Background: The UK 100,000 Genomes Project was a transformational research project which facilitated whole genome sequencing (WGS) diagnostics for rare diseases. We evaluated experiences of ...introducing WGS in Northern Ireland, providing recommendations for future projects. Methods: This formative evaluation included (1) an appraisal of the logistics of implementing and delivering WGS, (2) a survey of participant self-reported views and experiences, (3) semi-structured interviews with healthcare staff as key informants who were involved in the delivery of WGS and (4) a workshop discussion about interprofessional collaboration with respect to molecular diagnostics. Results: We engaged with >400 participants, with detailed reflections obtained from 74 participants including patients, caregivers, key National Health Service (NHS) informants, and researchers (patient survey n = 42; semi-structured interviews n = 19; attendees of the discussion workshop n = 13). Overarching themes included the need to improve rare disease awareness, education, and support services, as well as interprofessional collaboration being central to an effective, mainstreamed molecular diagnostic service. Conclusions: Recommendations for streamlining precision medicine for patients with rare diseases include administrative improvements (e.g., streamlining of the consent process), educational improvements (e.g., rare disease training provided from undergraduate to postgraduate education alongside genomics training for non-genetic specialists) and analytical improvements (e.g., multidisciplinary collaboration and improved computational infrastructure).
Abstract Background The CanRisk tool, which operationalises the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) is used by Clinical Geneticists, Genetic ...Counsellors, Breast Oncologists, Surgeons and Family History Nurses for breast cancer risk assessments both nationally and internationally. There are currently no guidelines with respect to the day-to-day clinical application of CanRisk and differing inputs to the model can result in different recommendations for practice. Methods To address this gap, the UK Cancer Genetics Group in collaboration with the Association of Breast Surgery and the CanGene-CanVar programme held a workshop on 16 th of May 2023, with the aim of establishing best practice guidelines. Results Using a pre-workshop survey followed by structured discussion and in-meeting polling, we achieved consensus for UK best practice in use of CanRisk in making recommendations for breast cancer surveillance, eligibility for genetic testing and the input of available information to undertake an individualised risk assessment. Conclusions Whilst consensus recommendations were achieved, the meeting highlighted some of the barriers limiting the use of CanRisk in clinical practice and identified areas that require further work and collaboration with relevant national bodies and policy makers to incorporate wider use of CanRisk into routine breast cancer risk assessments.
Unilateral leg swelling in an infant Shah, Shilpa; Berry, Sarah; Bingham, Laura ...
Archives of disease in childhood. Education and practice edition,
04/2020, Letnik:
105, Številka:
2
Journal Article
Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we ...evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders.
Spinocerebellar ataxia type 5 (SCA-5) is a predominantly slowly progressive adult onset ataxia. We describe a child with a presentation of ataxic cerebral palsy (CP) and developmental delay at 6 ...months of age. Genetic testing confirmed a c.812C>T p.(Thr271Ile) mutation within the
SPTBN2
gene. Seven previous cases of infantile onset SCA-5 are reported in the literature, four of which had a CP presentation. Early onset of SCA-5 presents with ataxic CP and is a rare cause of cerebral palsy.
Abstract As the rate of people openly identifying as transgender or gender diverse (TGD) is increasing, UK cancer genetics services are seeing growing numbers of TGD patients. Lack of appropriate ...clinical guidelines and a scarcity of robust data about the impact of gender-affirming treatments on cancer risk has led to uncertainty of how best to support TGD patients, and inequity in standards of care. To address this gap, the UK Cancer Genetics Group and Central & South Genomic Medicine Service Alliance facilitated a 2-day meeting to develop national consensus to support the management of TGD patients with inherited cancer risks. Key stakeholders from a broad range of clinical specialties, patients advocates, and those with lived experience discussed and voted on recommendations for best practice. The consensus was reached on topics including family history questionnaires, pedigrees, clinical information, breast tissue management, gynaecological and prostate management, patient pathways, and education. Further work is required to reach consensus on the breast screening recommendations for TGD patients assigned female at birth who have had masculinising chest surgery. Here we present a summary of the processes used to reach consensus, and the recommendations from this meeting.
Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting in reduced or complete loss-of-function (LOF) of the encoded chloride/proton exchanger ClC-4, were recently ...demonstrated to cause a neurocognitive phenotype in both males and females. Through international clinical matchmaking and interrogation of public variant databases we assembled a database of 90 rare CLCN4 missense variants in 90 families: 41 unique and 18 recurrent variants in 49 families. For 43 families, including 22 males and 33 females, we collated detailed clinical and segregation data. To confirm causality of variants and to obtain insight into disease mechanisms, we investigated the effect on electrophysiological properties of 59 of the variants in Xenopus oocytes using extended voltage and pH ranges. Detailed analyses revealed new pathophysiological mechanisms: 25% (15/59) of variants demonstrated LOF, characterized by a "shift" of the voltage-dependent activation to more positive voltages, and nine variants resulted in a toxic gain-of-function, associated with a disrupted gate allowing inward transport at negative voltages. Functional results were not always in line with in silico pathogenicity scores, highlighting the complexity of pathogenicity assessment for accurate genetic counselling. The complex neurocognitive and psychiatric manifestations of this condition, and hitherto under-recognized impacts on growth, gastrointestinal function, and motor control are discussed. Including published cases, we summarize features in 122 individuals from 67 families with CLCN4-related neurodevelopmental condition and suggest future research directions with the aim of improving the integrated care for individuals with this diagnosis.
