Impact of genetic counseling strategy on diagnostic yield and workload for genome-sequencing-based tumor diagnostics.

PURPOSE: Genome sequencing (GS) enables comprehensive molecular analysis of tumors and identification of hereditary cancer predisposition. According to guidelines, directly determining pathogenic germline variants (PGVs) requires pretest genetic counseling, which is cost-ineffective. Referral for genetic counseling based on tumor variants alone could miss relevant PGVs and/or result in unnecessary referrals. METHODS: We validated GS for detection of germline variants and simulated 3 strategies using paired tumor-normal GS data of 937 metastatic patients. In strategy-1, genetic counseling before tumor testing allowed direct PGV analysis. In strategy-2 and -3, germline testing and referral for post-test genetic counseling is based on tumor variants using Dutch (strategy-2) or Europen Society for Medical Oncology (ESMO) Precision Medicine Working Group (strategy-3) guidelines. RESULTS: In strategy-1, PGVs would be detected in 50 patients (number-needed-to counsel; NTC = 18.7). In strategy-2, 86 patients would have been referred for genetic counseling and 43 would have PGVs (NTC = 2). In strategy-3, 94 patients would have been referred for genetic counseling and 32 would have PGVs (NTC = 2.9). Hence, 43 and 62 patients, respectively, were unnecessarily referred based on a somatic variant. CONCLUSION: Both post-tumor test counseling strategies (2 and 3) had significantly lower NTC, and strategy-2 had the highest PGV yield. Combining pre-tumor test mainstreaming and post-tumor test counseling may maximize the clinically relevant PGV yield and minimize unnecessary referrals.

CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD.

We describe an autosomal dominant disorder associated with loss-of-function variants in the Cell cycle associated protein 1 (CAPRIN1; MIM*601178). CAPRIN1 encodes a ubiquitous protein that regulates the transport and translation of neuronal mRNAs critical for synaptic plasticity, as well as mRNAs encoding proteins important for cell proliferation and migration in multiple cell types. We identified 12 cases with loss-of-function CAPRIN1 variants, and a neurodevelopmental phenotype characterized by language impairment/speech delay (100%), intellectual disability (83%), attention deficit hyperactivity disorder (82%) and autism spectrum disorder (67%). Affected individuals also had respiratory problems (50%), limb/skeletal anomalies (50%), developmental delay (42%) feeding difficulties (33%), seizures (33%) and ophthalmologic problems (33%). In patient-derived lymphoblasts and fibroblasts, we showed a monoallelic expression of the wild-type allele, and a reduction of the transcript and protein compatible with a half dose. To further study pathogenic mechanisms, we generated sCAPRIN1+/- human induced pluripotent stem cells via CRISPR-Cas9 mutagenesis and differentiated them into neuronal progenitor cells and cortical neurons. CAPRIN1 loss caused reduced neuronal processes, overall disruption of the neuronal organization and an increased neuronal degeneration. We also observed an alteration of mRNA translation in CAPRIN1+/- neurons, compatible with its suggested function as translational inhibitor. CAPRIN1+/- neurons also showed an impaired calcium signalling and increased oxidative stress, two mechanisms that may directly affect neuronal networks development, maintenance and function. According to what was previously observed in the mouse model, measurements of activity in CAPRIN1+/- neurons via micro-electrode arrays indicated lower spike rates and bursts, with an overall reduced activity. In conclusion, we demonstrate that CAPRIN1 haploinsufficiency causes a novel autosomal dominant neurodevelopmental disorder and identify morphological and functional alterations associated with this disorder in human neuronal models.

Does a proactive procedure lead to a higher uptake of predictive testing in families with a pathogenic BRCA1/BRCA2 variant? A family cancer clinic evaluation.

The uptake of genetic counseling and predictive genetic testing by family members at risk for hereditary tumor syndromes is generally below 50%. To address this issue, a new guideline was introduced in the Netherlands in 2019 that aims to improve the sharing of information within families. In addition to cascade screening supported by follow-up telephone calls with the proband, municipal records were accessed to allow the geneticist to contact at-risk family members directly. We evaluated this procedure in 32 families with a (likely) pathogenic germline BRCA1/BRCA2 variant diagnosed at our hospital between May 1, 2020, and July 31, 2021, comparing current uptake with outcomes achieved for 33 families diagnosed in 2014. Fifteen months after diagnostic testing of the proband, the uptake was 43% (120/277), comparable to the 44% (87/200) registered previously. Among a subgroup of women at 50% risk aged 25-75 years, 71% (47/66) were tested, comparable to an earlier uptake of 69% (59/86). Of the 34 at-risk relatives we contacted directly, 17 (50%) underwent predictive testing. In conclusion, we found no evidence that the new procedure leads to a substantially increased uptake. Future research should be primarily aimed at understanding intrafamilial communication barriers.

Personalized assent for pediatric biobanks.

Pediatric biobanking is considered important for generating biomedical knowledge and improving (pediatric) health care. However, the inclusion of children's samples in biobanks involves specific ethical issues. One of the main concerns is how to appropriately engage children in the consent procedure. We suggest that children should be involved through a personalized assent procedure, which means that both the content and the process of assent are adjusted to the individual child. In this paper we provide guidance on how to put personalized assent into pediatric biobanking practice and consider both the content and process of personalized assent. In the discussion we argue that the assent procedure itself is formative. Investing in the procedure should be a requirement for pediatric biobank research. Although personalized assent will require certain efforts, the pediatric (biobank) community must be aware of its importance. The investment and trust earned can result in ongoing engagement, important longitudinal information, and stability in/for the research infrastructure, as well as increased knowledge among its participants about research activity. Implementing personalized assent will both respect the child and support biobank research.

Inclusion of residual tissue in biobanks: opt-in or opt-out?

