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.

The Economic, Medical and Psychosocial Consequences of Whole Genome Sequencing for the Genetic Diagnosis of Patients With Intellectual Disability: The DEFIDIAG Study Protocol.

Introduction: Like other countries, France has invested in a national medical genomics program. Among the four pilot research studies, the DEFIDIAG project focuses on the use of whole genome sequencing (WGS) for patients with intellectual disability (ID), a neurodevelopmental condition affecting 1-3% of the general population but due to a plethora of genes. However, the access to genomic analyses has many potential individual and societal issues in addition to the technical challenges. In order to help decision-makers optimally introduce genomic testing in France, there is a need to identify the socio-economic obstacles and leverages associated with the implementation of WGS. Methods and Analysis: This humanities and social sciences analysis is part of the DEFIDIAG study. The main goal of DEFIDIAG is to compare the percentage of causal genetic diagnoses obtained by trio WGS (including the patient and both parents) (WGST) to the percentage obtained using the minimal reference strategy currently used in France (Fragile-X testing, chromosomal microarray analysis, and gene panel strategy including 44 ID genes) for patients with ID having their first clinical genetics consultation. Additionally, four complementary studies will be conducted. First, a cost-effectiveness analysis will be undertaken in a subsample of 196 patients consulting for the first time for a genetic evaluation; in a blinded fashion, WGST and solo (index case, only) genomic analysis (WGSS) will be compared to the reference strategy. In addition, quantitative studies will be conducted: the first will estimate the cost of the diagnostic odyssey that could potentially be avoidable with first-line WGST in all patients previously investigated in the DEFIDIAG study; the second will estimate changes in follow-up of the patients in the year after the return of the WGST analysis compared to the period before inclusion. Finally, through semi-directive interviews, we will explore the expectations of 60 parents regarding genomic analyses. Discussion: Humanities and social sciences studies can be used to demonstrate the efficiency of WGS and assess the value that families associate with sequencing. These studies are thus expected to clarify trade-offs and to help optimize the implementation of genomic sequencing in France. Ethics Statement: The protocol was approved by the Ethics Committee Sud Méditerranée I (June 2019)-identification number: 2018-A00680-55 and the French data privacy commission (CNIL, authorization 919361). Clinical Trial Registration: (ClinicalTrials.gov), identifier (NCT04154891).

Who and Why? Requests for Presymptomatic Genetic Testing for Amyotrophic Lateral Sclerosis/Frontotemporal Dementia vs Huntington Disease.

OBJECTIVE: We aimed to describe the population of subjects seeking presymptomatic counseling for amyotrophic lateral sclerosis and/or frontotemporal dementia (ALS/FTD) and compared them with those demanding the well-established presymptomatic test for Huntington disease (HD). METHODS: We retrospectively examined the requests of a cohort of individuals at risk of familial ALS/FTD and 1 at risk of HD over the same time frame of 11 years. The individuals were seen in the referral center of our neurogenetics unit. RESULTS: Of the 106 presymptomatic testing (PT) requests from subjects at risk of ALS/FTD, 65% were seen in the last 3 years. Over two-thirds of the subjects were at risk of carrying mutations responsible for ALS, FTD, or both. Sixty-two percent of the subjects came from families with a known hexanucleotide repeat expansion in C9ORF72. During the same period, we counseled 840 subjects at risk of HD. Subjects at risk of ALS/FTD had the presymptomatic test significantly sooner after being aware of their risk, but were older than those at risk of HD. The youngest subjects requesting the test had the highest disease load in the family (p < 0.05). CONCLUSIONS: Demands for PT for ALS/FTD have been increasingly growing, particularly since the discovery of the C9ORF72 gene. The major specificity of the genetic counseling for these diseases is the unpredictability of the clinical phenotype for most of the genes involved. Awareness of this added uncertainty does not prevent individuals from taking the test, as the dropout rate is not higher than that for HD.

