Perceptions of reproductive healthcare providers regarding their involvement in offering expanded carrier screening in fertility clinics: a qualitative study.

RESEARCH QUESTION: What are the main arguments of reproductive healthcare providers in favour or against their involvement in offering expanded carrier screening (ECS) for recessive disorders at fertility clinics in the Netherlands? DESIGN: Semi-structured interview study with 20 reproductive healthcare providers between May 2020 and January 2021. Participants included 11 gynaecologists, seven fertility doctors, one nurse practitioner and one clinical embryologist, recruited from academic medical centres (n = 13), peripheral facilities associated with academic centres (n = 4), and independent fertility treatment centres (n = 3) in the Netherlands. An interview guide was developed, and thematic content analysis was performed using ATLAS.ti software. RESULTS: Arguments of reproductive healthcare providers in favour of their potential involvement in offering ECS included: (i) opportunities offered by the setting; (ii) motivation to assist in reproduction and prevent suffering; and (iii) to counter unwanted commercialization offers. Arguments against involvement included: (i) lack of knowledge and familiarity with offering ECS; (ii) insufficient staff and resources, and potential high costs for clinics and/or couples; (iii) the emotional impact it may have on couples; (iv) perceived complexity of counselling and expected elongation of waiting lists; and (v) expected low impact on reducing the burden of diseases. Participants felt that more evidence and research on the costs-benefits, implications and demand are needed prior to their involvement. CONCLUSION: While agreeing that the field of medically assisted reproduction provides a unique opportunity to offer ECS, reproductive healthcare workers feel a lack of capability and limited motivation to offer ECS to all or a selection of couples at their fertility clinics.

Systematic reanalysis of genomic data by diagnostic laboratories: a scoping review of ethical, economic, legal and (psycho)social implications.

With the introduction of Next Generation Sequencing (NGS) techniques increasing numbers of disease-associated variants are being identified. This ongoing progress might lead to diagnoses in formerly undiagnosed patients and novel insights in already solved cases. Therefore, many studies suggest introducing systematic reanalysis of NGS data in routine diagnostics. Introduction will, however, also have ethical, economic, legal and (psycho)social (ELSI) implications that Genetic Health Professionals (GHPs) from laboratories should consider before possible implementation of systematic reanalysis. To get a first impression we performed a scoping literature review. Our findings show that for the vast majority of included articles ELSI aspects were not mentioned as such. However, often these issues were raised implicitly. In total, we identified nine ELSI aspects, such as (perceived) professional responsibilities, implications for consent and cost-effectiveness. The identified ELSI aspects brought forward necessary trade-offs for GHPs to consciously take into account when considering responsible implementation of systematic reanalysis of NGS data in routine diagnostics, balancing the various strains on their laboratories and personnel while creating optimal results for new and former patients. Some important aspects are not well explored yet. For example, our study shows GHPs see the values of systematic reanalysis but also experience barriers, often mentioned as being practical or financial only, but in fact also being ethical or psychosocial. Engagement of these GHPs in further research on ELSI aspects is important for sustainable implementation.

Predicting personal cardiovascular disease risk based on family health history: Development of expert-based family criteria for the general population.

In inherited and familial cardiovascular diseases (CVDs), relatives without current symptoms can still be at risk for early and preventable cardiovascular events. One way to help people evaluate their potential risk of CVD is through a risk-assessment tool based on family health history. However, family criteria including inherited CVD risk to be used by laypersons are non-existent. In this project, we employed a qualitative study design to develop expert-based family criteria for use in individual risk assessment. In the first phase of the project, we identified potential family criteria through an online focus group with physicians with expertise in monogenic and/or multifactorial CVDs. The family criteria from phase one were then used as input for a three-round Delphi procedure carried out in a larger group of expert physicians to reach consensus on appropriate criteria. This led to consensus on five family criteria that focus on cardiovascular events at young age (i.e., sudden death, any CVD, implantable cardioverter-defibrillator, aortic aneurysm) and/or an inherited CVD in one or more close relatives. We then applied these family criteria to a high-risk cohort from a clinical genetics department and demonstrated that they have substantial diagnostic accuracy. After further evaluation in a general population cohort, we decided to only use the family criteria for first-degree relatives. We plan to incorporate these family criteria into a digital tool for easy risk assessment by the public and, based on expert advice, will develop supporting information for general practitioners to act upon potential risks identified by the tool. Results from an expert focus group, a Delphi method in a larger group of experts, and evaluation in two cohorts were used to develop family criteria for assessing cardiovascular disease risk based on family health history for a digital risk-prediction tool for use by the general population. CVD Cardiovascular disease, ICD Implantable cardioverter defibrillator, TAA Thoracic aortic aneurysm, AAA Abdominal aortic aneurysm.

