Mapping genetic variations to three- dimensional protein structures to enhance variant interpretation: a proposed framework

The translation of personal genomics to precision medicine depends on the accurate interpretation of the multitude of genetic variants observed for each individual. However, even when genetic variants are predicted to modify a protein, their functional implications may be unclear. Many diseases are caused by genetic variants affecting important protein features, such as enzyme active sites or interaction interfaces. The scientific community has catalogued millions of genetic variants in genomic databases and thousands of protein structures in the Protein Data Bank. Mapping mutations onto three-dimensional (3D) structures enables atomic-level analyses of protein positions that may be important for the stability or formation of interactions; these may explain the effect of mutations and in some cases even open a path for targeted drug development. To accelerate progress in the integration of these data types, we held a two-day Gene Variation to 3D (GVto3D) workshop to report on the latest advances and to discuss unmet needs. The overarching goal of the workshop was to address the question: what can be done together as a community to advance the integration of genetic variants and 3D protein structures that could not be done by a single investigator or laboratory? Here we describe the workshop outcomes, review the state of the field, and propose the development of a framework with which to promote progress in this arena. The framework will include a set of standard formats, common ontologies, a common application programming interface to enable interoperation of the resources, and a Tool Registry to make it easy to find and apply the tools to specific analysis problems. Interoperability will enable integration of diverse data sources and tools and collaborative development of variant effect prediction methods

GA4GH: International policies and standards for data sharing across genomic research and healthcare.

The Global Alliance for Genomics and Health (GA4GH) aims to accelerate biomedical advances by enabling the responsible sharing of clinical and genomic data through both harmonized data aggregation and federated approaches. The decreasing cost of genomic sequencing (along with other genome-wide molecular assays) and increasing evidence of its clinical utility will soon drive the generation of sequence data from tens of millions of humans, with increasing levels of diversity. In this perspective, we present the GA4GH strategies for addressing the major challenges of this data revolution. We describe the GA4GH organization, which is fueled by the development efforts of eight Work Streams and informed by the needs of 24 Driver Projects and other key stakeholders. We present the GA4GH suite of secure, interoperable technical standards and policy frameworks and review the current status of standards, their relevance to key domains of research and clinical care, and future plans of GA4GH. Broad international participation in building, adopting, and deploying GA4GH standards and frameworks will catalyze an unprecedented effort in data sharing that will be critical to advancing genomic medicine and ensuring that all populations can access its benefits

Recontacting patients in clinical genetics services: recommendations of the European Society of Human Genetics

Technological advances have increased the availability of genomic data in research and the clinic. If, over time, interpretation of the significance of the data changes, or new information becomes available, the question arises as to whether recontacting the patient and/or family is indicated. The Public and Professional Policy Committee of the European Society of Human Genetics (ESHG), together with research groups from the UK and the Netherlands, developed recommendations on recontacting which, after public consultation, have been endorsed by ESHG Board. In clinical genetics, recontacting for updating patients with new, clinically significant information related to their diagnosis or previous genetic testing may be justifiable and, where possible, desirable. Consensus about the type of information that should trigger recontacting converges around its clinical and personal utility. The organization of recontacting procedures and policies in current health care systems is challenging. It should be sustainable, commensurate with previously obtained consent, and a shared responsibility between healthcare providers, laboratories, patients, and other stakeholders. Optimal use of the limited clinical resources currently available is needed. Allocation of dedicated resources for recontacting should be considered. Finally, there is a need for more evidence, including economic and utility of information for people, to inform which strategies provide the most cost-effective use of healthcare resources for recontacting

EMQN best practice guidelines for genetic testing in dystrophinopathies.

Dystrophinopathies are X-linked diseases, including Duchenne muscular dystrophy and Becker muscular dystrophy, due to DMD gene variants. In recent years, the application of new genetic technologies and the availability of new personalised drugs have influenced diagnostic genetic testing for dystrophinopathies. Therefore, these European best practice guidelines for genetic testing in dystrophinopathies have been produced to update previous guidelines published in 2010.These guidelines summarise current recommended technologies and methodologies for analysis of the DMD gene, including testing for deletions and duplications of one or more exons, small variant detection and RNA analysis. Genetic testing strategies for diagnosis, carrier testing and prenatal diagnosis (including non-invasive prenatal diagnosis) are then outlined. Guidelines for sequence variant annotation and interpretation are provided, followed by recommendations for reporting results of all categories of testing. Finally, atypical findings (such as non-contiguous deletions and dual DMD variants), implications for personalised medicine and clinical trials and incidental findings (identification of DMD gene variants in patients where a clinical diagnosis of dystrophinopathy has not been considered or suspected) are discussed

Action myoclonus–renal failure syndrome: A cause for worsening tremor in young adults

