How do women talk about self-funded breast cancer genetic testing?: Small stories and stance-taking strategies.

Genetic testing for breast cancer genes is an experience which is inextricably linked with health communication practices and the broader social context in which it occurs. Linguistic approaches can provide perspective on how women seeking self-funded BRCA1/2 gene testing represent their experiences, knowledge, roles, choices and emotions through the way they talk. A discursive constructionist epistemology and narrative theoretical framework informed the applied linguistics methodology. Analysis of 'small stories' and stance-taking was performed on eight transcripts of audio-recorded telephone interviews with women at low to moderate risk of carrying BRCA1/2 pathogenic variants who self-funded genetic testing. We found a high prevalence of 'small stories' including accounts of events, hypotheticals, habitual narratives, and stories which combined multiple genres. Stance-taking was a means by which participants constructed personal identities in the conversational context, such as that of a responsible person. Via stance-taking strategies, participants also actively negotiated the conversational agenda, for example expressing different degrees of alignment with the interviewer's orientation towards emotions. This study provides a basis for recognizing linguistic markers in genetic counseling interactions about genetic testing for breast cancer genes. Enhanced awareness of client language choice, and the ways in which small stories and stance can signify the client's evaluation of experience and choices, alignment with the genetic counselor's questions/statements, and investment in the conversation, has potential to improve the therapeutic interaction.

Psychiatric genetic counseling: A survey of Australian genetic counselors' practice and attitudes.

Genetic counseling plays a critical role in supporting individuals and their families' adaption to psychiatric conditions, addressing the multifactorial nature of these conditions in a personally meaningful and empowering way. Yet data related to the practice and attitudes of Australian genetic counselors about psychiatric genetic counseling (PGC) is limited. This survey investigated the practice of Australian genetic counselors, and their attitudes toward PGC. Genetic counselors (N = 393) were invited to participate in an anonymous online survey between March and May 2022. Forty-four genetic counselors (response rate = 11%) from Australia and New Zealand responded. No respondents practice in psychiatric genetics as their speciality area; most respondents do not see any patients where the primary indication is a personal and/or family history of psychiatric disorders (91%). Greater than half of respondents (56%) believed there was sufficient evidence to support PGC, and 64% enquire about personal and/or family history of psychiatric disorders, but only 25% provide genetic counseling on this topic. Most respondents do not feel confident providing risk assessments for psychiatric disorders (72%), while the majority expressed interest in attending specialist training (95%), and in incorporating PGC into future practice (77%). Australian genetic counselors would benefit from psychiatric genetic education and training, and establishment of specialized PGC services would address this gap in patient care, while providing opportunities for genetic counselors to gain skills and experience in PGC.

Real world outcomes and implementation pathways of exome sequencing in an adult genetic department.

PURPOSE: This study aimed to correlate the indications and diagnostic yield of exome sequencing (ES) in adult patients across various clinical settings. The secondary aim was to examine the clinical utility of ES in adult patients. METHODS: Data on demographics, clinical indications, results, management changes, and cascade testing were collected for 250 consecutive patients who underwent ES through an adult genetics department between 2016 and 2021. Data were analyzed using descriptive and inferential statistics. Testing in which traditional gene panels were in standard use, such as in heritable cancers, was excluded. RESULTS: The average age at testing was 43 years (range = 17-80 years). A molecular diagnosis was identified in 29% of patients. Older age at symptom onset did not pre-exclude a substantial diagnostic yield. Patients with syndromic intellectual disability and multiple system disorders had the highest yield. In >50% of patients with an exome diagnosis, the results changed management. Cascade testing occured in at least one family member for 30% of patients with a diagnosis. Diagnostic results had reproductive implications for 26% of patients and 31% of patients' relatives. CONCLUSION: ES has a robust diagnostic yield and clear clinical utility in adult patients across a range of ages and phenotypes.

Clinical impact of whole-genome sequencing in patients with early-onset dementia.

