Danielle R. Azzariti

The Matchmaker Exchange: a platform for rare disease gene discovery.

There are few better examples of the need for data sharing than in the rare disease community, where patients, physicians, and researchers must search for “the needle in a haystack” to uncover rare, novel causes of disease within the genome. Impeding the pace of discovery has been the existence of many small siloed datasets within individual research or clinical laboratory databases and/or disease‐specific organizations, hoping for serendipitous occasions when two distant investigators happen to learn they have a rare phenotype in common and can “match” these cases to build evidence for causality. However, serendipity has never proven to be a reliable or scalable approach in science. As such, the Matchmaker Exchange (MME) was launched to provide a robust and systematic approach to rare disease gene discovery through the creation of a federated network connecting databases of genotypes and rare phenotypes using a common application programming interface (API). The core building blocks of the MME have been defined and assembled. Three MME services have now been connected through the API and are available for community use. Additional databases that support internal matching are anticipated to join the MME network as it continues to grow.

Clinical laboratories collaborate to resolve differences in variant interpretations submitted to ClinVar

Purpose:Data sharing through ClinVar offers a unique opportunity to identify interpretation differences between laboratories. As part of a ClinGen initiative, four clinical laboratories (Ambry, GeneDx, Partners Healthcare Laboratory for Molecular Medicine, and University of Chicago Genetic Services Laboratory) collaborated to identify the basis of interpretation differences and to investigate if data sharing and reassessment resolve interpretation differences by analyzing a subset of variants.Methods:ClinVar variants with submissions from at least two of the four participating laboratories were compared. For a subset of identified differences, laboratories documented the basis for discordance, shared internal data, independently reassessed with the American College of Medical Genetics and Genomics–Association for Molecular Pathology (ACMG-AMP) guidelines, and then compared interpretations.Results:At least two of the participating laboratories interpreted 6,169 variants in ClinVar, of which 88.3% were initially concordant. Laboratories reassessed 242/724 initially discordant variants, of which 87.2% (211) were resolved by reassessment with current criteria and/or internal data sharing; 12.8% (31) of reassessed variants remained discordant owing to differences in the application of the ACMG-AMP guidelines.Conclusion:Participating laboratories increased their overall concordance from 88.3 to 91.7%, indicating that sharing variant interpretations in ClinVar—thereby allowing identification of differences and motivation to resolve those differences—is critical to moving toward more consistent variant interpretations.Genet Med advance online publication 09 March 2017

A systematic approach to the reporting of medically relevant findings from whole genome sequencing.

BackgroundThe MedSeq Project is a randomized clinical trial developing approaches to assess the impact of integrating genome sequencing into clinical medicine. To facilitate the return of results of potential medical relevance to physicians and patients participating in the MedSeq Project, we sought to develop a reporting approach for the effective communication of such findings.MethodsGenome sequencing was performed on the Illumina HiSeq platform. Variants were filtered, interpreted, and validated according to methods developed by the Laboratory for Molecular Medicine and consistent with current professional guidelines. The GeneInsight software suite, which is integrated with the Partners HealthCare electronic health record, was used for variant curation, report drafting, and delivery.ResultsWe developed a concise 5–6 page Genome Report (GR) featuring a single-page summary of results of potential medical relevance with additional pages containing structured variant, gene, and disease information along with supporting evidence for reported variants and brief descriptions of associated diseases and clinical implications. The GR is formatted to provide a succinct summary of genomic findings, enabling physicians to take appropriate steps for disease diagnosis, prevention, and management in their patients.ConclusionsOur experience highlights important considerations for the reporting of results of potential medical relevance and provides a framework for interpretation and reporting practices in clinical genome sequencing.

GenomeConnect: Matchmaking Between Patients, Clinical Laboratories, and Researchers to Improve Genomic Knowledge

As the utility of genetic and genomic testing in healthcare grows, there is need for a high‐quality genomic knowledge base to improve the clinical interpretation of genomic variants. Active patient engagement can enhance communication between clinicians, patients, and researchers, contributing to knowledge building. It also encourages data sharing by patients and increases the data available for clinicians to incorporate into individualized patient care, clinical laboratories to utilize in test interpretation, and investigators to use for research. GenomeConnect is a patient portal supported by the Clinical Genome Resource (ClinGen), providing an opportunity for patients to add to the knowledge base by securely sharing their health history and genetic test results. Data can be matched with queries from clinicians, laboratory personnel, and researchers to better interpret the results of genetic testing and build a foundation to support genomic medicine. Participation is online, allowing patients to contribute regardless of location. GenomeConnect supports longitudinal, detailed clinical phenotyping and robust “matching” among research and clinical communities. Phenotype data are gathered using online health questionnaires; genotype data are obtained from genetic test reports uploaded by participants and curated by staff. GenomeConnect empowers patients to actively participate in the improvement of genomic test interpretation and clinical utility.

