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OBJECTIVE: Faster and cheaper next generation sequencing technologies have enabled expansion of carrier screening for recessive disorders, potentially facilitating population-based implementation regardless of ancestry or family history. Little is known, however, about the attitudes regarding population-based carrier screening among families with genetic disorders. This study assessed views among parents and patients with a recessive disorder and parents of children with Down syndrome (DS) on expanded carrier screening (ECS).METHOD: In total, 85 patients with various recessive disorders, 110 parents of a child with a recessive disorder and 89 parents of a child with DS participated in an online survey in the Netherlands. Severity of recessive disorders was classified as mild/moderate or severe/profound.RESULTS: The majority of the (parents of) patients with a recessive disorder had a positive attitude towards population-based ECS, including screening for their own or their child's disorder. DS parents were significantly less positive towards ECS. Subgroup analyses showed that the severity of the disorder, rather than being a patient or parent, influences the attitudes, beliefs and intention to participate in ECS.CONCLUSION: Our findings have important implications for future implementation initiatives as they demonstrate the different perspectives from people with experiential knowledge with genetic disorders.

Genetic heart diseases (GHDs) can be clinically heterogeneous and pose an increased risk of sudden cardiac death (SCD). The implantable cardioverter-defibrillator (ICD) is a lifesaving therapy. Impacts on prospective and long-term psychological and health-related quality of life (HR-QoL) after ICD implant in patients with GHDs are unknown.Investigate the psychological functioning and HR-QoL over time in patients with GHDs who receive an ICD, and identify risk factors for poor psychological functioning and HR-QoL.A longitudinal, prospective study design was used. Patients attending a specialized clinic, diagnosed with a GHD for which they received an ICD between May 2012 and January 2015, were eligible. Baseline surveys were completed prior to ICD implantation with 5-year follow-up after ICD implant. We measured psychological functioning (Hospital Anxiety Depression Scale, Florida Shock Anxiety Scale), HR-QoL (Short-Form 36v2), and device acceptance (Florida Patient Acceptance Scale).Forty patients were included (mean age 46.3 ± 14.2 years; 65.0% male). Mean psychological and HR-QoL measures were within normative ranges during follow-up. After 12 months, 33.3% and 19.4% of participants showed clinically elevated levels of anxiety and depression, respectively. Longitudinal mixed-effect analysis showed significant improvements from baseline to first follow-up for the overall cohort, with variability increasing after 36 months. Nontertiary education and female sex predicted worse mental HR-QoL and anxiety over time, while comorbidities predicted depression and worse physical HR-QoL.While the majority of patients with a GHD adjust well to their ICD implant, a subset of patients experience poor psychological and HR-QoL outcomes.

Background Population-based expanded carrier screening (ECS) involves screening for multiple recessive diseases offered to all couples considering a pregnancy or during pregnancy. Previous research indicates that in some countries primary care professionals are perceived as suitable providers for ECS. However, little is known about their perspectives. We therefore aimed to explore primary care professionals’ views on population-based ECS. Methods Four online focus groups with 14 general practitioners (GPs) and 16 community midwives were conducted in the Netherlands. Results Our findings highlight various perspectives on the desirability of population-based ECS. Participants agreed that ECS could enhance reproductive autonomy and thereby prevent suffering of the child and/or parents. However, they also raised several ethical, societal, and psychological concerns, including a tendency towards a perfect society, stigmatization, unequal access to screening and negative psychosocial consequences. Participants believed that provision of population-based ECS would be feasible if prerequisites regarding training and reimbursement for providers would be fulfilled. most GPs considered themselves less suitable or capable of providing ECS, in contrast to midwives who did consider themselves suitable. Nevertheless, participants believed that, if implemented, ECS should be offered in primary care or by public health services rather than as hospital-based specialized care, because they believed a primary care ECS offer increases access in terms of time and location. Conclusions While participants believed that an ECS offer would be feasible, they questioned its desirability and priority. Studies on the desirability and feasibility of population-based ECS offered in primary care or public health settings are needed.