Residual samples are an important source of tissue for biobanks. They refer to leftover tissue that is obtained in the course of clinical care. Residual samples can be included through an opt-in method--that is, a person explicitly expresses consent to include residual tissue--or an opt-out method--that is, the tissue is stored unless a person explicitly refuses. At the moment there is a renewed interest in the appropriate method for the inclusion of residual samples in biobanks. The expansion of biobanks and rapid developments in biomedical research underscore the need to evaluate the proper procedure. In this article we revisit the arguments in favor and against opt-in and opt-out methods for residual tissue research. We conclude firstly that an opt-out method is only justifiable when certain conditions are met: (1) awareness has to be raised, (2) sufficient information has to be provided, and (3) a genuine possibility to object has to be offered. An opt-out procedure that fulfills these conditions can be called a "thick" opt-out method. As a consequence, the dichotomy between opt-in and opt-out is less stark than usually suggested, as both methods require a certain amount of effort. Secondly, we conclude that because of the diversity of tissue and research, not every situation can be treated alike. There are at least four situations that require opt-in procedures: (1) research with higher risks or increased burdens, (2) the use of controversial or high-impact techniques, (3) research on sensitive tissue types, and (4) research involving vulnerable patients. We suggest that further interdisciplinary debate should answer the question when to opt-in or when to opt-out.

Vascular Ehlers-Danlos Syndrome: A Comprehensive Natural History Study in a Dutch National Cohort of 142 Patients.

BACKGROUND: Vascular Ehlers-Danlos syndrome (vEDS) is a rare connective tissue disorder with a high risk for arterial, bowel, and uterine rupture, caused by heterozygous pathogenic variants in COL3A1. The aim of this cohort study is to provide further insights into the natural history of vEDS and describe genotype-phenotype correlations in a Dutch multicenter cohort to optimize patient care and increase awareness of the disease. METHODS: Individuals with vEDS throughout the Netherlands were included. The phenotype was charted by retrospective analysis of molecular and clinical data, combined with a one-time physical examination. RESULTS: A total of 142 individuals (50% female) participated the study, including 46 index patients (32%). The overall median age at genetic diagnosis was 41.0 years. More than half of the index patients (54.3%) and relatives (53.1%) had a physical appearance highly suggestive of vEDS. In these individuals, major events were not more frequent (P=0.90), but occurred at a younger age (P=0.01). A major event occurred more often and at a younger age in men compared with women (P<0.001 and P=0.004, respectively). Aortic aneurysms (P=0.003) and pneumothoraces (P=0.029) were more frequent in men. Aortic dissection was more frequent in individuals with a COL3A1 variant in the first quarter of the collagen helical domain (P=0.03). CONCLUSIONS: Male sex, type and location of the COL3A1 variant, and physical appearance highly suggestive of vEDS are risk factors for the occurrence and early age of onset of major events. This national multicenter cohort study of Dutch individuals with vEDS provides a valuable basis for improving guidelines for the diagnosing, follow-up, and treatment of individuals with vEDS.

Duty to recontact in genomic cancer care: A tool helping to assess the professional's responsibility.

Tumour DNA and germline testing, based on DNA-wide sequencing analysis, are becoming more and more routine in clinical-oncology practice. A promising step in medicine, but at the same time leading to challenging ethicolegal questions. An important one is under what conditions individuals (patients and their relatives, research participants) should be recontacted with new information, even if many years have passed since the last contact. Based on legal- and ethical study, we developed a tool to help professionals to decide whether or not to recontact an individual in specific cases. It is based on four assessment criteria: (1) professional relationship (2) clinical impact (3) individual's preferences and (4) feasibility. The tool could also serve as a framework for guidelines on the topic.

Consent procedures in pediatric biobanks.

The inclusion of children's samples in biobanks brings forward specific ethical issues. Guidelines indicate that children should be involved in the consent procedure. It is, however, unclear how to allocate an appropriate role for children. Knowledge of current practice will be helpful in addressing this issue. Therefore, we conducted an international multiple-case study on the child's role in consent procedures in pediatric biobanks. Four biobanks were included: (1) LifeLines, (2) Prevention and Incidence of Asthma and Mite Allergy (PIAMA), (3) Young-HUNT3 and (4) the Oxford Radcliffe Biobank contribution to the Children's Cancer and Leukaemia Group tissue bank (ORB/CCLG). Four themes linked to the child's role in the consent procedure emerged from the multiple-case study: (1) motives to involve the child, (2) informing the child, (3) the role of dissent, assent and consent and (4) voluntariness of children to participate. We conclude that biobank characteristics influence the biobank's motives to include children in the consent procedure. Moreover, the motives to include children influence how the children are involved in the consent procedure, and the extent to which children are able to make voluntary decisions as part of the consent procedure. This insight is valuable when designing pediatric biobank governance.

Clarifying assent in pediatric research.

Assent is a relatively young term in research ethics, but became an often mentioned ethical requirement in current pediatric research guidelines. Also, the European Society of Human Genetics considers assent an important condition for the inclusion of children in biobanks. However, although many emphasize the importance of assent, few explain how they understand the concept and few have elaborated on the underlying grounds. In this paper, we will discuss the different underlying ethical principles of assent. In the first category, assent appears to be derived from informed consent. This understanding is grounded in respect for autonomy and protection against harm. We conclude that this interpretation of assent is not of added value as a majority of children cannot be considered competent to make autonomous decisions. In addition, other safeguards are more appropriate to protect children against harm. The grounds from the second category can be classified as engagement grounds. These grounds do justice to the specifics of childhood and are of added value. Furthermore, we argue that it follows that both the content and the process of assent should be adjusted to the individual child. This can be referred to as personalized assent. Personalized assent is an appeal to the moral responsibility and integrity of the researcher.