Primary care professionals' views on population-based expanded carrier screening: an online focus group study.

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.

Societal implications of expanded universal carrier screening: a scoping review.

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.

Views of patients and parents of children with genetic disorders on population-based expanded carrier screening.

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.

Parental experiences of rapid exome sequencing in cases with major ultrasound anomalies during pregnancy.

BACKGROUND: Adding rapid exome sequencing (rES) to conventional genetic tests improves the diagnostic yield of pregnancies showing ultrasound abnormalities but also carries a higher chance of unsolicited findings. We evaluated how rES, including pre- and post-test counseling, was experienced by parents investigating its impact on decision-making and experienced levels of anxiety. METHODS: A mixed-methods approach was adopted. Participating couples (n = 46) were asked to fill in two surveys (pre-test and post-test counseling) and 11 couples were approached for an additional interview. RESULTS: All couples accepted the rES test-offer with the most important reason for testing emphasizing their hope of finding an underlying diagnosis that would aid decision-making. The actual impact on decision-making was low, however, since most parents decided to terminate the pregnancy based on the major and multiple fetal ultrasound anomalies and did not wait for their rES results. Anxiety was elevated for most participants and decreased over time. CONCLUSION: Major congenital anomalies detected on ultrasound seem to have more impact on prenatal parental decision-making and anxiety then the offer and results of rES. However, the impact of rES on reproductive decision-making and experienced anxiety requires further investigation, especially in pregnancies where less (severe) fetal anomalies are detected on ultrasound.

Couple-based expanded carrier screening provided by general practitioners to couples in the Dutch general population: psychological outcomes and reproductive intentions.

PURPOSE: The aim of expanded preconception carrier screening (ECS) is to inform any couple wishing to conceive about their chances of having children with severe autosomal or X-linked recessive conditions. Responsible implementation of ECS as reproductive genetic screening in routine care requires assessment of benefits and harms. We examined the psychological outcomes of couple-based ECS for 50 autosomal recessive (AR) conditions provided by general practitioners (GPs) to couples from the Dutch general population. METHODS: Dutch GPs invited 4,295 women aged 18-40. We examined anxiety (State-Trait Anxiety Inventory, STAI-6), worry, decisional conflict (DCS) over time in participants declining GP counseling or attending GP counseling with/without testing. RESULTS: One hundred ninety couples participated; 130 attended counseling, of whom 117 proceeded with testing. No carrier couples were identified. Before counseling, worry (median 6.0) and anxiety (mean 30-34) were low and lower than the population reference (36.4), although some individuals reported increased anxiety or worry. At follow-up, test acceptors reported less anxiety than test decliners (mean 29 vs. 35); differences in anxiety after testing compared to before counseling were not meaningful. Most participants (90%) were satisfied with their decision (not) to undergo testing. CONCLUSION: Some individuals reported temporarily clinically relevant distress. Overall, the psychological outcomes are acceptable and no barrier to population-wide implementation.

Long-Term Follow-Up Study on the Uptake of Genetic Counseling and Predictive DNA Testing in Inherited Cardiac Conditions.

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 <40 years. CONCLUSIONS: During median follow-up of 16 years, 60.0% of relatives attended genetic counseling, with 41.0% in the first year. Our results may suggest that some relatives are not or inadequately informed or that barriers against genetic counseling are present. Further research is needed into interventions facilitating family communication, increasing awareness among families and healthcare professionals, and lowering thresholds for genetic counseling.

