Dyadic concordance and associations of beliefs with intentions to learn carrier results from genomic sequencing

Although romantic couple concordance has been demonstrated across a wide array of health behaviors, little research has examined dyadic concordance in health beliefs. This study examined the extent to which cohabitating romantic dyads' attitudes and beliefs coincide (i.e., dyadic concordance) in addition to how well they predict intentions to learn genomic sequencing results. The actor-partner interdependence model was applied to cross-sectional data from 81 dyads in an exome sequencing study who were surveyed about their risk perceptions, worry, information avoidance, attitudes, and intentions toward learning carrier results. Information avoidance tendencies were positively correlated between partners, but there was low concordance on other beliefs. Individuals' attitudes and information avoidance predicted their own intentions to learn results. Additionally, partners' information avoidance tendencies predicted their partner's intentions to learn results. Future research should explore mechanisms through which one's partner's information avoidance may affect one's own intentions and behaviors

Enrolling Children in Clinical Trials for Genetic Neurodevelopmental Conditions: Ethics, Parental Decisions, and Children's Identities.

Knowledge of genetic mechanisms contributing to neurodevelopmental conditions is advancing. This is informing development of new drugs to treat or ameliorate these conditions, through targeting underlying genetic pathways. Drugs are tested in clinical trials, necessitating parents to engage with decisions about whether to enroll their child. In this article, we consider important ethical issues to anticipate as clinical research opportunities in genetic neurodevelopmental conditions arise. For example, genetic pathways targeted by the drugs may interact with valued character and personality traits. It is essential that recruitment and consent processes are optimized for families who will grapple with whether these novel drug treatments interact with their child's personality and authentic identity. We call for focused social science research and further normative analysis so that parents are better supported to make informed choices. Additionally, clinical research regulators should have a sound understanding of the contextual experiences regarding how this population of parents engages with decisions

Web platform vs in-person genetic counselor for return of carrier results from exome sequencing a randomized clinical trial

© 2018 American Medical Association. All rights reserved. IMPORTANCE A critical bottleneck in clinical genomics is the mismatch between large volumes of results and the availability of knowledgeable professionals to return them. OBJECTIVE To test whether a web-based platform is noninferior to a genetic counselor for educating patients about their carrier results from exome sequencing. DESIGN, SETTING, AND PARTICIPANTS A randomized noninferiority trial conducted in a longitudinal sequencing cohort at the National Institutes of Health from February 5, 2014, to December 16, 2016, was used to compare the web-based platform with a genetic counselor. Among the 571 eligible participants, 1 to 7 heterozygous variants were identified in genes that cause a phenotype that is recessively inherited. Surveys were administered after cohort enrollment, immediately following trial education, and 1 month and 6 months later to primarily healthy postreproductive participants who expressed interest in learning their carrier results. Both intention-to-treat and per-protocol analyses were applied. INTERVENTIONS A web-based platform that integrated education on carrier results with personal test results was designed to directly parallel disclosure education by a genetic counselor. The sessions took a mean (SD) time of 21 (10.6), and 27 (9.3) minutes, respectively. MAIN OUTCOMES AND MEASURES The primary outcomes and noninferiority margins (dNI) were knowledge (0 to 8, dNI = -1), test-specific distress (0 to 30, dNI = +1), and decisional conflict (15 to 75, dNI = +6). RESULTS After 462 participants (80.9%) provided consent and were randomized, all but 3 participants (n = 459) completed surveys following education and counseling; 398 (86.1%) completed 1-month surveys and 392 (84.8%) completed 6-month surveys. Participants were predominantly well-educated, non-Hispanic white, married parents; mean (SD) age was 63 (63.1) years and 246 (53.6%) were men. The web platform was noninferior to the genetic counselor on outcomes assessed at 1 and 6 months: knowledge (mean group difference, -0.18; lower limit of 97.5% CI, -0.63; dNI = -1), test-specific distress (median group difference, 0; upper limit of 97.5% CI, 0; dNI = +1), and decisional conflict about choosing to learn results (mean group difference, 1.18; upper limit of 97.5% CI, 2.66; dNI = +6). There were no significant differences between the genetic counselors and web-based platform detected between modes of education delivery in disclosure rates to spouses (151 vs 159; relative risk [RR], 1.04; 95% CI, 0.64-1.69; P > .99), children (103 vs 117; RR, 1.07; 95% CI, 0.85-1.36; P = .59), or siblings (91 vs 78; RR, 1.17; 95% CI, 0.94-1.46; P = .18). CONCLUSIONS AND RELEVANCE This trial demonstrates noninferiority of web-based return of carrier results among postreproductive, mostly healthy adults. Replication studies among younger and more diverse populations are needed to establish generalizability. Yet return of results via a web-based platform may be sufficient for subsets of test results, reserving genetic counselors for return of results with a greater health threat