BACKGROUND: In the clinical setting, identification of the genetic cause in patients with early-onset dementia (EOD) is challenging due to multiple types of genetic tests required to arrive at a diagnosis. Whole-genome sequencing (WGS) has the potential to serve as a single diagnostic platform, due to its superior ability to detect common, rare and structural genetic variation. METHODS: WGS analysis was performed in 50 patients with EOD. Point mutations, small insertions/deletions, as well as structural variants (SVs) and short tandem repeats (STRs), were analysed. An Alzheimer's disease (AD)-related polygenic risk score (PRS) was calculated in patients with AD. RESULTS: Clinical genetic diagnosis was achieved in 7 of 50 (14%) of the patients, with a further 8 patients (16%) found to have established risk factors which may have contributed to their EOD. Two pathogenic variants were identified through SV analysis. No expanded STRs were found in this study cohort, but a blinded analysis with a positive control identified a C9orf72 expansion accurately. Approximately 37% (7 of 19) of patients with AD had a PRS equivalent to >90th percentile risk. DISCUSSION: WGS acts as a single genetic test to identify different types of clinically relevant genetic variations in patients with EOD. WGS, if used as a first-line clinical diagnostic test, has the potential to increase the diagnostic yield and reduce time to diagnosis for EOD.

Metaphors and why these are important in all aspects of genetic counseling.

Metaphors appear simple but are fundamental schemata allowing expression and processing of complex emotions and information. They are so embedded in language and thinking that we are often unaware of their impact, despite the crucial role of metaphors in communication, learning and creating meaning from experiences. A deeper understanding of how to recognize and work with client-generated and counselor-generated metaphors has great potential as an addition to the genetic counseling 'tool-box'. Here, we draw on studies from related health and psychotherapy fields to discuss how working purposefully with metaphors may offer a powerful way to enhance communication within a reciprocally engaged client-counselor relationship. Metaphors present ways to explain complex genetic concepts in a personally meaningful form, to gain a deeper understanding of client's experiences and emotions, to assist processing of experiences, emotions, and concepts, and to assist client and counselor to access and reflect on subconscious emotions, self-concept, and motivations. In addition, working with metaphors has been shown to facilitate coping and action. This paper sets the scene for why and how genetic counselors can utilize client-generated and counselor-generated metaphors purposefully in all areas of practice, including enhancing the therapeutic interaction with clients, as well as in supervision, training, cultural competence, and shaping of societal attitudes toward genetics.

Assessing the acceptability, feasibility, and usefulness of a psychosocial screening tool to patients and clinicians in a clinical genetics service in Australia.

Increasing demand for clinical genetic services may impact the resources and quality of genetic counseling, potentially impacting patient outcomes. Using a psychosocial screening tool may aid the provision of genetic counseling by reliably identifying patients' psychosocial needs. The Genetic Psychosocial Risk Instrument (GPRI) is a validated genetic-specific screening tool designed to identify psychological risk factors that predict distress in patients having genetic testing. This questionnaire-based study investigated the perceived acceptability, feasibility, and usefulness of the GPRI in patients and clinicians in routine clinical genetic practice. From December 2018 to January 2019, 154 patients attending an Australian clinical genetic service were invited to complete a paper-based survey that included the GPRI. The GPRI was scored and provided to the clinician for use in the appointment. In February 2019, clinicians completed an anonymous online survey regarding acceptability, feasibility, and usefulness of the GPRI. Descriptive statistics, chi-squared, t tests, and regression analyses were used to analyze the patient data, and descriptive statistics were employed for clinician surveys. A total of 145 patients participated (94% response rate). The average GPRI score was 46.3 (95% CI 43.6-49.0) with 41% of patients meeting the 50-point threshold indicating high risk for psychological distress. The GPRI was highly acceptable to patients, regardless of their level of psychosocial risk. Fourteen clinicians participated (54% response rate): 85% found the GPRI not too time consuming, and 86% believed it improved patient care by identifying patient needs. All were willing to use the GPRI routinely. The use of the GPRI is highly acceptable to patients and clinicians in this setting, assisting in identifying patients at risk for distress, prompting clinicians to address concerns, provide psychosocial support, and consider ongoing referral. As 41% of patients' scores indicated a high risk of distress, the GPRI is an important tool for potentially enhancing overall patient outcomes.

Genetic testing in dementia-A medical genetics perspective.

