Pulmonary arterial hypertension (PAH) is a rare disease that can be caused by (likely) pathogenic germline genomic variants. In addition to the most prevalent disease gene, BMPR2 (bone morphogenetic protein receptor 2), several genes, some belonging to distinct functional classes, are also now known to predispose to the development of PAH. As a consequence, specialist and non-specialist clinicians and healthcare professionals are increasingly faced with a range of questions regarding the need for, approaches to and benefits/risks of genetic testing for PAH patients and/or related family members. We provide a consensus-based approach to recommendations for genetic counselling and assessment of current best practice for disease gene testing. We provide a framework and the type of information to be provided to patients and relatives through the process of genetic counselling, and describe the presently known disease causal genes to be analysed. Benefits of including molecular genetic testing within the management protocol of patients with PAH include the identification of individuals misclassified by other diagnostic approaches, the optimisation of phenotypic characterisation for aggregation of outcome data, including in clinical trials, and importantly through cascade screening, the detection of healthy causal variant carriers, to whom regular assessment should be offered.

暂无摘要。

UNASSIGNED: Germline and tumour genetic testing in prostate cancer (PCa) is becoming more broadly accepted, but testing indications and clinical consequences for carriers in each disease stage are not yet well defined.
UNASSIGNED: To determine the consensus of a Dutch multidisciplinary expert panel on the indication and application of germline and tumour genetic testing in PCa.
UNASSIGNED: The panel consisted of 39 specialists involved in PCa management. We used a modified Delphi method consisting of two voting rounds and a virtual consensus meeting.
UNASSIGNED: Consensus was reached if ≥75% of the panellists chose the same option. Appropriateness was assessed by the RAND/UCLA appropriateness method.
UNASSIGNED: Of the multiple-choice questions, 44% reached consensus. For men without PCa having a relevant family history (familial PCa/BRCA-related hereditary cancer), follow-up by prostate-specific antigen was considered appropriate. For patients with low-risk localised PCa and a family history of PCa, active surveillance was considered appropriate, except in case of the patient being a BRCA2 germline pathogenic variant carrier. Germline and tumour genetic testing should not be done for nonmetastatic hormone-sensitive PCa in the absence of a relevant family history of cancer. Tumour genetic testing was deemed most appropriate for the identification of actionable variants, with uncertainty for germline testing. For tumour genetic testing in metastatic castration-resistant PCa, consensus was not reached for the timing and panel composition. The principal limitations are as follows: (1) a number of topics discussed lack scientific evidence, and therefore the recommendations are partly opinion based, and (2) there was a small number of experts per discipline.
UNASSIGNED: The outcomes of this Dutch consensus meeting may provide further guidance on genetic counselling and molecular testing related to PCa.
UNASSIGNED: A group of Dutch specialists discussed the use of germline and tumour genetic testing in prostate cancer (PCa) patients, indication of these tests (which patients and when), and impact of these tests on the management and treatment of PCa.

BACKGROUND: Homologous recombination repair (HRR) enables fault-free repair of double-stranded DNA breaks. Homologous recombination repair deficiency (HRR deficiency) is predicted to occur in around half of high-grade serous ovarian carcinomas. Ovarian cancers harbouring HRR deficiency typically exhibit sensitivity to poly-ADP ribose polymerase inhibitors (PARPi). Current guidelines recommend a range of approaches for genetic testing to identify predictors of sensitivity to PARPi in ovarian cancer and to identify genetic predisposition.
METHODS: To establish a European-wide consensus for genetic testing (including the genetic care pathway), decision making and clinical management of patients with recently diagnosed advanced ovarian cancer, and the validity of biomarkers to predict the effectiveness of PARPi in the first-line setting. The collaborative European experts\' consensus group consisted of a steering committee (N=14) and contributors (N=84). A (modified) Delphi process was used to establish consensus statements based on a systematic literature search, conducted according to the PRISMA guidelines.
RESULTS: A consensus was reached on 34 statements amongst 98 caregivers (including oncologists, pathologists, clinical geneticists, genetic researchers and patient advocates). The statements concentrated on (i) the value of testing for BRCA1/2 mutations and HRR deficiency testing, including when and whom to test; (ii) the importance of developing new and better HRR deficiency tests; (iii) the importance of germline non-BRCA HRR and mismatch repair gene mutations for predicting familial risk, but not for predicting sensitivity to PARPi, in the first-line setting; (iv) who should be able to inform patients about genetic testing, and what training and education should these caregivers receive.
CONCLUSIONS: These consensus recommendations, from a multidisciplinary panel of experts from across Europe, provide clear guidance on the use of BRCA and HRR deficiency testing for recently diagnosed patients with advanced ovarian cancer.

