discriminate between the faces of ASD boys and those of matched controls (AUC=0.82) and also discriminate between the faces of unaffected mothers of ASD children and matched female controls (AUC=0.76). We detected significant facial asymmetry in boys with ASD (P<0.01), notably depth-wise in the supra- and periorbital regions anterior to the frontal pole of the right hemisphere of the brain. Unaffected mothers of children with ASD display similar significant facial asymmetry, more exaggerated than that in matched controls (P<0.03) and, in particular, show vertical asymmetry of the periorbital region. Unaffected fathers of children with ASD did not show facial asymmetry to a significant degree compared to controls. Two thirds of unaffected male siblings tested were classified unseen as more facially similar to unrelated boys with ASD than to unrelated controls. These unaffected male siblings and two small groups of girls with ASD and female siblings, all show overall directional asymmetry, but without achieving statistical significance in two-tailed t-tests of individual asymmetry of ASD family and matched control groups. We conclude that previously identified right dominant asymmetry of the frontal poles of boys with ASD could explain their facial asymmetry through the direct effect of brain growth. The atypical facial asymmetry of unaffected mothers of children with ASD requires further brain studies before the same explanation can be proposed. An alternative explanation, not mutually exclusive, is a simultaneous and parallel action on face and brain growth by genetic factors. Both possibilities suggest the need for coordinated face and brain studies on ASD probands and their first-degree relatives, especially on unaffected mothers, given that their unusual facial asymmetry suggests an ASD susceptibility arising from maternal genes.

Further delineation of cardio-facio-cutaneous syndrome: clinical features of 38 individuals with proven mutations.

BACKGROUND: Cardio-facio-cutaneous syndrome (CFC) is a multiple congenital anomaly/mental retardation syndrome named because of a characteristic facies, cardiac anomalies, and ectodermal abnormalities. While considerable literature describes the main features, few studies have documented the frequencies of less common features allowing a greater appreciation of the full phenotype. METHODS: We have analysed clinical data on 38 individuals with CFC and a confirmed mutation in one of the genes known to cause the condition. We provide data on well-established features, and those that are less often described. RESULTS: Polyhydramnios (77%) and prematurity (49%) were common perinatal issues. 71% of individuals had a cardiac anomaly, the most common being pulmonary valve stenosis (42%), hypertrophic cardiomyopathy (39%), and atrial septal defect (28%). Hair anomalies were also typical: 92% had curly hair, 84% sparse hair, and 86% absent or sparse eyebrows. The most frequent cutaneous features were keratosis pilaris (73%), hyperkeratosis (61%) and nevi (76%). Significant and long lived gastrointestinal dysmotility (71%), seizures (49%), optic nerve hypoplasia (30%) and renal anomalies, chiefly hydronephrosis (20%), were among the less well known issues reported. CONCLUSION: This study reports a broad range of clinical issues in a large cohort of individuals with molecular confirmation of CFC.

Autosomal dominant dystonia-plus with cerebral calcifications.

OBJECTIVE: To report genealogic, clinical, imaging, neuropathologic, and genetic data from a Canadian kindred with dystonia and brain calcinosis originally described in 1985. METHODS: The authors performed clinical examinations and CT and PET studies of the head and analyzed blood samples. One autopsy was performed. RESULTS: The family tree was expanded to 166 individuals. No individuals were newly affected with dystonia, but postural tremor developed in two. The mean age at symptom onset was 19 years. Eight individuals had dystonia: three focal, one segmental, one multifocal, and three generalized. Seven displayed additional signs: chorea, intellectual decline, postural tremor, and dysarthria. CT studies were performed on five affected and 10 at-risk family members. All affected individuals and eight at-risk individuals had brain calcinosis. PET scans in two individuals showed reduced D(1)- and D(2)-receptor binding and reduced uptake of 6-[(18)F]fluoro-l-dopa. Autopsy of one affected individual showed extensive depositions of calcium in the basal ganglia, thalamus, cerebral white matter, and cerebellum. No specific immunohistochemistry abnormalities were seen. Genome search data showed no evidence of linkage to the previously described loci IBGC1, DYT1, and DYT12. CONCLUSIONS: The phenotype of this family consists of dystonia-plus syndrome. Brain calcium deposits vary in severity and distribution, suggesting that calcifications alone are not entirely responsible for the observed clinical signs. Further studies are needed to elucidate the etiology of this heterogeneous group of disorders.

The cardiofaciocutaneous syndrome.