Parent clinical trial priorities for fragile X syndrome: a best-worst scaling.

An expansion in the availability of clinical drug trials for genetic neurodevelopmental conditions is underway. Delineating patient priorities is key to the success of drug development and clinical trial design. There is a lack of evidence about parent decision-making in the context of clinical drug trials for genetic neurodevelopmental conditions. We assessed parents' priorities when making a decision whether to enroll their child with fragile X syndrome (FXS) in a clinical drug trial. An online survey included a best-worst scaling method for parents to prioritize motivating and discouraging factors for child enrollment. Parents were recruited through the National Fragile X Foundation and FRAXA. Sequential best-worst with conditional logit analysis was used to determine how parents prioritize motivating and discouraging factors about trial enrollment decisions. Respondents (N = 354) were largely biological mothers (83%) of an individual with FXS who ranged in age from under 5 to over 21 years. The highest motivating factor was a trial to test a drug targeting the underlying FXS mechanism (coeff = 3.28, p < 0.001), followed by the potential of the drug to help many people (coeff = 3.03, p < 0.001). Respondents rated requirement of blood draws (coeff = -3.09, p < 0.001), loss of access to the drug post trial (coeff = -3.01, p < 0.001), and drug side effects (coeff = -2.96, p < 0.001) as most discouraging. The priorities defined by parents can be incorporated into evidence-based trial design and execution to enhance the enrollment process

Cancer Patient Experience of Uncertainty While Waiting for Genome Sequencing Results.

There is limited knowledge about cancer patients' experiences of uncertainty while waiting for genome sequencing results, and whether prolonged uncertainty contributes to psychological factors in this context. To investigate uncertainty in patients with a cancer of likely hereditary origin while waiting for genome sequencing results, we collected questionnaire and interview data at baseline, and at three and 12 months follow up (prior to receiving results). Participants (N = 353) had negative attitudes towards uncertainty (M = 4.03, SD 0.68) at baseline, and low levels of uncertainty at three (M = 8.23, SD 7.37) and 12 months (M = 7.95, SD 7.64). Uncertainty about genome sequencing did not change significantly over time [t(210) = 0.660, p = 0.510]. Greater perceived susceptibility for cancer [r(348) = 0.14, p < 0.01], fear of cancer recurrence [r(348) = 0.19, p < 0.01], perceived importance of genome sequencing [r(350) = 0.24, p < 0.01], intention to change behavior if a gene variant indicating risk is found [r(349) = 0.29, p < 0.01], perceived ability to cope with results [r(349) = 0.36, p < 0.01], and satisfaction with decision to have genome sequencing [r(350) = 0.52, p < 0.01] were significantly correlated with negative attitudes towards uncertainty at baseline. Multiple primary cancer diagnoses [B = -2.364 [-4.238, -0.491], p = 0.014], lower perceived ability to cope with results [B = -0.1.881 [-3.403, -0.359], p = 0.016] at baseline, greater anxiety about genome sequencing (avoidance) [B = 0.347 [0.148, 0.546], p = 0.0012] at 3 months, and greater perceived uncertainty about genome sequencing [B = 0.494 [0.267, 0.721] p = 0.000] at 3 months significantly predicted greater perceived uncertainty about genome sequencing at 12 months. Greater perceived uncertainty about genome sequencing at 3 months significantly predicted greater anxiety (avoidance) about genome sequencing at 12 months [B = 0.291 [0.072, 0.509], p = 0.009]. Semi-structured interviews revealed that while participants were motivated to pursue genome sequencing as a strategy to reduce their illness and risk uncertainty, genome sequencing generated additional practical, scientific and personal uncertainties. Some uncertainties were consistently discussed over the 12 months, while others emerged over time. Similarly, some uncertainty coping strategies were consistent over time, while others emerged while patients waited for their genome sequencing results. This study demonstrates the complexity of uncertainty generated by genome sequencing for cancer patients and provides further support for the inter-relationship between uncertainty and anxiety. Helping patients manage their uncertainty may ameliorate psychological morbidity