A consensus protocol for genetic counselling and testing of familial dementia, the Italian Dominantly Inherited Alzheimer\'s and Frontotemporal Network (IT-DIAfN) protocol, has been developed in Italy by a network of expert dementia centres. The aim of this study is to evaluate feasibility and acceptability of the genetic counselling and testing process, as undertaken according to the IT-DIAfN protocol in one of the IT-DIAfN dementia research centres.
The protocol was tested by a multidisciplinary team at the IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy, on affected individuals with suspected inherited forms of Alzheimer\'s disease (AD) or frontotemporal dementia (FTD), and to healthy at-risk relatives. The genetic counselling and testing process consisted of (i) pre-test consultation and psychological assessment (ii) genetic testing, (iii) genetic test result disclosure and (iv) follow-up consultation and psychological assessment.
Twenty affected individuals from 17 families fulfilled the family history criteria of the IT-DIAfN protocol for suspected inherited dementia (17 for AD, 2 for FTD, 1 for inclusion body myopathy with Paget disease of bone and frontotemporal dementia) and were included in the protocol. Nineteen out of 20 affected individuals received the genetic test result (one left after the pre-test consultation being not ready to cope with an unfavourable outcome). A pathogenic mutation was found in 6 affected individuals (1 in PSEN1, 2 in PSEN2, 1 in GRN, 1 in MAPT, 1 in VCP). Eleven healthy at-risk relatives asked to undergo predictive testing and were included in the protocol. Three completed the protocol, including follow-up; one did not ask for the genetic test result after genetic testing; and eight withdrew before the genetic testing, mainly due to an increased awareness about the possible consequences of an unfavourable test result. To date, no catastrophic reactions were reported at the follow-up.
Our case series shows that a structured genetic counselling and testing protocol for inherited dementia can be implemented in both affected individuals and at-risk relatives in a research setting. The procedure was shown to be safe in terms of occurrence of catastrophic events. A formal validation in larger cohorts is needed.

To determine the proportion of patients with colorectal cancer and abnormal immunohistochemistry testing of tumour tissue who were referred to a cancer genetic clinic for genetic counselling and possible germline testing of a blood sample for Lynch syndrome.
This is a retrospective cohort study of patients with colorectal cancer and abnormal immunohistochemistry tumour tissue testing from St Vincent\'s Hospital (between November 2007 and December 2016). Patient list was compared against a state-wide database TrakGene to ascertain the overall referral rate for these patients.
Of 216 patients, the total referral rate was 33.8% (n = 73), of which 27.8% (n = 60) were referred to St Vincent\'s Hospital\'s Cancer Genetics Service, 6% (n = 13) were referred externally and the remaining 66.2% (n = 143) were not referred. Binomial regression analysis performed displayed that age influenced likelihood of referral, where patients were 7.7% more likely to be referred for every decreasing year in age (P = 0.0004). Some clinicians were 4.3 times more likely to refer patients compared to others (P = 0.002).
Suboptimal patient uptake for cancer genetics evaluation was found. Identifying barriers to patient referral should lead to changes that increase patient referrals. This will ensure that patients receive adequate education, counselling and management of Lynch syndrome. It would also allow for the identification of further at-risk relatives for whom preventative strategies can be employed. In addition, identification of relatives not at risk by genetic testing will liberate them from unnecessary colonoscopies. Discussion with the clinicians involved has since allowed for copies of the immunohistochemistry results to be forwarded by the Pathology Department to the Cancer Genetics Unit for checking and follow up with the clinician to ensure that their patients are aware of the result and have been offered referral for cancer genetic evaluation. This process is subject to ongoing audit.

An international panel of experts representing 17 European countries and Israel convened to discuss current needs and future developments in BRCA testing and counselling and to issue consensus recommendations. The experts agreed that, with the increasing availability of high-throughput testing platforms and the registration of poly-ADP-ribose-polymerase inhibitors, the need for genetic counselling and testing will rapidly increase in the near future. Consequently, the already existing shortage of genetic counsellors is expected to worsen and to compromise the quality of care particularly in individuals and families with suspected or proven hereditary breast or ovarian cancer. Increasing educational efforts within the breast cancer caregiver community may alleviate this limitation by enabling all involved specialities to perform genetic counselling. In the therapeutic setting, for patients with a clinical suspicion of genetic susceptibility and if the results may have an immediate impact on the therapeutic strategy, the majority voted that BRCA1/2 testing should be performed after histological diagnosis of breast cancer, regardless of oestrogen receptor and human epidermal growth factor receptor 2 (HER2) status. Experts also agreed that, in the predictive and therapeutic setting, genetic testing should be limited to individuals with a personal or family history suggestive of a BRCA1/2 pathogenic variant and should also include high-risk actionable genes beyond BRCA1/2. Of high-risk actionable genes, all pathological variants (i.e. class IV and V) should be reported; class III variants of unknown significance, should be reported provided that the current lack of clinical utility of the variant is expressly stated. Genetic counselling should always address the possibility that already tested individuals might be re-contacted in case new information on a particular variant results in a re-classification.