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.

[Clinical Cancer Genetics: A guide for the pathologist]. / Les trois temps de la prise en charge oncogénétique : la consultation, l'analyse en laboratoire et le suivi personnalisé.

It is paramount to identify patients whose cancer is associated with genetic susceptibility to the disease, since their long-term management depends on it. Anatomical and molecular pathologists play a key role in the process. Indeed, their diagnosis supports or even sometimes warrants germline genetic testing. For example, a colorectal cancer with mismatch repair protein expression loss suggests Lynch syndrome, while a rare type of renal cell carcinoma with fumarate hydrate expression loss is highly evocative of hereditary leiomyomatosis and renal cell carcinoma syndrome. Similarly, the presence of the T790M EGFR variant before treatment in a non-small-cell lung carcinoma warrants further testing as the variant is likely of germline origin. Patients with suspected genetic susceptibility to cancer are referred to the nearest clinical cancer genetics clinic. The cancer geneticist, assisted by a genetic counsellor, then collects detailed personal and familial information, sometimes feeds them into bioinformatics tools or clinico-pathological scores, decides whether germline genetic analysis is justified, determines which genes should be analysed and prescribes testing. Germline testing is carried out on a blood sample by expert laboratories using next generation sequencing on panels of cancer susceptibility genes. The cancer geneticists then return the result to the patient. When a pathogenic variant is identified, the patient's management is modified, with recommendations ranging from intensified surveillance to risk-reducing surgery. Treatment is sometimes adapted to the pathogenic variant. In addition, relatives can undergo genetic testing, should they wish to know whether they carry the familial variant. In the near future, we expect clinical cancer genetics to move towards strengthened partnerships with molecular pathologists and medical oncologists. Somatic genetic analyses are now routine, at least in metastatic cancer, and a proportion of the tumoral variants identified are actually of germline origin. As for the oncologists, the development of mainstreaming programs where they are allowed to prescribe germline testing under the supervision of a cancer genetics team is unavoidable.

Genetic Testing in Prion Disease: Psychological Consequences of the Decisions to Know or Not to Know.

Purpose: Presymptomatic testing for susceptibility to genetic prion diseases is often delivered in difficult circumstances, as the index case is often dying when a genetic diagnosis is obtained. Since test requests in these diseases are very rare, the factors underlying decisions of relatives to be tested or not and the long-term psychological consequences are not reported. Methods: We contacted subjects who had consulted between 2004 and 2017 because a relative carried a pathological PRNP variant. Standardized psychological scales and semistructured interviews were proposed. Results: We did contact 19 of the 30 subjects who had consulted: 6 of 10 who did not undergo testing, 10 of 12 noncarriers, and 3 of 8 mutation carriers. Anxiety rates were high and similar between noncarriers and untested subjects. Conclusions: Living in a family with inherited prion disease produced psychological burden, regardless of the decision to undergo testing and its results. Decisions in favor of being testing did not allow relief of anxiety about the family disease. The dilemmatic decision not to know remained a burden to be coped with. Genetic counseling procedures should take into account all these situations, even that of noncarriers and that of untested.