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PurposeBy incorporating major developments in genetics, ophthalmology, dermatology, and neuroimaging, to revise the diagnostic criteria for neurofibromatosis type 1 (NF1) and to establish diagnostic criteria for Legius syndrome (LGSS).MethodsWe used a multistep process, beginning with a Delphi method involving global experts and subsequently involving non-NF experts, patients, and foundations/patient advocacy groups.ResultsWe reached consensus on the minimal clinical and genetic criteria for diagnosing and differentiating NF1 and LGSS, which have phenotypic overlap in young patients with pigmentary findings. Criteria for the mosaic forms of these conditions are also recommended.ConclusionThe revised criteria for NF1 incorporate new clinical features and genetic testing, whereas the criteria for LGSS were created to differentiate the two conditions. It is likely that continued refinement of these new criteria will be necessary as investigators (1) study the diagnostic properties of the revised criteria, (2) reconsider criteria not included in this process, and (3) identify new clinical and other features of these conditions. For this reason, we propose an initiative to update periodically the diagnostic criteria for NF1 and LGSS.

The neurofibromatoses, which include neurofibromatosis type I (NF1), neurofibromatosis type II (NF2), and schwannomatosis, are a group of syndromes characterized by tumor growth in the nervous system. The RASopathies are a group of syndromes caused by germline mutations in genes that encode components of the RAS/mitogen-activated protein kinase (MAPK) pathway. The RASopathies include NF1, Noonan syndrome, Noonan syndrome with multiple lentigines, Costello syndrome, cardio-facio-cutaneous syndrome, Legius syndrome, capillary malformation arterio-venous malformation syndrome, and SYNGAP1 autism. Due to their common underlying pathogenetic etiology, all these syndromes have significant phenotypic overlap of which one common feature include a predisposition to tumors, which may be benign or malignant. Together as a group, they represent one of the most common multiple congenital anomaly syndromes estimating to affect approximately one in 1000 individuals worldwide. The subcontinent of India represents one of the largest populations in the world, yet remains underserved from an aspect of clinical genetics services. In an effort to bridge this gap, the First International Conference on RASopathies and Neurofibromatoses in Asia: Identification and Advances of New Therapeutics was held in Kochi, Kerala, India. These proceedings chronicle this timely and topical international symposium directed at discussing the best practices and therapies for individuals with neurofibromatoses and RASopathies.

NSW Health is implementing genomics as a mainstream component of clinical care. The strategic, holistic approach is considering infrastructure, data governance and management, workforce, education, service planning and delivery. This work is generating insights about how to realise the promise of genomics in healthcare, highlighting the need for strong foundations, real-world application, accessibility and a focus on people using genomic information in clinical care. [ABSTRACT FROM AUTHOR]

Internationally, Tay- Sachs disease ( TSD) preconception screening of Ashkenazi Jewish ( AJ) individuals and couples has led to effective primary prevention of TSD. In Australia, adolescent preconception genetic screening programs operate mainly in Jewish community high schools. These existing programs offer an effective means of primary prevention of TSD, are cost effective and safe. However, in the broader Australian community TSD screening is not systematically performed and cases still occur in unscreened AJ individuals. In order to improve the effectiveness of Australian screening, there is a need for definitive guidelines for healthcare professionals to facilitate extension of the proven benefits of preconception TSD screening to all AJ individuals at risk. We performed a systematic review of the relevant literature relating to AJ pre-conception and antenatal screening for TSD. The evidence was assessed using an established National Health and Medical Research Council evidence grading system. Evaluations of efficacy of TSD screening programs design and execution, cost-benefit and cost-utility health economic evaluation, and population outcomes were undertaken. The results have been used to propose a model for universal AJ TSD preconception and antenatal screening for the primary care setting. [ABSTRACT FROM AUTHOR]

Introduction: Loss of function variants in plakophilin-2 (PKP2) are a well-established cause of arrhythmogenic right ventricular cardiomyopathy (ARVC). Sustained ventricular arrhythmias have been shown only to occur in variant carriers with clear structural disease on cardiac imaging. Here we describe the yield and characteristics of PKP2 loss-of-function variants in probands who present with sudden cardiac death (SCD) events in the absence of ARVC features. Methods: Patients or family members attending a specialised inherited heart disease clinic in Sydney, Australia, where the proband suffered an unexplained SCD event (SCD or resuscitated cardiac arrest) and comprehensive genetic testing were included. Information was collected from the medical record. Results: Four of 173 (2%) were found to have pathogenic or likely pathogenic loss-of-function variants in PKP2. All had SCD events <30 years of age, with no diagnosis of ARVC, and no family history of any cardiac disease. Patient 1 had a SCD event aged 29 years while playing sport, with no structural disease. Genetic testing demonstrated a pathogenic variant c.2489+1G>A. Patient 2 suffered SCD event at 23 years playing football, with no cardiac disease. Genetic testing identified a novel, likely pathogenic variant, p.Leu744Serfs*3. Patient 3 had a SCD aged 21 years during a physical altercation, and postmortem examination revealed no abnormalities macroscopically or on histology, and carried a likely pathogenic 2 base pair deletion, p.Glu85Metfs*26. Patient 4 had a SCD during sleep aged 30 years and postmortem examination showed some isolated areas of fibrosis and fat infiltration on histology, and a likely pathogenic nonsense variant, p.Tyr797Ter. Conclusions: The yield of PKP2 causative variants in sudden unexplained death events is 2%. We demonstrate multiple cases of severe arrhythmia in the absence of structural disease, suggesting a concealed phase of ARVC and highlighting the need for greater understanding of the full PKP2 phenotype spectrum. [ABSTRACT FROM AUTHOR]