Using ClinVar as a Resource to Support Variant Interpretation

ClinVar is a freely accessible, public archive of reports of the relationships among genomic variants and phenotypes. To facilitate evaluation of the clinical significance of each variant, ClinVar aggregates submissions of the same variant, displays supporting data from each submission, and determines if the submitted clinical interpretations are conflicting or concordant. The unit describes how to (1) identify sequence and structural variants of interest in ClinVar by multiple searching approaches, including Variation Viewer and (2) understand the display of submissions to ClinVar and the evidence supporting each interpretation. By following this protocol, ClinVar users will be able to learn how to incorporate the wealth of resources and knowledge in ClinVar into variant curation and interpretation.

ClinGen Pathogenicity Calculator: a configurable system for assessing pathogenicity of genetic variants

BackgroundThe success of the clinical use of sequencing based tests (from single gene to genomes) depends on the accuracy and consistency of variant interpretation. Aiming to improve the interpretation process through practice guidelines, the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) have published standards and guidelines for the interpretation of sequence variants. However, manual application of the guidelines is tedious and prone to human error. Web-based tools and software systems may not only address this problem but also document reasoning and supporting evidence, thus enabling transparency of evidence-based reasoning and resolution of discordant interpretations.ResultsIn this report, we describe the design, implementation, and initial testing of the Clinical Genome Resource (ClinGen) Pathogenicity Calculator, a configurable system and web service for the assessment of pathogenicity of Mendelian germline sequence variants. The system allows users to enter the applicable ACMG/AMP-style evidence tags for a specific allele with links to supporting data for each tag and generate guideline-based pathogenicity assessment for the allele. Through automation and comprehensive documentation of evidence codes, the system facilitates more accurate application of the ACMG/AMP guidelines, improves standardization in variant classification, and facilitates collaborative resolution of discordances. The rules of reasoning are configurable with gene-specific or disease-specific guideline variations (e.g. cardiomyopathy-specific frequency thresholds and functional assays). The software is modular, equipped with robust application program interfaces (APIs), and available under a free open source license and as a cloud-hosted web service, thus facilitating both stand-alone use and integration with existing variant curation and interpretation systems. The Pathogenicity Calculator is accessible at http://calculator.clinicalgenome.org.ConclusionsBy enabling evidence-based reasoning about the pathogenicity of genetic variants and by documenting supporting evidence, the Calculator contributes toward the creation of a knowledge commons and more accurate interpretation of sequence variants in research and clinical care.

ClinVar Miner: Demonstrating utility of a Web-based tool for viewing and filtering ClinVar data

ClinVar Miner is a Web‐based suite that utilizes the data held in the National Center for Biotechnology Informations ClinVar archive. The goal is to render the data more accessible to processes pertaining to conflict resolution of variant interpretation as well as tracking details of data submission and data management for detailed variant curation. Here, we establish the use of these tools to address three separate use cases and to perform analyses across submissions. We demonstrate that the ClinVar Miner tools are an effective means to browse and consolidate data for variant submitters, curation groups, and general oversight. These tools are also relevant to the variant interpretation community in general.

Short-term costs of integrating whole-genome sequencing into primary care and cardiology settings: a pilot randomized trial

PurposeGreat uncertainty exists about the costs associated with whole-genome sequencing (WGS).MethodsOne hundred cardiology patients with cardiomyopathy diagnoses and 100 ostensibly healthy primary care patients were randomized to receive a family-history report alone or with a WGS report. Cardiology patients also reviewed prior genetic test results. WGS costs were estimated by tracking resource use and staff time. Downstream costs were estimated by identifying services in administrative data, medical records, and patient surveys for 6 months.ResultsThe incremental cost per patient of WGS testing was

Points to consider for sharing variant-level information from clinical genetic testing with ClinVar

5,098 in cardiology settings and

Automated typing of red blood cell and platelet antigens: a whole-genome sequencing study

5,073 in primary care settings compared with family history alone. Mean 6-month downstream costs did not differ statistically between the control and WGS arms in either setting (cardiology: difference = −