A prospective study on rapid exome sequencing as a diagnostic test for multiple congenital anomalies on fetal ultrasound.

OBJECTIVE: Conventional genetic tests (quantitative fluorescent-PCR [QF-PCR] and single nucleotide polymorphism-array) only diagnose ~40% of fetuses showing ultrasound abnormalities. Rapid exome sequencing (rES) may improve this diagnostic yield, but includes challenges such as uncertainties in fetal phenotyping, variant interpretation, incidental unsolicited findings, and rapid turnaround times. In this study, we implemented rES in prenatal care to increase diagnostic yield. METHODS: We prospectively studied 55 fetuses. Inclusion criteria were: (a) two or more independent major fetal anomalies, (b) hydrops fetalis or bilateral renal cysts alone, or (c) one major fetal anomaly and a first-degree relative with the same anomaly. In addition to conventional genetic tests, we performed trio rES analysis using a custom virtual gene panel of ~3850 Online Mendelian Inheritance in Man (OMIM) genes. RESULTS: We established a genetic rES-based diagnosis in 8 out of 23 fetuses (35%) without QF-PCR or array abnormalities. Diagnoses included MIRAGE (SAMD9), Zellweger (PEX1), Walker-Warburg (POMGNT1), Noonan (PTNP11), Kabuki (KMT2D), and CHARGE (CHD7) syndrome and two cases of Osteogenesis Imperfecta type 2 (COL1A1). In six cases, rES diagnosis aided perinatal management. The median turnaround time was 14 (range 8-20) days. CONCLUSION: Implementing rES as a routine test in the prenatal setting is challenging but technically feasible, with a promising diagnostic yield and significant clinical relevance.

Expanding the clinical and genetic spectrum of ALPK3 variants: Phenotypes identified in pediatric cardiomyopathy patients and adults with heterozygous variants.

INTRODUCTION: Biallelic damaging variants in ALPK3, encoding alpha-protein kinase 3, cause pediatric-onset cardiomyopathy with manifestations that are incompletely defined. METHODS AND RESULTS: We analyzed clinical manifestations of damaging biallelic ALPK3 variants in 19 pediatric patients, including nine previously published cases. Among these, 11 loss-of-function (LoF) variants, seven compound LoF and deleterious missense variants, and one homozygous deleterious missense variant were identified. Among 18 live-born patients, 8 exhibited neonatal dilated cardiomyopathy (44.4%; 95% CI: 21.5%-69.2%) that subsequently transitioned into ventricular hypertrophy. The majority of patients had extracardiac phenotypes, including contractures, scoliosis, cleft palate, and facial dysmorphisms. We observed no association between variant type or location, disease severity, and/or extracardiac manifestations. Myocardial histopathology showed focal cardiomyocyte hypertrophy, subendocardial fibroelastosis in patients under 4 years of age, and myofibrillar disarray in adults. Rare heterozygous ALPK3 variants were also assessed in adult-onset cardiomyopathy patients. Among 1548 Dutch patients referred for initial genetic analyses, we identified 39 individuals with rare heterozygous ALPK3 variants (2.5%; 95% CI: 1.8%-3.4%), including 26 missense and 10 LoF variants. Among 149 U.S. patients without pathogenic variants in 83 cardiomyopathy-related genes, we identified six missense and nine LoF ALPK3 variants (10.1%; 95% CI: 5.7%-16.1%). LoF ALPK3 variants were increased in comparison to matched controls (Dutch cohort, P = 1.6×10-5; U.S. cohort, P = 2.2×10-13). CONCLUSION: Biallelic damaging ALPK3 variants cause pediatric cardiomyopathy manifested by DCM transitioning to hypertrophy, often with poor contractile function. Additional extracardiac features occur in most patients, including musculoskeletal abnormalities and cleft palate. Heterozygous LoF ALPK3 variants are enriched in adults with cardiomyopathy and may contribute to their cardiomyopathy. Adults with ALPK3 LoF variants therefore warrant evaluations for cardiomyopathy.