OBJECTIVE: When a genetic cause is suspected in a person with dementia, it creates unique diagnostic and management challenges to the treating clinician. Many clinicians may be unaware of the practicalities surrounding genetic testing for their patients, such as when to test and what tests to use and how to counsel patients and their families. This review was conducted to provide guidance to clinicians caring for patients with dementia regarding clinically relevant genetics. METHODS: We searched PubMed for studies that involved genetics of dementia up to March 2020. Patient file reviews were also conducted to create composite cases. RESULTS: In addition to families where a strong Mendelian pattern of family history is seen, people with younger age of onset, especially before the age of 65 years were found to be at an increased risk of harbouring a genetic cause for their dementia. This review discusses some of the most common genetic syndromes, including Alzheimer disease, frontotemporal dementia, vascular dementia, Parkinson disease dementia/dementia with Lewy bodies and some rarer types of genetic dementias, along with illustrative clinical case studies. This is followed by a brief review of the current genetic technologies and a discussion on the unique genetic counselling issues in dementia. CONCLUSIONS: Inclusion of genetic testing in the diagnostic pathway in some patients with dementia could potentially reduce the time taken to diagnose the cause of their dementia. Although a definite advantage as an addition to the diagnostic repository, genetic testing has many pros and cons which need to be carefully considered first.

Genetic Dominant Variants in STUB1, Segregating in Families with SCA48, Display In Vitro Functional Impairments Indistinctive from Recessive Variants Associated with SCAR16.

Variants in STUB1 cause both autosomal recessive (SCAR16) and dominant (SCA48) spinocerebellar ataxia. Reports from 18 STUB1 variants causing SCA48 show that the clinical picture includes later-onset ataxia with a cerebellar cognitive affective syndrome and varying clinical overlap with SCAR16. However, little is known about the molecular properties of dominant STUB1 variants. Here, we describe three SCA48 families with novel, dominantly inherited STUB1 variants (p.Arg51_Ile53delinsProAla, p.Lys143_Trp147del, and p.Gly249Val). All the patients developed symptoms from 30 years of age or later, all had cerebellar atrophy, and 4 had cognitive/psychiatric phenotypes. Investigation of the structural and functional consequences of the recombinant C-terminus of HSC70-interacting protein (CHIP) variants was performed in vitro using ubiquitin ligase activity assay, circular dichroism assay and native polyacrylamide gel electrophoresis. These studies revealed that dominantly and recessively inherited STUB1 variants showed similar biochemical defects, including impaired ubiquitin ligase activity and altered oligomerization properties of the CHIP. Our findings expand the molecular understanding of SCA48 but also mean that assumptions concerning unaffected carriers of recessive STUB1 variants in SCAR16 families must be re-evaluated. More investigations are needed to verify the disease status of SCAR16 heterozygotes and elucidate the molecular relationship between SCA48 and SCAR16 diseases.

"It wasn't just for me": Motivations and implications of genetic testing for women at a low risk of hereditary breast and ovarian cancer syndrome.

OBJECTIVE: Genetic testing for hereditary breast and ovarian cancer (HBOC) due to pathogenic variants in BRCA1 or BRCA2 is why most women present to familial cancer centers. Despite being assessed as low risk for HBOC, many women proceed with genetic testing. This study explored the genetic testing experiences of unaffected women at low risk of HBOC to clarify what motivates these women to have testing, and what are the implications of the results. METHODS: A qualitative approach was taken. Participants included women who had genetic testing for HBOC from 2016-2018 at the Parkville Familial Cancer Centre in Melbourne, Australia. In-depth, semi-structured interviews were conducted, and thematic analysis was undertaken on transcripts; transcripts were coded, codes were organized into a hierarchical system of categories/subcategories, and key themes were identified. RESULTS: Analysis of 19 transcripts identified five themes: family underpinned all motivators for HBOC genetic testing; health professionals were influential throughout the process; participants were planning for a positive result; results influenced screening-anxiety and frequency; and negative results gave participants relief in many different ways. The three participants with positive results reported feeling shocked at the results and empowered giving this information to family members. CONCLUSIONS: Women at low HBOC risk may be motivated to seek genetic testing, and access to this is increasingly offered through non-genetic health professionals. Professionals can support clients through genetic testing by recognizing familial experiences, providing accurate information, addressing risk perceptions, and understanding cancer anxiety felt by many women.