Carrier screening aims to identify couples at risk of conceiving children with a recessive condition. Until recently, carrier screening was primarily offered ancestry-based. Technological advances now facilitate expanded universal carrier screening (EUCS). This scoping review aimed to map EUCS’s potential societal implications based on both theoretical studies and empirical evidence. To this aim, we performed a CoCites search to find relevant articles, including articles describing carrier screening for at-risk populations, based on five selected query articles. Forty articles were included. Three main potential societal implications were identified: (1) unwanted medicalization, (2) stigmatization and discrimination of carriers and people affected with the conditions screened and (3) challenges in achieving equitable access. Within these themes, potential positive implications are reduction of ethnic stigmatization in ancestry-based offers and increased equity. Potential negative implications are reinforcement of disability-based stigmatization, less possibility for developing expertise in healthcare and societal pressure to partake in screening. Empirical evidence on all these implications is however scarce. In conclusion, both positive and negative potential societal implications of implementing EUCS, primarily theoretical, were identified, even in at-risk groups where evidence is mostly lacking. Empirical research in EUCS pilots is needed to identify which societal implications are likely to occur and therefore should be overcome when implementing EUCS.

Background With advances in sequencing technologies, increasing numbers of people are being informed about a genetic disease identified in their family. In current practice, probands (the first person in a family in whom a genetic predisposition is identified) are asked to inform at-risk relatives about the diagnosis. However, previous research has shown that relatives are sometimes not informed due to barriers such as family conflicts. Research on family communication in genetic diseases aims to explore the difficulties encountered in informing relatives and to identify ways to support probands in this. Main body Research on family communication may also reveal that participants did not inform their relatives about the risk of a serious genetic condition, even when preventive and treatment options are available. Researchers may then face a dilemma: Do they need to warn at-risk relatives about the finding? Or do they keep silent due to prior confidentiality agreements with study participants? Conclusions We believe that the absolute confidence promised to research participants outweighs the interests of their relatives, even though it can be claimed that relatives at risk of a genetic disease do, in principle, have a right to know information collected about their health. Not respecting confidentiality agreements could cause distrust between researchers and research participants and possibly harm the relationship between probands and relatives. Relatives' health interests can still be taken into account without jeopardizing participant trust, by considering alternative scenarios, including sharing general study findings on the barriers participants experience with their healthcare professionals and by offering participants psychosocial support for family communication.

The uptake of predictive DNA testing in families with a hereditary disease is

Supplemental Digital Content is available in the text., Background: Inherited cardiac conditions present with a wide range of symptoms and may even result in sudden cardiac death. Relatives of probands with a confirmed pathogenic genetic variant are advised predictive DNA testing to enable prevention and treatment. In 2 previous cohort studies of 115 probands with a pathogenic variant, family uptake of genetic counseling was assessed in the first year(s) after test result disclosure to the proband. This study assesses uptake in these cohorts in the 14 to 23 years following disclosure. Methods: Uptake was determined retrospectively using patient records. First-degree relatives, and second-degree relatives of a deceased first-degree relative suspected of having an inherited cardiac condition, were considered eligible. Results: Of 717 eligible relatives (598 first-degree and 119 second-degree relatives), 60% attended genetic counseling. Most of them (68.6%) attended genetic counseling in the first year. A total of 98.4% of counseled relatives pursued predictive DNA testing. A total of 49.2% was identified as carrier. Median time between disclosure to the proband and counseling of relatives was 6 months (range: 0–187 months). Attending genetic counseling was observed more frequently in first-degree relatives, female relatives, primary arrhythmia syndromes, relatives with manifest inherited cardiac condition, relatives without children and families with sudden cardiac death in first-degree relatives

Chromosomal microarray analysis is an important diagnostic tool to identify copy number variations (CNV). Some of the CNVs affect susceptibility regions, which means that deletions or duplications in these regions have partial penetrance and often give an increased risk for a spectrum of neurocognitive disorders. Not much is known about the impact of rare CNV susceptibility syndromes on the life of patients or their parents. In this study, we focus on one specific susceptibility CNV disorder, 16p11.2 deletion syndrome. This rare condition is characterised by an increased risk of mild intellectual disability, autism spectrum disorder, epilepsy, and obesity. We aimed to explore the impact of such a disorder on the family members involved in the daily care of children with this syndrome. Three focus group discussions were held with 23 Dutch (grand)parents. Thematic analysis was performed by two independent researchers. The following five themes emerged: (1) the end of a diagnostic odyssey and response to the diagnosis, (2) after the diagnosis-life with a child with 16p11.2 deletion syndrome, (3) access to medical care and support services, (4) nobody knows what 16p11.2 deletion syndrome is, and (5) future perspective-ideal care. The participants experienced a lack of knowledge among involved professionals. Together with the large variability of the syndrome, this led to fragmented care and unfulfilled needs regarding healthcare, social, and/or educational assistance. Care for children with a CNV susceptibility syndrome could be improved by a multidisciplinary approach or central healthcare professional, providing education and information for all involved professionals.