Cognitive and affective outcomes of genetic counselling in the Netherlands at group and individual level: a personalized approach seems necessary.

We performed a large outcome study at group and individual level in which the goals of genetic counselling were operationalized into cognitive and affective outcomes: empowerment, perceived personal control and anxiety. We then examined which socio-demographic and clinical variables were associated with changes in these outcomes. Data came from 1479 counselees who completed questionnaires (GCOS-18, PPC and STAI) at three time points: before the start of genetic counselling, after the first consultation and after the results of genetic counselling were disclosed. Results showed that at group level empowerment, perceived personal control and anxiety improved significantly after the whole genetic counselling process. Effect-sizes were medium for empowerment and small for the other outcomes. At individual level, 48% of counselees improved in empowerment, 21% in perceived personal control and 17% in anxiety. Around 10% of counselees worsened on all outcomes. Only 'reason for referral' and 'genetic test result' were significantly associated with changes in outcomes. This study demonstrated improvements among counselees in cognitive and affective outcomes after genetic counselling at group level. However, our results also suggest that there are opportunities for improvement at individual level, as many counselees remained stable and some even worsened on all outcomes. Routine outcome monitoring could help to explore the needs of counselees and could help to identify counselees who worsen.

GP-provided couple-based expanded preconception carrier screening in the Dutch general population: who accepts the test-offer and why?

Next generation sequencing has enabled fast and relatively inexpensive expanded carrier screening (ECS) that can inform couples' reproductive decisions before conception and during pregnancy. We previously showed that a couple-based approach to ECS for autosomal recessive (AR) conditions was acceptable and feasible for both health care professionals and the non-pregnant target population in the Netherlands. This paper describes the acceptance of this free test-offer of preconception ECS for 50 severe conditions, the characteristics of test-offer acceptors and decliners, their views on couple-based ECS and reasons for accepting or declining the test-offer. We used a survey that included self-rated health, intention to accept the test-offer, barriers to test-participation and arguments for and against test-participation. Fifteen percent of the expected target population-couples potentially planning a pregnancy-attended pre-test counselling and 90% of these couples proceeded with testing. Test-offer acceptors and decliners differed in their reproductive characteristics (e.g. how soon they wanted to conceive), educational level and stated barriers to test-participation. Sparing a child a life with a severe genetic condition was the most important reason to accept ECS. The most important reason for declining was that the test-result would not affect participants' reproductive decisions. Our results demonstrate that previously uninformed couples of reproductive age, albeit a selective part, were interested in and chose to have couple-based ECS. Alleviating practical barriers, which prevented some interested couples from participating, is recommended before nationwide implementation.

TRIDENT-2: National Implementation of Genome-wide Non-invasive Prenatal Testing as a First-Tier Screening Test in the Netherlands.

The Netherlands launched a nationwide implementation study on non-invasive prenatal testing (NIPT) as a first-tier test offered to all pregnant women. This started on April 1, 2017 as the TRIDENT-2 study, licensed by the Dutch Ministry of Health. In the first year, NIPT was performed in 73,239 pregnancies (42% of all pregnancies), 7,239 (4%) chose first-trimester combined testing, and 54% did not participate. The number of trisomies 21 (239, 0.33%), 18 (49, 0.07%), and 13 (55, 0.08%) found in this study is comparable to earlier studies, but the Positive Predictive Values (PPV)-96% for trisomy 21, 98% for trisomy 18, and 53% for trisomy 13-were higher than expected. Findings other than trisomy 21, 18, or 13 were reported on request of the pregnant women; 78% of women chose to have these reported. The number of additional findings was 207 (0.36%); these included other trisomies (101, 0.18%, PPV 6%, many of the remaining 94% of cases are likely confined placental mosaics and possibly clinically significant), structural chromosomal aberrations (95, 0.16%, PPV 32%,) and complex abnormal profiles indicative of maternal malignancies (11, 0.02%, PPV 64%). The implementation of genome-wide NIPT is under debate because the benefits of detecting other fetal chromosomal aberrations must be balanced against the risks of discordant positives, parental anxiety, and a potential increase in (invasive) diagnostic procedures. Our first-year data, including clinical data and laboratory follow-up data, will fuel this debate. Furthermore, we describe how NIPT can successfully be embedded into a national screening program with a single chain for prenatal care including counseling, testing, and follow-up.