Communication about spinal muscular atrophy and genetic risk within families: An Australian pilot study.

AIM: In families with a child diagnosed with spinal muscular atrophy (SMA), siblings who do not have SMA could still be genetic carriers of the condition. This study is the first to explore how siblings of patients with SMA learn about the condition and their genetic risk. METHOD: In-depth, semi-structured interviews were conducted with several parents and unaffected siblings of people with SMA types II and III in Australia. Thematic analysis was performed. RESULTS: Siblings described learning about SMA gradually over time through conversations with their parents and other sources, including the Internet, biology classes and support groups. Parents and unaffected siblings described challenges in family communication due to the emotional intensity associated with having SMA in the family. Most siblings did not report learning from their family how the inheritance of SMA related to their own genetic carrier risk and possible reproductive implications. CONCLUSION: Siblings described their parents as being open and honest in communicating about SMA; however, this study found that communication before the age of understanding abstract concepts, in combination with the emotional intensity of SMA, resulted in gaps in knowledge about SMA.

Consumer attitudes and preferences toward psychiatric genetic counselling and educational resources: A scoping review.

INTRODUCTION: The etiology of psychiatric disorders is multifactorial including genomic and environmental risk factors. Psychiatric genetic counseling is an emerging field that may promote processes of adaptation to, and the management of, psychiatric disorders. Many countries lack dedicated services leading to a gap in care. This scoping review will inform the development of psychiatric genetics-based educational resources. OBJECTIVES: To explore individuals with a psychiatric disorder and their relatives' attitudes and beliefs toward psychiatric genetics, genetic counseling, and genetics-based education. To evaluate how best to convey education to consumers. METHOD: Database literature searches occurred on May 2nd, 2023, using PubMed, Medline, and PsycINFO. Reviews, letters to the editor, case reports, and publications before 2003 were excluded. RESULTS: Twenty-four papers met the inclusion criteria. Results suggest individuals with a psychiatric disorder and their relatives tended to overestimate risk, and express concern about reproductive decision- making. Genetic counseling and educational resources were perceived to be useful and empowering. CONCLUSION: Affected individuals and relatives are interested in gaining greater insight into their own and/or their relative's psychiatric disorder, management strategies, and understanding familial risks. PRACTICE IMPLICATIONS: The evidence from this review may inform the development of genetics-based educational resources or guide future research.

The protocol for an observational Australian cohort study of CADASIL: The AusCADASIL study.

Introduction: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a rare genetic condition with a broad phenotypic presentation. This study aims to establish the first Australian cohort of individuals affected by CADASIL (AusCADASIL) and examine its clinical features and longitudinal course, and to investigate neuroimaging and blood biomarkers to assist in early diagnosis and identify disease progression. Methods: Participants will be recruited from six study centres across Australia for an observational study of CADASIL. We aim to recruit 150 participants with diagnosed CADASIL, family history of CADASIL or suspected CADASIL symptoms, and 150 cognitively normal NOTCH3 negative individuals as controls. Participants will complete: 1) online questionnaires on medical and family history, mental health, and wellbeing; 2) neuropsychological evaluation; 3) neurological examination and brain MRI; 4) ocular examination and 5) blood sample donation. Participants will have annual follow-up for 4 years to assess their progression and will be asked to invite a study partner to corroborate their self-reported cognitive and functional abilities.Primary outcomes include cognitive function and neuroimaging abnormalities. Secondary outcomes include investigation of genetics and blood and ocular biomarkers. Data from the cohort will contribute to an international consortium, and cohort participants will be invited to access future treatment/health intervention trials. Discussion: AusCADASIL will be the first study of an Australian cohort of individuals with CADASIL. The study will identify common pathogenic variants in this cohort, and characterise the pattern of clinical presentation and longitudinal progression, including imaging features, blood and ocular biomarkers and cognitive profile.

Young-onset dementia: A systematic review of the psychological and social impact on relatives.