Psychosocial Impact of Predictive Genetic Testing in Hereditary Heart Diseases: The PREDICT Study.

Predictive genetic testing (PGT) is offered to asymptomatic relatives at risk of hereditary heart disease, but the impact of result disclosure has been little studied. We evaluated the psychosocial impacts of PGT in hereditary heart disease, using self-report questionnaires (including the State-Trait Anxiety Inventory) in 517 adults, administered three times to the prospective cohort (PCo: n = 264) and once to the retrospective cohort (RCo: n = 253). The main motivations for undergoing PGT were "to remove doubt" and "for their children". The level of anxiety increased between pre-test and result appointments (p <0.0001), returned to baseline after the result (PCo), and was moderately elevated at 4.4 years (RCo). Subjects with a history of depression or with high baseline anxiety were more likely to develop anxiety after PGT result (p = 0.004 and p <0.0001, respectively), whatever it was. Unfavourable changes in professional and/or family life were observed in 12.4% (PCo) and 18.7% (RCo) of subjects. Few regrets about PGT were expressed (0.8% RCo, 2.3% PCo). Medical benefit was not the main motivation, which emphasises the role of pre/post-test counselling. When PGT was performed by expert teams, the negative impact was modest, but careful management is required in specific categories of subjects, whatever the genetic test result.

Prenatal molecular diagnosis in RASA1-related disease.

RASA1-related disease is a rare autosomal dominant disease characterized by capillary malformations, arteriovenous malformations (AVMs), and/or arteriovenous fistulas (AFVs). Penetrance is nearly complete and vascular malformations may cause serious complications such as organ injury due to oxygenation disorder, brain abscess, hemorrhage, and stroke. Early diagnosis is useful in order to discuss optimal management, including AVMs/AVFs embolization or surgical procedures, and try to prevent some of the complications. In this context, molecular testing of RASA1 gene mutation in relatives may help to better manage the family. All arteriovenous malformations are however not accessible to such procedures. In addition, these therapeutic procedures may result in potential side effects and complications. A couple was referred to our genetics unit and asked us for prenatal genetic testing about a RASA1 mutation. Here, we discuss about arguments that led our team to accept prenatal testing. To the best of our knowledge, no molecular prenatal diagnosis was reported until now in RASA1-related diseases. This first report of prenatal diagnosis in RASA1-related diseases may also offer perspectives for a more general discussion in the field of inherited arteriovenous malformations.

Comparison of patient- and physician-based descriptions of symptoms of endometriosis: a qualitative study.