Expanded carrier screening for autosomal recessive conditions in health care: Arguments for a couple-based approach and examination of couples' views.

BACKGROUND: Expanded carrier screening (ECS) is aimed at detecting carrier states for autosomal recessive (AR) or X-linked conditions in couples from the general population planning a pregnancy. ECS is currently usually offered on an individual basis despite the fact that, for AR conditions, only carrier couples are at risk of affected offspring. In this paper, we present a couple-based ECS test-offer for AR conditions, where results are offered as couple-results only, and describe how couples view such an offer. METHODS AND RESULTS: An online survey covering attitudes, perceived difficulty, and intention to take up couple-based ECS was used to examine couples' views. Results show that in 76% of the participating couples there is no objection at all towards receiving couple-results only. Most couples display similar views. Observed discrepancies usually involved one of the couple members having a positive view, whilst the other was neutral. Although views stayed strikingly stable after discussion, the partner's opinion was regarded as important in deciding whether or not to have testing. CONCLUSION: This study shows that most couples do not object to receiving couple rather than individual ECS results, have similar views towards the offer, and are able to discuss differences in views and intentions.

Feasibility of couple-based expanded carrier screening offered by general practitioners.

Expanded carrier screening (ECS) aims to inform couples' reproductive choice, preferably before conception. As part of an implementation study in which trained general practitioners (GPs) offered a population-based ECS couple-test, we evaluated the feasibility of the test-offer and degree of participant informed choice (IC). Trained GPs from nine practices in the northern Netherlands invited 4295 female patients aged 18-40 to take part in couple-based ECS. Inclusion criteria were having a male partner, planning for children and not being pregnant. We evaluated the feasibility of the organizational aspects, GP competence and the content of the pre-test counselling. Participant satisfaction, evaluation of pre-test counselling and degree of IC were measured using a longitudinal survey. We explored GP experiences and their views on future implementation through semi-structured interviews. 130 consultations took place. All participating GPs were assessed by genetic professionals to be competent to conduct pre-test counselling. Most (63/108 (58%)) consultations took place within the planned 20 min (median 20, IQR 18-28). GPs considered couples' prior knowledge level an important determinant of consultation length. 91% of patients were (very) satisfied with the GP counselling. After pre-test counselling, 231/237(97%) participants had sufficient knowledge and 206/231(88%) had a positive attitude and proceeded with testing. Our pilot demonstrates that offering couple-based ECS through trained and motivated GPs is feasible. Future large-scale implementation requires a well-informed general public and a discussion about appropriate reimbursement for GPs and health care coverage for couples. Providing (more) test information pre-appointment may help reduce average consultation time.

A validated PROM in genetic counselling: the psychometric properties of the Dutch version of the Genetic Counselling Outcome Scale.

Patient empowerment has been identified as a key outcome goal in genetic counselling, and a patient reported outcome measure (PROM) has been developed to measure empowerment in genetic services: the Genetic Counselling Outcome Scale (GCOS). Here we validate the GCOS for a large and diverse Dutch study sample of 2194 patients referred to two clinical genetic centres for counselling about a wide range of conditions (heart disease, neurological disorders, cancer, congenital syndromes, intellectual disability and prenatal pathology). Our results suggest that the GCOS consists of a hierarchical 6-factor structure, with a main scale for empowerment and six subscales: uncertainty about heredity, hope, negative emotions, knowledge about the condition, knowledge about genetic services and uncertainty about the treatment. Six of the original 24 GCOS items were removed due to low factor loadings and small inter-item correlations. Internal consistency and test-retest reliability of the main scale and most subscales were satisfactory. Convergent validity was confirmed by moderate positive and moderate/strong negative associations between the GCOS main scale and other validated outcome measures. Responsiveness was comparable to that of other validated outcome measures. We saw significant improvement in the GCOS main scale and all the subscales after the first genetic counselling session. This study contributes to the international validation process of the GCOS, with the ultimate goal of using this instrument as a PROM, with empowerment as an outcome measure, to evaluate and improve the quality of genetic counselling in various clinical genetics settings.