Carrier screening aims to identify couples at risk of conceiving children with a recessive condition. Until recently, carrier screening was primarily offered ancestry-based. Technological advances now facilitate expanded universal carrier screening (EUCS). This scoping review aimed to map EUCS's potential societal implications based on both theoretical studies and empirical evidence. To this aim, we performed a CoCites search to find relevant articles, including articles describing carrier screening for at-risk populations, based on five selected query articles. Forty articles were included. Three main potential societal implications were identified: (1) unwanted medicalization, (2) stigmatization and discrimination of carriers and people affected with the conditions screened and (3) challenges in achieving equitable access. Within these themes, potential positive implications are reduction of ethnic stigmatization in ancestry-based offers and increased equity. Potential negative implications are reinforcement of disability-based stigmatization, less possibility for developing expertise in healthcare and societal pressure to partake in screening. Empirical evidence on all these implications is however scarce. In conclusion, both positive and negative potential societal implications of implementing EUCS, primarily theoretical, were identified, even in at-risk groups where evidence is mostly lacking. Empirical research in EUCS pilots is needed to identify which societal implications are likely to occur and therefore should be overcome when implementing EUCS.

BackgroundGenetic heart diseases often affect young people, can be clinically heterogeneous and pose an increased risk of sudden cardiac death (SCD). The implantable cardioverter defibrillator (ICD) is a lifesaving therapy. Impacts on prospective and long-term psychological and health-related quality of life (HR-QoL) after ICD implant in patients with genetic heart diseases are unknown. We investigate the psychological functioning and HR-QoL over time in patients with genetic heart diseases who receive an ICD, and identify risk factors for poor psychological functioning and HR-QoL.MethodsA longitudinal, prospective study design was used. Patients attending a specialised clinic and diagnosed with a genetic heart disease, for which they received an ICD between May 2012 and January 2015, were eligible. Baseline surveys were completed prior to ICD implantation with five-year follow-up after ICD implant. We measured psychological functioning (Hospital Anxiety Depression Scale, Florida Shock Anxiety Scale), HR-QoL (Short-Form 36v2) and device acceptance (Florida Patient Acceptance Scale).ResultsThere were 40 patients with an inherited cardiomyopathy or arrhythmia syndrome included (mean age 46.3 ± 14.2 years; 65.0% males). Mean psychological and HR-QoL measures were within normative ranges during follow-up. After 12 months, 33.3% and 19.4% of participants showed clinically elevated levels of anxiety and depression, respectively. Longitudinal mixed effect analysis showed significant improvements from baseline to first follow-up for the overall cohort, with variability increasing after 36 months. Low education and female gender predicted worse mental HR-QoL and anxiety over time, while comorbidities predicted depression and worse physical HR-QoL.ConclusionWhile the majority of patients with a genetic heart disease adjust well to their ICD implant, a subset of patients’ experience poor psychological and HR-QoL outcomes.

If undetected, inherited cardiac conditions can lead to sudden cardiac death, while treatment options are available. Predictive DNA testing is therefore advised for at-risk relatives, and probands are currently asked to inform relatives about this. However, fewer than half of relatives attend genetic counselling. In this trial, we compared a tailored approach to informing relatives, in which probands were asked whether they preferred relatives to be informed by themselves or by the genetic counsellor, with current practice. Our primary outcome was uptake of genetic counselling in relatives in the first year after test result disclosure. Secondary outcomes were evaluation of the approach and impact on psychological/family functioning measured 3 (T1) and 9 (T2) months post-disclosure via telephone interviews and questionnaires. We included 96 probands; 482 relatives were eligible for counselling and genetic testing. We observed no significant difference in uptake of genetic counselling between the control (38%) and the intervention (37%) group (p = 0.973). Nor were there significant differences between groups in impact on family/psychological functioning. Significantly more probands in the tailored group were satisfied (p = 0.001) and felt supported (p = 0.003) by the approach, although they also felt somewhat coerced to inform relatives (p < 0.001) and perceived room for improvement (p < 0.001). To conclude, we observed no differences in uptake and impact on family/psychological functioning between the current and tailored approach, but probands in the tailored group more often felt satisfied. Further research on barriers to relatives attending genetic counselling and on how to optimize the provision of a tailored approach is needed.