OBJECTIVE: Young-onset dementia (YOD) has significant impact for the affected person, but also has far-reaching effects on the family. Additionally, biological relatives have an increased genetic risk of developing the condition themselves. This review aimed to identify the psychological and social impacts of YOD in the family, for asymptomatic relatives. METHODS: A systematic review of key databases for empirical studies about the lived experience of biological relatives at risk for YOD was performed. Data was collated and interpreted via narrative synthesis. RESULTS: The majority of the nineteen included studies were qualitative and explored the experiences of children with a parent with YOD. Five themes were developed: (1) Onset of YOD disrupts family functioning (2) Emotional impact is significant and varied (3) Uncertain future (due to uncertainty of diagnosis, care-giving responsibilities, and their own increased genetic risk) (4) Lack of visibility in health care and society (5) Coping strategies include physical/cognitive distancing, and emotion-focused coping. CONCLUSION: Our findings demonstrate a diagnosis of YOD significantly impacts the lives of relatives, yet their experiences and needs often go unnoticed. PRACTICE IMPLICATIONS: We present a practical framework of questions and strategies for care of relatives, mapped to the self-regulation model of genetic counselling.

Family Communication about Diagnostic Genetic Testing for Younger-Onset Dementia.

Younger-onset dementia (YOD) refers to onset before 65 years of age and may be associated with a genetic cause. Family communication surrounding any genetic risk is complex, and this process may be further complicated in a YOD context due to its effects on cognition, behaviour, and associated psychosocial consequences. This study aimed to investigate how individuals experience family communication about potential genetic risk and testing for YOD. Thematic analysis was performed on verbatim transcripts of nine semi-structured interviews undertaken with family members who attended a neurogenetics clinic due to a relative diagnosed with YOD. The interviews explored the participants' experiences of learning that YOD might be inherited and the ensuing family communication about genetic testing. Four key themes emerged: (1) a clinical diagnostic odyssey was common and could be a motivator for genomic testing, (2) pre-existing family tension and/or disconnection was a common barrier, (3) family members' autonomy was considered, and (4) avoidant coping strategies influenced communication. Communication regarding potential YOD genetic risk is a complicated process and may be influenced by pre-existing family dynamics, individual coping mechanisms, and a desire to promote autonomy in relatives. To promote effective risk communication, genetic counsellors should pre-emptively address family tensions that may be exacerbated in the context of genetic testing for YOD, with awareness that family strain during a preceding period of diagnostic odyssey is common. Genetic counsellors can offer psychosocial support to facilitate coping with this tension in an adaptive way. The findings also indicated the importance of extending genetic counselling support to relatives.

Personalising genetic counselling (POETIC) trial: Protocol for a hybrid type II effectiveness-implementation randomised clinical trial of a patient screening tool to improve patient empowerment after cancer genetic counselling.

BACKGROUND: Genetic counselling aims to identify, and address, patient needs while facilitating informed decision-making about genetic testing and promoting empowerment and adaptation to genetic information. Increasing demand for cancer genetic testing and genetic counsellor workforce capacity limitations may impact the quality of genetic counselling provided. The use of a validated genetic-specific screening tool, the Genetic Psychosocial Risk Instrument (GPRI), may facilitate patient-centred genetic counselling. The aim of this study is to assess the effectiveness and implementation of using the GPRI in improving patient outcomes after genetic counselling and testing for an inherited cancer predisposition. METHODS: The PersOnalising gEneTIc Counselling (POETIC) trial is a hybrid type 2 effectiveness-implementation trial using a randomised control trial to assess the effectiveness of the GPRI in improving patient empowerment (primary outcome), while also assessing implementation from the perspective of clinicians and the healthcare service. Patients referred for a cancer risk assessment to the conjoint clinical genetics service of two metropolitan hospitals in Victoria, Australia, who meet the eligibility criteria and consent to POETIC will be randomised to the usual care or intervention group. Those in the intervention group will complete the GPRI prior to their appointment with the screening results available for the clinicians' use during the appointment. Appointment audio recordings, clinician-reported information about the appointment, patient-reported outcome measures, and clinical data will be used to examine the effectiveness of using the GPRI. Appointment audio recordings, health economic information, and structured interviews will be used to examine the implementation of the GPRI. DISCUSSION: The POETIC trial takes a pragmatic approach by deploying the GPRI as an intervention in the routine clinical practice of a cancer-specific clinical genetics service that is staffed by a multidisciplinary team of genetics and oncology clinicians. Therefore, the effectiveness and implementation evidence generated from this real-world health service setting aims to optimise the relevance of the outcomes of this trial to the practice of genetic counselling while enhancing the operationalisation of the screening tool in routine practice. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry registration number 12621001582842p. Date of registration: 19th November 2021.