The cardiofaciocutaneous (CFC) syndrome is a condition of sporadic occurrence, with patients showing multiple congenital anomalies and mental retardation. It is characterised by failure to thrive, relative macrocephaly, a distinctive face with prominent forehead, bitemporal constriction, absence of eyebrows, hypertelorism, downward-slanting palpebral fissures often with epicanthic folds, depressed nasal root and a bulbous tip of the nose. The cutaneous involvement consists of dry, hyperkeratotic, scaly skin, sparse and curly hair, and cavernous haemangiomata. Most patients have a congenital heart defect, most commonly pulmonic stenosis and hypertrophic cardiomyopathy. The developmental delay usually is moderate to severe. The syndrome is caused by gain-of-function mutations in four different genes BRAF, KRAS, mitogen-activated protein/extracellular signal-regulated kinase MEK1 and MEK2, all belonging to the same RAS-extracellular signal-regulated kinase (ERK) pathway that regulates cell differentiation, proliferation and apoptosis. The CFC syndrome is a member of a family of syndromes that includes the Noonan and Costello syndromes, presenting with phenotypic similarities. Noonan syndrome is caused by mutations in the protein tyrosine phosphatase SHP-2 gene (PTPN11), with a few people having a mutation in KRAS. Costello syndrome is caused by mutations in HRAS. The protein products of these genes also belong to the RAS-ERK pathway. Thus, the clinical overlap of these three conditions, which often poses a problem of differential diagnosis, is explained by their pathogenetic relatedness.

Psychological and genetic counseling implications for adolescent daughters of mothers with breast cancer.

Adolescent daughters of women with breast cancer (BC) are themselves at risk for heritable BC. Although some preliminary evidence suggests this group is at an increased risk for emotional problems, evidence is limited to studies with small samples and no comparison groups. This study examined psychological and family functioning, health attitudes and beliefs about genetic risks in adolescent females. A case-comparison design was used to compare 55 mother-daughter pairs in which the mother had been treated for BC (BC group) to 55 families from the general population (GP). Participants completed an assessment battery measuring perceptions of personal risk for BC and attitudes about gene testing for BC susceptibility, family functioning, and adolescent psychological adjustment. Based on manova, no significant differences were found between the two groups on measures of the psychological functioning. However, BC group adolescents reported significant (p < 0.01) worries about their future health and genetic risk for BC. About 68% of BC adolescents compared with 12% of GP adolescents reported being moderately to greatly concerned about their susceptibility to genetic mutations. Further, 85% of BC group adolescents believed they were susceptible to BC compared with 10% of GP adolescents. The results indicated no evidence of emotional, behavioral, or familial distress in these families. However, BC adolescents have significant worries about their future health. The results of this study demonstrate the need to develop a comprehensive model of care where accurate information about genetics and health risks can be provided. The adolescents also need support to help them cope and communicate with their mothers their worries about BC.

A randomized trial comparing alternative approaches to prenatal diagnosis counseling in advanced maternal age patients.

Prenatal diagnosis (PND) is offered routinely as part of pregnancy care to a large number of women at increased risk of fetal anomalies. Despite an extraordinary growth in the use of PND and significant resource allocation, few studies have examined outcomes of PND counseling, and virtually no research has evaluated the relative efficacy of various approaches to genetic counseling. This study was a randomized trial that compared which counseling methods - individual, group, and use of a decision aid - are effective in PND counseling for women of advanced maternal age (>/=35 years) and their partners. Three hundred and fifty-two women and 225 partners completed pre- and post-intervention questionnaires assessing changes in knowledge, decisional conflict, state anxiety, satisfaction, use of PND, and pregnancy outcomes. All participants showed a significant increase in knowledge and a decrease in decisional conflict post intervention. Those in the group intervention showed a significantly greater increase in knowledge than those in the individual counseling intervention. While high levels of satisfaction were reported by all, those in individual counseling were significantly more satisfied than those receiving group counseling or the decision aid. This study has shown unique benefits with each type of intervention such that women and their partners preferred individual genetic counseling, while they learned best in group-counseling sessions, and experienced the least decisional conflict regarding genetic testing with a decision aid.

A locus for spondylocarpotarsal synostosis syndrome at chromosome 3p14.

Spondylocarpotarsal synostosis syndrome is a rare autosomal recessive disorder characterised by vertebral fusions, frequently manifesting as an unsegmented vertebral bar, as well as fusions of the carpal and tarsal bones. In a study of three consanguineous families and one non-consanguineous family, linkage analysis was used to establish the chromosomal location of the disease gene. Linkage analysis localised the disease gene to chromosome 3p14. A maximum lod score of 6.49 (q = 0) was obtained for the marker at locus D3S3532 on chromosome 3p. Recombination mapping narrowed the linked region to the 5.7 cM genetic interval between the markers at loci D3S3724 and D3S1300. A common region of homozygosity was found between the markers at loci D3S3724 and D3S1300, defining a physical interval of approximately 4 million base pairs likely to contain the disease gene. Identification of the gene responsible for this disorder will provide insight into the genes that play a role in the formation of the vertebral column and joints.

