Expectations, needs and mid-term outcomes in people accessing to secondary findings from ES: 1st French mixed study (FIND Study).

Generation and subsequently accessibility of secondary findings (SF) in diagnostic practice is a subject of debate around the world and particularly in Europe. The French FIND study has been set up to assess patient/parent expectations regarding SF from exome sequencing (ES) and to collect their real-life experience until 1 year after the delivery of results. 340 patients who had ES for undiagnosed developmental disorders were included in this multicenter mixed study (quantitative N = 340; qualitative N = 26). Three groups of actionable SF were rendered: predisposition to late-onset actionable diseases; genetic counseling; pharmacogenomics. Participants expressed strong interest in obtaining SF and a high satisfaction level when a SF is reported. The medical actionability of the SF reinforced parents' sense of taking action for their child and was seen as an opportunity. While we observed no serious psychological concerns, we showed that these results could have psychological consequences, in particular for late-onset actionable diseases SF, within families already dealing with rare diseases. This study shows that participants remain in favor of accessing SF despite the potential psychological, care, and lifestyle impacts, which are difficult to anticipate. The establishment of a management protocol, including the support of a multidisciplinary team, would be necessary if national policy allows the reporting of these data.

Access to social services for undiagnosed rare disease patients in France: A pilot study.

Although the challenge of access to care for undiagnosed rare disease patients is well documented in the literature, little is known about lack of diagnosis preventing access to social services. Yet this has serious consequences for patients and their families because disability associated with rare disease requires frequent and costly multi-disciplinary support. The aim of this research is to explore, in the French context, access to social assistance for rare disease patients. We investigate the link between diagnosis and access to social services to identify potential barriers and unmet needs for patients. Our study is based on a self-administered online questionnaire, adressed to parents or legal representatives of a child under ten years old with a rare disease and development disorders. The survey has been carried out between November 2019 and the end of January 2020 and includes 103 respondents. While our data does not show any differences in the possibility of obtaining a social benefit depending on the diagnosis status, there are differences in the length of time they are granted and in the satisfaction of families with the assistance obtained. Families with an undiagnosed child obtained social assistance for a shorter period on average. They were also more likely to be dissatisfied with the amount of benefit they received. The results of this pilot study need to be confirmed by further extended studies.

Exome sequencing in clinical settings: preferences and experiences of parents of children with rare diseases (SEQUAPRE study).

Exome sequencing (ES) has revolutionized diagnostic procedures in medical genetics, particularly for developmental diseases. The variety and complexity of the information produced has raised issues regarding its use in a clinical setting. Of particular interest are patients' expectations regarding the information disclosed, the accompaniment provided, and the value patients place on these. To explore these issues in parents of children with developmental disorders and no diagnosis with known etiology, a multidisciplinary group of researchers from social and behavioral sciences and patient organizations conducted a mixed-methodology study (quantitative and qualitative) in two centers of expertise for rare diseases in France. The quantitative study aimed to determine the preferences of 513 parents regarding the disclosure of ES results. It showed that parents wished to have exhaustive information, including variants of unknown significance possibly linked to their child's disorder and secondary findings. This desire for information could be a strategy to maximize the chances of obtaining a diagnosis. The qualitative study aimed to understand the expectations and reactions of 57 parents interviewed just after the return of ES results. In-depth analysis showed that parents had ambivalent feelings about the findings whatever the results returned. The contrasting results from these studies raise questions about the value of the information provided and parents' high expectations regarding the results. The nature of parental expectations has emerged as an important topic in efforts to optimize accompaniment and support for families during the informed decision-making process and after disclosure of the results in an overall context of uncertainty.

Secondary actionable findings identified by exome sequencing: expected impact on the organisation of care from the study of 700 consecutive tests.

With exome/genome sequencing (ES/GS) integrated into the practice of medicine, there is some potential for reporting incidental/secondary findings (IFs/SFs). The issue of IFs/SFs has been studied extensively over the last 4 years. In order to evaluate their implications in care organisation, we retrospectively evaluated, in a cohort of 700 consecutive probands, the frequency and burden of introducing the search for variants in a maximum list of 244 medically actionable genes (genes that predispose carriers to a preventable or treatable disease in childhood/adulthood and genes for genetic counselling issues). We also focused on the 59 PharmGKB class IA/IB pharmacogenetic variants. We also compared the results in different gene lists. We identified variants (likely) affecting protein function in genes for care in 26 cases (3.7%) and heterozygous variants in genes for genetic counselling in 29 cases (3.8%). Mean time for the 700 patients was about 6.3 min/patient for medically actionable genes and 1.3 min/patient for genes for genetic counselling, and a mean time of 37 min/patients for the reinterpreted variants. These results would lead to all 700 pre-test counselling sessions being longer, to 55 post-test genetic consultations and to 27 secondary specialised medical evaluations. ES also detected 42/59 pharmacogenetic variants or combinations of variants in the majority of cases. An extremely low metabolizer status in genes relevant for neurodevelopmental disorders (CYP2C9 and CYP2C19) was found in 57/700 cases. This study provides information regarding the need to anticipate the implementation of genomic medicine, notably the work overload at various steps of the process.

Preference heterogeneity with respect to whole genome sequencing. A discrete choice experiment among parents of children with rare genetic diseases.

The information to which whole genome sequencing (WGS) provides access raises questions about its disclosure to patients. The literature focused on the nature of findings, shows patients share the same expectations while evoking possible heterogeneity. Our objective is to test this hypothesis of preference heterogeneity with respect to the disclosure of results from WGS by means of a discrete choice experiment (DCE). Our DCE includes six attributes for studying preferences with respect to (1) variants of unknown significance and (2) secondary findings, and more innovatively with respect to (3) repeat analysis of the tests, (4) the decision-making process, (5) patient support and (6) the cost of testing. The survey was conducted at two genetic centres in France from February to December 2015 and included 528 parents of patients with development disorders with no aetiological diagnosis. By using a latent class model, it was possible to identify two preference profiles with parents opting for either a prospective (75% of sample) or a targeted (25%) diagnostic approach. The former valued the exhaustive and diverse genetic information the test can provide, even when the information is uncertain or not directly related to their child's illness; the latter valued only the least uncertain information relating to their child's illness. Understanding patients' preference patterns can help professionals to better accommodate and support patients and enables policy-makers to measure the diversity of expectations in the face of current developments in genomic medicine.