Action myoclonus–renal failure syndrome (AMRF) is an autosomal recessive disorder first described in 4 French Canadian patients, followed by a recent description of 15 cases from various countries. The condition independently affects the kidney, with focal glomerulosclerosis causing renal failure and the brain causing progressive myoclonus epilepsy (PME) or progressive myoclonic ataxia (PMA). Tremor is often an early feature. The diagnosis of tremor and myoclonus in patients with severe renal disease is challenging. Here we highlight the evolution of tremor in this syndrome in two new cases and emphasize problems in early diagnosis. Copyright: ©2006AAN Enterprises, Inc

Points to consider for laboratories reporting results from diagnostic genomic sequencing

Although NGS technologies are well-embedded in the clinical setting for identification of genetic causes of disease, guidelines issued by professional bodies are inconsistent regarding some aspects of reporting results. Most recommendations do not give detailed guidance about whether variants of uncertain significance (VUS) should be reported by laboratory personnel to clinicians, and give conflicting messages regarding whether unsolicited findings (UF) should be reported. There are also differences both in their recommendations regarding whether actively searching for secondary findings (SF) is appropriate, and in the extent to which they address the duty (or lack thereof) to reanalyse variants when new information arises. An interdisciplinary working group considered the current guidelines, their own experiences, and data from a recent qualitative study to develop a set of points to consider for laboratories reporting results from diagnostic NGS. These points to consider fall under six categories: (i) Testing approaches and technologies used, (ii) Approaches for VUS; (iii) Approaches for reporting UF, (iv) Approaches regarding SF; (v) Reanalysis of data & re-contact; and vi) Minors. While it is unclear whether uniformity in reporting across all laboratories is desirable, we hope these points to consider will be useful to diagnostic laboratories as they develop their processes for making decisions about reporting VUS and UF from NGS in the diagnostic context

Analysis of VUS reporting, variant reinterpretation and recontact policies in clinical genomic sequencing consent forms

There are several key unsolved issues relating to the clinical use of next generation sequencing, such as: should laboratories report variants of uncertain significance (VUS) to clinicians and/or patients ? Should they reinterpret VUS in response to growing knowledge in the field ? And should patients be recontacted regarding such results ? We systematically analyzed 58 consent forms in English used in the diagnostic context to investigate their policies for (a) reporting VUS, (b) reinterpreting variants, including who should initiate this, and (c) recontacting patients and the mechanisms for undertaking any recontact. One-third (20/58) of the forms did not mention VUS in any way. Of the 38 forms that mentioned VUS, only half provided some description of what a VUS is. Approximately one-third of forms explicitly stated that reinterpretation of variants for clinical purposes may occur. Less than half mentioned recontact for clinical purposes, with variation as to whether laboratories, patients, or clinicians should initiate this. We suggest that the variability in variant reporting, reinterpretation, and recontact policies and practices revealed by our analysis may lead to diffused responsibility, which could result in missed opportunities for patients or family members to receive a diagnosis in response to updated variant classifications. Finally, we provide some suggestions for ethically appropriate inclusion of policies for reporting VUS, reinterpretation, and recontact on consent forms.SIENNA project - Stakeholder-informed ethics for new technologies with high socio-economic and human rights impac

SCARB2 Mutations in Progressive Myoclonus Epilepsy (PME) Without Renal Failure

Copyright © 2009 American Neurological AssociationObjectiveMutations in SCARB2 were recently described as causing action myoclonus renal failure syndrome (AMRF). We hypothesized that mutations in SCARB2 might account for unsolved cases of progressive myoclonus epilepsy (PME) without renal impairment, especially those resembling Unverricht-Lundborg disease (ULD). Additionally, we searched for mutations in the PRICKLE1 gene, newly recognized as a cause of PME mimicking ULD.MethodsWe reviewed cases of PME referred for diagnosis over two decades in which a molecular diagnosis had not been reached. Patients were classified according to age of onset, clinical pattern, and associated neurological signs into "ULD-like" and "not ULD-like." After exclusion of mutations in cystatin B (CSTB), DNA was examined for sequence variation in SCARB2 and PRICKLE1.ResultsOf 71 cases evaluated, 41 were "ULD-like" and five had SCARB2 mutations. None of 30 "not ULD-like" cases were positive. The five patients with SCARB2 mutations had onset between 14 and 26 years of age, with no evidence of renal failure during 5.5 to 15 years of follow-up; four were followed until death. One living patient had slight proteinuria. A subset of 25 cases were sequenced for PRICKLE1 and no mutations were found.InterpretationMutations in SCARB2 are an important cause of hitherto unsolved cases of PME resembling ULD at onset. SCARB2 should be evaluated even in the absence of renal involvement. Onset is in teenage or young adult life. Molecular diagnosis is important for counseling the patient and family, particularly as the prognosis is worse than classical ULD.L.M. Dibbens, R. Michelucci, A. Gambardella, F. Andermann, G. Rubboli, M.A. Bayly, T. Joensuu, D.F. Vears, S. Franceschetti, L. Canafoglia, R. Wallace, A.G. Bassuk, D.A. Power, C.A. Tassinari, E. Andermann, A.E. Lehesjoki and S.F. Berkovi