SDHA pathogenic germline variants (PGVs) are identified in up to 10% of patients with paraganglioma and phaeochromocytoma and up to 30% with wild-type gastrointestinal stromal tumours. Most SDHA PGV ...carriers present with an apparently sporadic tumour, but often the pathogenic variant has been inherited from parent who has the variant, but has not developed any clinical features. Studies of SDHA PGV carriers suggest that lifetime penetrance for SDHA-associated tumours is low, particularly when identified outside the context of a family history. Current recommended surveillance for SDHA PGV carriers follows an intensive protocol. With increasing implementation of tumour and germline large panel and whole-genome sequencing, it is likely more SDHA PGV carriers will be identified in patients with tumours not strongly associated with SDHA, or outside the context of a strong family history. This creates a complex situation about what to recommend in clinical practice considering low penetrance for tumour development, surveillance burden and patient anxiety. An expert SDHA working group was formed to discuss and consider this situation. This paper outlines the recommendations from this working group for testing and management of SDHA PGV carriers in clinical practice.
Aims
To examine the relevance of genetic and cardiovascular magnetic resonance (CMR) features of dilated cardiomyopathy (DCM) in individuals with coronary artery disease (CAD).
Methods and results
...This study includes two cohorts. First, individuals with CAD recruited into the UK Biobank (UKB) were evaluated. Second, patients with CAD referred to a tertiary centre for evaluation with late gadolinium enhancement (LGE)‐CMR were recruited (London cohort); patients underwent genetic sequencing as part of the research protocol and long‐term follow‐up. From 31 154 individuals with CAD recruited to UKB, rare pathogenic variants in DCM genes were associated with increased risk of death or major adverse cardiac events (hazard ratio 1.57, 95% confidence interval CI 1.22–2.01, p < 0.001). Of 1619 individuals with CAD included from the UKB CMR substudy, participants with a rare variant in a DCM‐associated gene had lower left ventricular ejection fraction (LVEF) compared to genotype negative individuals (mean 47 ± 10% vs. 57 ± 8%, p < 0.001). Of 453 patients in the London cohort, 63 (14%) had non‐infarct pattern LGE (NI‐LGE) on CMR. Patients with NI‐LGE had lower LVEF (mean 38 ± 18% vs. 48 ± 16%, p < 0.001) compared to patients without NI‐LGE, with no significant difference in the burden of rare protein altering variants in DCM‐associated genes between groups (9.5% vs. 6.7%, odds ratio 1.5, 95% CI 0.4–4.3, p = 0.4). NI‐LGE was not independently associated with adverse clinical outcomes.
Conclusion
Rare pathogenic variants in DCM‐associated genes impact left ventricular remodelling and outcomes in stable CAD. NI‐LGE is associated with adverse remodelling but is not an independent predictor of outcome and had no rare genetic basis in our study.
In this study, two independent cohorts were used to investigate for cardiovascular magnetic resonance (CMR) and genetic features of dilated cardiomyopathy (DCM) in individuals with coronary artery disease (CAD). First, the UK Biobank was used to assess for the association between rare variants in DCM‐associated genes, phenotype and outcomes in participants with CAD. Individuals with rare pathogenic variants in DCM‐associated genes had greater adverse cardiac remodelling and worse clinical outcomes as compared to genotype negative individuals; a result that suggests the presence of a high‐risk subgroup of patients with CAD and concomitant vulnerability to DCM. Second, the prevalence, distribution and prognostic relevance of non‐infarct pattern late gadolinium enhancement (NI‐LGE) in patients recruited into a CMR and genetics registry was assessed (the London cohort). NI‐LGE was associated with adverse left ventricular remodelling but was not an independent prognostic indicator. There was no enrichment of rare variants in DCM‐associated genes in patients with NI‐LGE compared to patients without this imaging biomarker. LAVi, indexed left atrial volume; LVEDVi, indexed left ventricular end‐diastolic volume; LVEF, left ventricular ejection fraction; MI, myocardial infarction; RVEF, right ventricular ejection fraction; TTNtv, titin truncating variant.
BackgroundTesting for germline pathogenic variants (GPVs) in cancer predisposition genes is increasingly offered as part of routine care for patients with cancer. This is often urgent in oncology ...clinics due to potential implications on treatment and surgical decisions. This also allows identification of family members who should be offered predictive genetic testing. In the UK, it is common practice for healthcare professionals to provide a patient information leaflet (PIL) at point of care for diagnostic genetic testing in patients with cancer, after results disclosure when a GPV is identified, and for predictive testing of at-risk relatives. Services usually create their own PIL, resulting in duplication of effort and wide variability regarding format, content, signposting and patient input in co-design and evaluation.MethodsRepresentatives from UK Cancer Genetics Group (UKCGG), Cancer Research UK (CRUK) funded CanGene-CanVar programme and Association of Genetic Nurse Counsellors (AGNC) held a 2-day meeting with the aim of making recommendations for clinical practice regarding co-design of PIL for germline cancer susceptibility genetic testing. Lynch syndrome and haematological malignancies were chosen as exemplar conditions.ResultsMeeting participants included patient representatives including as co-chair, multidisciplinary clinicians and other experts from across the UK. High-level consensus for UK recommendations for clinical practice was reached on several aspects of PIL using digital polling, including that PIL should be offered, accessible, co-designed and evaluated with patients.ConclusionsRecommendations from the meeting are likely to be applicable for PIL co-design for a wide range of germline genetic testing scenarios.
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