Predictive, pre-natal and diagnostic genetic testing for Huntington's disease: the experience in Canada from 1987 to 2000.

Predictive and pre-natal testing for Huntington's Disease (HD) has been available since 1987. Initially this was offered by linkage analysis, which was surpassed by the advent of the direct mutation test for HD in 1993. Direct mutation analysis provided an accurate test that not only enhanced predictive and pre-natal testing, but also permitted the diagnostic testing of symptomatic individuals. The objective of this study was to investigate the uptake, utilization, and outcome of predictive, pre-natal and diagnostic testing in Canada from 1987 to April 1, 2000. A retrospective design was used; all Canadian medical genetics centres and their affiliated laboratories offering genetic testing for HD were invited to participate. A total of 15 of 22 centres (68.2%), currently offering or ever having offered genetic testing for HD, responded, providing data on test results, demographics, and clinical history. A total of 1061 predictive tests, 15 pre-natal tests, and 626 diagnostic tests were performed. The uptake for predictive testing was approximately 18% of the estimated at-risk Canadian population, ranging from 12.5% in the Maritimes to 20.7% in British Columbia. There appears to have been a decline in the rate of testing in recent years. Of the predictive tests, 45.0% of individuals were found to have an increased risk, and a preponderance of females (60.2%) sought testing. A greater proportion of those at < or = 25% risk sought predictive testing once direct CAG mutation analysis had become available (10.9% after mutation analysis vs 4.7% before mutation analysis, p = 0.0077). Very few pre-natal tests were requested. Of the 15 pre-natal tests, 12 had an increased risk, resulting in termination of pregnancy in all but one. Diagnostic testing identified 68.5% of individuals to be positive by mutation analysis, while 31.5% of those with HD-like symptoms were not found to have the HD mutation. The positive diagnostic tests included 24.5% of individuals with no known prior family history of HD.

Characteristics of patients with persistent severe disability and medically unexplained neurological symptoms: a pilot study.

This study audited 25 patients (21 female) from Oxfordshire who had been referred to either the liaison psychiatry or the neurological disability service between 1992 and 1998, reported a Barthel activities of daily living index score < 20 or a global assessment of functioning score of < or = 30, and had no pathology to explain their neurological disability. Levels of motor impairment, disability, mood, and cognitive status were assessed using standardised scales, and all patients were assigned a psychiatric diagnosis according to the International classification of diseases, 10th revision. Of the 25 patients, 13 had a motor conversion disorder, 8 had diverse somatoform disorders, and 3 had chronic fatigue syndrome. Nine had extensive previous contact with psychiatric services and 11 had experienced physical or sexual abuse. In 6 patients cessation of repeated self harm was closely associated with the onset of wheelchair use. Seven were receiving treatment for depression. The commonest putative diagnoses were multiple sclerosis (6) and epilepsy (5). Twelve were unable to walk and 20 owned a wheelchair but only 3 had formal care packages. The mean (SD) Barthel score was 14.1 (3.3) and the mean (SD) Frenchay activity index score was 12.9 (7.5). All were unemployed and receiving a disability living allowance, and some had benefits of up to pound 1815 a month. This small but significant group of disabled patients had a variety of psychiatric and neurological diagnoses and used considerable health care resources.

Measuring women's preferences for breast cancer treatments and BRCA1/BRCA2 testing.

In establishing decision models in the treatment and prevention of breast cancer, it is important to evaluate patients' preferences for such interventions. The objectives of the present study were: (i) to characterize women's preferences for breast cancer treatments and BRCA1/BRCA2 testing, using the rating scale and standard gamble techniques; and (ii) to identify factors associated with these quality of life indices. Data were collected from women with breast cancer (n = 60), high-risk relatives of women with breast cancer (n = 58), and women in the general population (n = 51). Regardless of group membership, participants favoured treatment and prevention options that involved minimal physical invasiveness. Women with breast cancer rated lumpectomy and radiation treatment more highly than high-risk relatives and women in the general population. Preferences did not differ according to participants' intentions to undergo BRCA testing. Age was the only demographic variable associated with health state preferences. These findings hold implications for the application of patient preferences to clinical decision making.