Suicide in frontotemporal dementia and Huntington disease: analysis of family-reported pedigree data and implications for genetic healthcare for asymptomatic relatives.

OBJECTIVE: Genomic testing for early-onset dementia is becoming more accessible, along with predictive testing for at-risk relatives; however, complex counselling issues are important to address. The topic of suicide often has stigma associated, and thoughts or experiences may not be volunteered without prompting. Little has been published with consideration to suicide rates in the context of family experiences and their significance in genetic counselling for relatives of people with Huntington disease and frontotemporal dementia. DESIGN: This study included pedigree information for 267 symptomatic individuals with frontotemporal dementia or Huntington disease, provided via genetic counselling clinics. MAIN OUTCOME MEASURES: Descriptive statistics and suicide rate calculations based on family reported pedigree data. RESULTS: The suicide rate was 2996 per 100,000 compared with the population rate of 10 per 100,000. Approximately one in 15 families reported suicide of an affected family member, and file notes indicated that one in five families had experienced suicide, suicidal thoughts or suicide attempts in one or more affected, unaffected or pre-symptomatic relative. CONCLUSION: Health professional awareness of family experiences, including suicide of a relative, is vital in facilitating client decisions about genetic testing, and in providing adequate psychosocial support during the process of genetic testing and adaption to results.

The clinical utility of exome sequencing and extended bioinformatic analyses in adolescents and adults with a broad range of neurological phenotypes: an Australian perspective.

Currently there is no secured ongoing funding in Australia for next generation sequencing (NGS) such as exome sequencing (ES) for adult neurological disorders. Studies have focused on paediatric populations in research or highly specialised settings, utilised standard NGS pipelines focusing only on small insertions, deletions and single nucleotide variants, and not explored impacts on management in detail. This prospective multi-site study performed ES and an extended bioinformatics repeat expansion analysis pipeline, on patients with broad phenotypes (ataxia, dementia, dystonia, spastic paraparesis, motor neuron disease, Parkinson's disease and complex/not-otherwise-specified), with symptom onset between 2 and 60 years. Genomic data analysis was phenotype-driven, using virtual gene panels, reported according to American College of Medical Genetics and Genomics guidelines. One-hundred-and-sixty patients (51% female) were included, median age 52 years (range 14-79) and median 9 years of symptoms. 34/160 (21%) patients received a genetic diagnosis. Highest diagnostic rates were in spastic paraparesis (10/25, 40%), complex/not-otherwise-specified (10/38, 26%) and ataxia (7/28, 25%) groups. Findings were considered 'possible/uncertain' in 21/160 patients. Repeat expansion detection identified an unexpected diagnosis of Huntington disease in an ataxic patient with negative ES. Impacts on management, such as more precise and tailored care, were seen in most diagnosed patients (23/34, 68%). ES and a novel bioinformatics analysis pipepline had a substantial diagnostic yield (21%) and management impacts for most diagnosed patients, in heterogeneous, complex, mainly adult-onset neurological disorders in real-world settings in Australia, providing evidence for NGS and complementary multiple, new technologies as valuable diagnostic tools.

Cloning, purification and characterisation of brassinin glucosyltransferase, a phytoalexin-detoxifying enzyme from the plant pathogen Sclerotinia sclerotiorum.

The plant-pathogenic fungus Sclerotinia sclerotiorum can detoxify cruciferous phytoalexins such as brassinin via glucosylation. Here we describe a multifaceted approach including genome mining, transcriptional induction, phytoalexin quantification, protein expression and enzyme purification that led to identification of a S. sclerotiorum glucosyltransferase that detoxifies brassinin. Transcription of this gene, denoted as brassinin glucosyltransferase 1 (SsBGT1), was induced significantly in response to the cruciferous phytoalexins camalexin, cyclobrassinin, brassilexin, brassinin and 3-phenylindole, a camalexin analogue. This gene was also up-regulated during infection of Brassica napus leaves. Levels of brassinin decreased significantly between 48 and 72h post-inoculation, with a concomitant increase in levels of 1-beta-d-glucopyranosylbrassinin, the product of the reaction catalysed by SsBGT1. These findings strongly implicate the involvement of this gene during infection of B. napus. This gene was cloned and expressed in Saccharomyces cerevisiae. The purified recombinant enzyme was able to glucosylate brassinin and two other phytoalexins, albeit much less effectively. This is the first report of a fungal gene involved in detoxification of plant defence molecules via glucosylation.