Mapping gene associations in human mitochondria using clinical disease phenotypes

Nuclear genes encode most mitochondrial proteins, and their mutations cause diverse and debilitating clinical disorders. To date, 1,200 of these mitochondrial genes have been recorded, while no standardized catalog exists of the associated clinical phenotypes. Such a catalog would be useful to develop methods to analyze human phenotypic data, to determine genotype-phenotype relations among many genes and diseases, and to support the clinical diagnosis of mitochondrial disorders. Here we establish a clinical phenotype catalog of 174 mitochondrial disease genes and study associations of diseases and genes. Phenotypic features such as clinical signs and symptoms were manually annotated from full-text medical articles and classified based on the hierarchical MeSH ontology. This classification of phenotypic features of each gene allowed for the comparison of diseases between different genes. In turn, we were then able to measure the phenotypic associations of disease genes for which we calculated a quantitative value that is based on their shared phenotypic features. The results showed that genes sharing more similar phenotypes have a stronger tendency for functional interactions, proving the usefulness of phenotype similarity values in disease gene network analysis. We then constructed a functional network of mitochondrial genes and discovered a higher connectivity for non-disease than for disease genes, and a tendency of disease genes to interact with each other. Utilizing these differences, we propose 168 candidate genes that resemble the characteristic interaction patterns of mitochondrial disease genes. Through their network associations, the candidates are further prioritized for the study of specific disorders such as optic neuropathies and Parkinson disease. Most mitochondrial disease phenotypes involve several clinical categories including neurologic, metabolic, and gastrointestinal disorders, which might indicate the effects of gene defects within the mitochondrial system. The accompanying knowledgebase (http://www.mitophenome.org/) supports the study of clinical diseases and associated genes

Breast cancer risk perception: what do we know and understand?

Women's perceptions of breast cancer risk are largely inaccurate and are often associated with high levels of anxiety about cancer. There are interesting cultural differences that are not well researched. Genetic risk counselling significantly improves accuracy of women's perceptions of risk, but not necessarily to the correct level. Reasons for this are unclear, but may relate to personal beliefs about susceptibility and to problems or variations in risk communication. Research into the impact of demographic and psychological factors on risk perception has been inconclusive. An understanding of the process of developing a perception of risk would help to inform risk counselling strategies. This is important, because knowledge of risk is needed both for appropriate health care decision making and to reassure women who are not at increased risk

Training Genetic Counsellors to Deliver an Innovative Therapeutic Intervention: their views and experience of facilitating multi-family discussion groups

Innovations in clinical genetics have increased diagnosis, treatment and prognosis of inherited genetic conditions (IGCs). This has led to an increased number of families seeking genetic testing and / or genetic counselling and increased the clinical load for genetic counsellors (GCs). Keeping pace with biomedical discoveries, interventions are required to support families to understand, communicate and cope with their Inherited Genetic Condition. The Socio-Psychological Research in Genomics (SPRinG) collaborative have developed a new intervention, based on multi-family discussion groups (MFDGs), to support families affected by IGCs and train GCs in its delivery. A potential challenge to implementing the intervention was whether GCs were willing and able to undergo the training to deliver the MFDG. In analysing three multi-perspective interviews with GCs, this paper evaluates the training received. Findings suggests that MFDGs are a potential valuable resource in supporting families to communicate genetic risk information and can enhance family function and emotional well-being. Furthermore, we demonstrate that it is feasible to train GCs in the delivery of the intervention and that it has the potential to be integrated into clinical practice. Its longer term implementation into routine clinical practice however relies on changes in both organisation of clinical genetics services and genetic counsellors' professional development