STUDY QUESTION: How do fully-comprehensive patient-centred descriptions of the symptoms of endometriosis compare with the physicians' description of the symptoms? SUMMARY ANSWER: The description of the painful symptoms due to endometriosis is based on numerous distinct parameters. The way these are used to describe symptoms and the way they are interpreted varies significantly between patients and clinicians. The descriptions of severe pelvic pain and dysmenorrhoea and dyspareunia by the clinicians were incomplete compared with those of the patients. WHAT IS KNOWN ALREADY: Painful symptoms due to endometriosis were found to be of little use to predict the location and severity of the disease. Currently there are few data on the patients' description of symptoms and no questionnaire is available to derive data from patients. STUDY DESIGN, SIZE, DURATION: Descriptions of painful symptoms by patients and by physicians were obtained by qualitative, interview-based study and analysed using Colaizzi's method. The patients planned to be operated on for painful endometriosis were volunteers for preoperative interview. They were recruited by purposeful sampling to represent different types of endometriosis [i.e. superficial endometriosis, ovarian endometriosis or deeply infiltrating endometriosis (DIE)], the women were selected so that at least five sites of endometriosis were included in the study. The clinicians were experts in endometriosis management. PARTICIPANTS/MATERIALS, SETTING, METHODS: Forty-one patients were recruited, in four reference centres. Among them, 33 had DIE in various locations, including intestinal endometriosis (n = 12) or bladder endometriosis (n = 5), 14 had ovarian endometriosis (including three without associated DIE) and 5 had only superficial endometriosis. The nine experts were French-speaking gynaecological surgeons practicing in university teaching hospitals (seven), a general hospital (one) or a private centre (one). MAIN RESULTS AND THE ROLE OF CHANCE: In total, 47 themes were identified of which 30 were perceived by both patients and clinicians, 12 by patients only and 5 by clinicians only. Themes fall into five general categories: (i) severe pelvic pain and dysmenorrhoea, (ii) dyspareunia, (iii) gastro-intestinal symptoms, (iv) bladder symptoms, (v) other symptoms. Patients' and clinicians' descriptions of symptoms were in agreement for general categories, but the clinicians' comprehensive description was incomplete, in particular concerning the severe pelvic pain and dysmenorrhoea's themes and the dyspareunia theme. Patients did not report any clear-cut distinction between pelvic pain and dysmenorrhoea and expressed a dimension of suffering and impaired quality of life inherent to painful symptoms. LIMITATIONS, REASONS FOR CAUTION: Most of the patients in the study had already had treatment for endometriosis, including ongoing hormonal treatment. Furthermore, all but a few patients had documented endometriotic lesions and no specific investigations to eliminate additional causes of functional pelvic pain were done. Finally due to the qualitative design of the study the result must be regarded as inferences. WIDER IMPLICATIONS OF THE FINDINGS: The present study provides a first person viewpoint of the painful experience of endometriosis by the patients in a subjective, phenomenological perspective, and points out the differences of perceptions between the physicians and the patients. The considerable variability in patients' descriptions suggests several distinct mechanisms are involved in explaining the pain related to endometriosis. The discordance between clinicians and patients might also reflect this kind of problem with the wording of the items. In future, if the goal is to properly understand the pain experienced by women with endometriosis, assessment tools using the words and phrases used in narratives of pain would potentially be very useful. STUDY FUNDING/COMPETING INTEREST(S): Funded by IPSEN, Boulogne-Billancourt, France. None of the authors has any conflict of interest to declare. TRIAL REGISTRATION NUMBER: Not applicable.

Adnexal torsion: a predictive score for pre-operative diagnosis.

BACKGROUND: Adnexal torsion (AT) is difficult to diagnose and requires immediate surgery. The aim of this study was to develop a simple score for assisting in the pre-operative diagnosis of AT in women with acute pelvic pain. METHODS: Using data from a retrospective cohort of 142 patients with acute pelvic pain, we developed a score based on multiple logistic regression after a jackknife procedure. We validated the score in a prospective cohort of 35 women with acute pelvic pain. RESULTS: Five criteria were independently associated with AT confirmed by surgery: unilateral lumbar or abdominal pain [adjusted odds ratio (aOR), 4.1; 95% confidence interval (95% CI), 1.2-14.0]; pain duration <8 h at first presentation (aOR, 8.0; 95% CI, 1.7-37.5), vomiting (aOR, 7.9; 95% CI, 2.3-27.0), absence of leucorrhoea and metrorrhagia (aOR, 12.6; 95% CI, 2.3-67.6) and ovarian cyst larger than 5 cm by ultrasonography (aOR, 10.6; 95% CI, 2.9-38.8). The torsion score was based on these five criteria. Low-risk and high-risk groups were derived from values of the score [probability of AT, 3.7% (95% CI, 0-7.8) and 69% (95% CI, 53-84), respectively]. Application of these criteria to the prospective cohort confirmed the diagnostic accuracy of the score [probability of AT, 0% (95% CI, 0-16) and 75% (95% CI, 26-100) in the low-risk and high-risk groups, respectively]. CONCLUSIONS: This easy-to-calculate score may prove useful for diagnosing AT in patients with acute pelvic pain seen at general or gynaecology emergency departments.