Living with Hereditary Haemorrhagic Telangiectasia: stigma, coping with unpredictable symptoms, and self-advocacy.

Objective: Hereditary Haemorrhagic Telangiectasia (HHT) is a genetic condition causing frequent nose bleeds, skin lesions (telangiectasia) and arteriovenous malformations. Approximately, 50% of people experience life-threatening HHT symptoms including haemorrhages in the brain, lungs and liver. This study aimed to gain a qualitative understanding of the psychosocial impact of HHT over time. Design: Using a phenomenological framework, a rigorous narrative analysis was performed on 20 semi-structured interviews with individuals with HHT aged 20s-60s. Main outcome measures: Qualitative themes explaining life experiences prior to and following a clinical diagnosis of HHT. Results: Narratives highlighted four psychosocial themes: (i) the psychological impact of visible symptoms was significant and related to experiences of social stigma, (ii) individuals struggled to identify triggers of symptoms in order to reduce unpredictability, (iii) an illness identity was rejected by minimising HHT when talking about the present self, and by positive reframing as 'lucky' and (iv) self-advocacy was necessitated due to lack of expert coordinated care. Conclusion: HHT has a demanding impact on social, physical and psychological well-being. These findings have significant implications for health care, as narratives about interactions with health professionals often used the terms 'frustrating' and 'not being heard'.

Fungi have three tetraspanin families with distinct functions.

BACKGROUND: Tetraspanins are small membrane proteins that belong to a superfamily encompassing 33 members in human and mouse. These proteins act as organizers of membrane-signalling complexes. So far only two tetraspanin families have been identified in fungi. These are Pls1, which is required for pathogenicity of the plant pathogenic ascomycetes, Magnaporthe grisea, Botrytis cinerea and Colletotrichum lindemuthianum, and Tsp2, whose function is unknown. In this report, we describe a third family of tetraspanins (Tsp3) and a new family of tetraspanin-like proteins (Tpl1) in fungi. We also describe expression of some of these genes in M. grisea and a basidiomycete, Laccaria bicolor, and also their functional analysis in M. grisea. RESULTS: The exhaustive search for tetraspanins in fungal genomes reveals that higher fungi (basidiomycetes and ascomycetes) contain three families of tetraspanins (Pls1, Tsp2 and Tsp3) with different distribution amongst phyla. Pls1 is found in ascomycetes and basidiomycetes, whereas Tsp2 is restricted to basidiomycetes and Tsp3 to ascomycetes. A unique copy of each of PLS1 and TSP3 was found in ascomycetes in contrast to TSP2, which has several paralogs in the basidiomycetes, Coprinus cinereus and Laccaria bicolor. A tetraspanin-like family (Tpl1) was also identified in ascomycetes. Transcriptional analyses in various tissues of L. bicolor and M. grisea showed that PLS1 and TSP2 are expressed in all tissues in L. bicolor and that TSP3 and TPL1 are overexpressed in the sexual fruiting bodies (perithecia) and mycelia of M. grisea, suggesting that these genes are not pseudogenes. Phenotypic analysis of gene replacementmutants Deltatsp3 and Deltatpl1 of M. grisea revealed a reduction of the pathogenicity only on rice, in contrast to Deltapls1 mutants, which are completely non-pathogenic on barley and rice. CONCLUSION: A new tetraspanin family (Tsp3) and a tetraspanin-like protein family (Tpl1) have been identified in fungi. Functional analysis by gene replacement showed that these proteins, as well as Pls1, are involved in the infection process of the plant pathogenic fungus M. grisea. The next challenge will be to decipher the role(s) of tetraspanins in a range of symbiotic, saprophytic and human pathogenic fungi.