Presymptomatic breast cancer in Egypt: role of BRCA1 and BRCA2 tumor suppressor genes mutations detection

<p>Abstract</p> <p>Background</p> <p>Breast cancer is one of the most common diseases affecting women. Inherited susceptibility genes, <it>BRCA1 </it>and <it>BRCA2</it>, are considered in breast, ovarian and other common cancers etiology. <it>BRCA1 </it>and <it>BRCA2 </it>genes have been identified that confer a high degree of breast cancer risk.</p> <p>Objective</p> <p>Our study was performed to identify germline mutations in some exons of <it>BRCA1 </it>and <it>BRCA2 </it>genes for the early detection of presymptomatic breast cancer in females.</p> <p>Methods</p> <p>This study was applied on Egyptian healthy females who first degree relatives to those, with or without a family history, infected with breast cancer. Sixty breast cancer patients, derived from 60 families, were selected for molecular genetic testing of <it>BRCA1 </it>and <it>BRCA2 </it>genes. The study also included 120 healthy first degree female relatives of the patients, either sisters and/or daughters, for early detection of presymptomatic breast cancer mutation carriers. Genomic DNA was extracted from peripheral blood lymphocytes of all the studied subjects. Universal primers were used to amplify four regions of the <it>BRCA1 </it>gene (exons 2,8,13 and 22) and one region (exon 9) of <it>BRCA2 </it>gene using specific PCR. The polymerase chain reaction was carried out. Single strand conformation polymorphism assay and heteroduplex analysis were used to screen for mutations in the studied exons. In addition, DNA sequencing of the normal and mutated exons were performed.</p> <p>Results</p> <p>Mutations in both <it>BRCA1 </it>and <it>BRCA2 </it>genes were detected in 86.7% of the families. Current study indicates that 60% of these families were attributable to <it>BRCA1 </it>mutations, while 26.7% of them were attributable to <it>BRCA2 </it>mutations. Results showed that four mutations were detected in the <it>BRCA1 </it>gene, while one mutation was detected in the <it>BRCA2 </it>gene. Asymptomatic relatives, 80(67%) out of total 120, were mutation carriers.</p> <p>Conclusions</p> <p><it>BRCA1 </it>and <it>BRCA2 </it>genes mutations are responsible for a significant proportion of breast cancer. <it>BRCA </it>mutations were found in individuals with and without family history.</p

A defect in myoblast fusion underlies Carey-Fineman-Ziter syndrome

Multinucleate cellular syncytial formation is a hallmark of skeletal muscle differentiation. Myomaker, encoded by Mymk (Tmem8c), is a well-conserved plasma membrane protein required for myoblast fusion to form multinucleated myotubes in mouse, chick, and zebrafish. Here, we report that autosomal recessive mutations in MYMK (OMIM 615345) cause Carey-Fineman-Ziter syndrome in humans (CFZS; OMIM 254940) by reducing but not eliminating MYMK function. We characterize MYMK-CFZS as a congenital myopathy with marked facial weakness and additional clinical and pathologic features that distinguish it from other congenital neuromuscular syndromes. We show that a heterologous cell fusion assay in vitro and allelic complementation experiments in mymk knockdown and mymk insT/insT zebrafish in vivo can differentiate between MYMK wild type, hypomorphic and null alleles. Collectively, these data establish that MYMK activity is necessary for normal muscle development and maintenance in humans, and expand the spectrum of congenital myopathies to include cell-cell fusion deficits