PurposeThorough investigation of sudden cardiac death (SCD) in those aged 1-40 years commonly reveals a heritable cause, yet access to postmortem genetic testing is variable. We explore practices of postmortem genetic testing and attitudes of healthcare professionals worldwide.MethodsA survey was administered among healthcare professionals recruited through professional associations, social media and networks of researchers. Topics included practices around postmortem genetic testing, level of confidence in healthcare professionals’ ability, and attitudes towards postmortem genetic testing practices.ResultsThere were 112 respondents, with 93% from North America, Europe and Australia and 7% from South America, Asia and Africa. Only 30% reported autopsy as mandatory, and overall practices were largely case-by-case and not standardised. North American respondents (87%) more often perceived practices as ineffective compared to those from Europe (58%) and Australia/New Zealand (48%, p=0.002). Where a heritable cause is suspected, 69% considered postmortem genetic testing and 61% offered genetic counseling to surviving family members; financial resources varied widely. Half believed practices in their countries perpetuated health inequalities.ConclusionPostmortem genetic testing is not consistently available in the investigation of young SCD despite being a recommendation in international guidelines. Access to postmortem genetic testing, guided by well-resourced multidisciplinary teams, is critical in ascertaining a cause of death in many cases.

Inherited cardiac conditions (ICCs) can lead to sudden cardiac death at young age, even without previous symptoms, yet often remain undetected. To prevent sudden cardiac death, cardiac monitoring and/or predictive DNA testing is advised for at-risk relatives. Probands in whom a causal variant is detected are asked to inform their relatives about the possibility of testing, often supported by a family letter. This qualitative study investigates experiences with and attitudes toward this family-mediated approach in ICCs and explores whether and how improvements can be made. Two online focus groups were conducted with 28 healthcare professionals (HCPs) from various disciplines, as were 25 face-to-face semi-structured interviews with counselees (10 probands; 15 relatives). Data were analysed by two researchers independently using a thematic approach. Participants, both HCPs and counselees, preferred that probands inform relatives about genetic risks in ICCs, but both groups struggled with the dependency on and burden on probands to inform their relatives. To overcome this, HCPs do see a more active role for themselves in informing relatives, but prefer uniformity in procedures in order to maintain their workload. Counselees, on the other hand, prefer a tailored information provision strategy adjusted to family dynamics and the personality characteristics of relatives. In conclusion, although it is generally preferred that probands inform relatives themselves, a more active role of HCPs could be considered to overcome the dependency and burden on probands. Further research is needed to study how HCPs can engage more actively in informing at-risk relatives in current clinical genetic practise.

IntroductionIn current practice, probands are asked to inform relatives about the possibility of predictive DNA testing when a pathogenic variant causing an inherited cardiac condition (ICC) is identified. Previous research on the uptake of genetic counselling and predictive DNA testing in relatives suggests that not all relatives are sufficiently informed. We developed a randomised controlled trial to evaluate the effectiveness of a tailored approach in which probands decide together with the genetic counsellor which relatives they inform themselves and which relatives they prefer to have informed by the genetic counsellor. Here, we present the study protocol of this randomised controlled trial.MethodsA multicentre randomised controlled trial with parallel-group design will be conducted in which an intervention group receiving the tailored approach will be compared with a control group receiving usual care. Adult probands diagnosed with an ICC in whom a likely pathogenic or pathogenic variant is identified will be randomly assigned to the intervention or control group (total sample: n=85 probands). Primary outcomes are uptake of genetic counselling and predictive DNA testing by relatives (total sample: n=340 relatives). Secondary outcomes are appreciation of the approach used and impact on familial and psychological functioning, which will be assessed using questionnaires. Relatives who attend genetic counselling will be asked to fill out a questionnaire as well.Ethics and disseminationEthical approval was obtained from the Medical Ethical Committee of the Amsterdam University Medical Centres (MEC 2017-145), the Netherlands. All participants will provide informed consent prior to participation in the study. Results of the study on primary and secondary outcome measures will be published in peer-reviewed journals.Trial registration numberNTR6657; Pre-results.