Recontacting patients in clinical genetics services: recommendations of the European Society of Human Genetics.

Technological advances have increased the availability of genomic data in research and the clinic. If, over time, interpretation of the significance of the data changes, or new information becomes available, the question arises as to whether recontacting the patient and/or family is indicated. The Public and Professional Policy Committee of the European Society of Human Genetics (ESHG), together with research groups from the UK and the Netherlands, developed recommendations on recontacting which, after public consultation, have been endorsed by ESHG Board. In clinical genetics, recontacting for updating patients with new, clinically significant information related to their diagnosis or previous genetic testing may be justifiable and, where possible, desirable. Consensus about the type of information that should trigger recontacting converges around its clinical and personal utility. The organization of recontacting procedures and policies in current health care systems is challenging. It should be sustainable, commensurate with previously obtained consent, and a shared responsibility between healthcare providers, laboratories, patients, and other stakeholders. Optimal use of the limited clinical resources currently available is needed. Allocation of dedicated resources for recontacting should be considered. Finally, there is a need for more evidence, including economic and utility of information for people, to inform which strategies provide the most cost-effective use of healthcare resources for recontacting.

Recontacting or not recontacting? A survey of current practices in clinical genetics centres in Europe.

Advances in genomic medicine are improving diagnosis and treatment of some health conditions, and the question of whether former patients should be recontacted is therefore timely. The issue of recontacting is becoming more important with increased integration of genomics in 'mainstream' medicine. Empirical evidence is needed to advance the discussion over whether and how recontacting should be implemented. We administered a web-based survey to genetic services in European countries to collect information about existing infrastructures and practices relevant to recontacting patients. The majority of the centres stated they had recontacted patients to update them about new significant information; however, there were no standardised practices or systems in place. There was also a multiplicity of understandings of the term 'recontacting', which respondents conflated with routine follow-up programmes, or even with post-test counselling. Participants thought that recontacting systems should be implemented to provide the best service to the patients and families. Nevertheless, many barriers to implementation were mentioned. These included: lack of resources and infrastructure, concerns about potential negative psychological consequences of recontacting, unclear operational definitions of recontacting, policies that prevent healthcare professionals from recontacting, and difficulties in locating patients after their last contact. These barriers are also intensified by the highly variable development (and establishment) of the specialties of medical genetics and genetic counselling across different European countries. Future recommendations about recontacting need to consider these barriers. It is also important to reach an 'operational definition' that can be useful in different countries.

Toward an effective exome-based genetic testing strategy in pediatric dilated cardiomyopathy.

PURPOSE: We evaluated the diagnostic yield in pediatric dilated cardiomyopathy (DCM) of combining exome sequencing (ES)-based targeted analysis and genome-wide copy-number variation (CNV) analysis. Based on our findings, we retrospectively designed an effective approach for genetic testing in pediatric DCM. METHODS: We identified 95 patients (in 85 families) with pediatric onset of DCM. We initially excluded 13 of these families because they already had a genetic diagnosis, leaving a total of 31 probands for single-nucleotide polymorphism (SNP) array and trio-ES. We used Human Phenotype Ontology (HPO)-based filtering for our data analysis. RESULTS: We reached a genetic diagnosis in 15/31 (48.4%) families. ES yielded a diagnosis in 13 probands (13/15; 86.7%), with most variants being found in genes encoding structural cardiomyocyte components. Two large deletions were identified using SNP array. If we had included the 13 excluded families, our estimated yield would have been 54%. CONCLUSION: We propose a standardized, stepwise analysis of (i) well-known cardiomyopathy genes, (ii) CNVs, (iii) all genes assigned to HPO cardiomyopathy, and (iv) if appropriate, genes assigned to other HPO terms. This diagnostic approach yields the highest increase at each subsequent step and reduces analytic effort, cost, the number of variants of unknown clinical significance, and the chance of incidental findings.