Joel B. Krier

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.

The MedSeq Project: a randomized trial of integrating whole genome sequencing into clinical medicine

BackgroundWhole genome sequencing (WGS) is already being used in certain clinical and research settings, but its impact on patient well-being, health-care utilization, and clinical decision-making remains largely unstudied. It is also unknown how best to communicate sequencing results to physicians and patients to improve health. We describe the design of the MedSeq Project: the first randomized trials of WGS in clinical care.Methods/DesignThis pair of randomized controlled trials compares WGS to standard of care in two clinical contexts: (a) disease-specific genomic medicine in a cardiomyopathy clinic and (b) general genomic medicine in primary care. We are recruiting 8 to 12 cardiologists, 8 to 12 primary care physicians, and approximately 200 of their patients. Patient participants in both the cardiology and primary care trials are randomly assigned to receive a family history assessment with or without WGS. Our laboratory delivers a genome report to physician participants that balances the needs to enhance understandability of genomic information and to convey its complexity. We provide an educational curriculum for physician participants and offer them a hotline to genetics professionals for guidance in interpreting and managing their patients’ genome reports. Using varied data sources, including surveys, semi-structured interviews, and review of clinical data, we measure the attitudes, behaviors and outcomes of physician and patient participants at multiple time points before and after the disclosure of these results.DiscussionThe impact of emerging sequencing technologies on patient care is unclear. We have designed a process of interpreting WGS results and delivering them to physicians in a way that anticipates how we envision genomic medicine will evolve in the near future. That is, our WGS report provides clinically relevant information while communicating the complexity and uncertainty of WGS results to physicians and, through physicians, to their patients. This project will not only illuminate the impact of integrating genomic medicine into the clinical care of patients but also inform the design of future studies.Trial registrationClinicalTrials.gov identifierNCT01736566

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.

Consumer Perceptions of Interactions With Primary Care Providers After Direct-to-Consumer Personal Genomic Testing

BACKGROUND Direct-to-consumer (DTC) personal genomic testing (PGT) allows individuals to learn about their genetic makeup without going through a physician, but some consumers share their results with their primary care provider (PCP). OBJECTIVE To describe the characteristics and perceptions of DTC PGT consumers who discuss their results with their PCP. DESIGN Longitudinal, prospective cohort study. SETTING Online survey before and 6 months after results. PARTICIPANTS DTC PGT consumers. MEASUREMENTS Consumer satisfaction with the DTC PGT experience; whether and, if so, how many results could be used to improve health; how many results were not understood; and beliefs about the PCPs understanding of genetics. Participants were asked with whom they had discussed their results. Genetic reports were linked to survey responses. RESULTS Among 1026 respondents, 63% planned to share their results with a PCP. At 6-month follow-up, 27% reported having done so, and 8% reported sharing with another health care provider only. Common reasons for not sharing results with a health care provider were that the results were not important enough (40%) or that the participant did not have time to do so (37%). Among participants who discussed results with their PCP, 35% were very satisfied with the encounter, and 18% were not at all satisfied. Frequently identified themes in participant descriptions of these encounters were actionability of the results or use in care (32%), PCP engagement or interest (25%), and lack of PCP engagement or interest (22%). LIMITATION Participants may not be representative of all DTC PGT consumers. CONCLUSION A comprehensive picture of DTC PGT consumers who shared their results with a health care provider is presented. The proportion that shares results is expected to increase with time after testing as consumers find opportunities for discussion at later appointments or if results become relevant as medical needs evolve. PRIMARY FUNDING SOURCE National Institutes of Health.

Summarizing polygenic risks for complex diseases in a clinical whole-genome report

Purpose:Disease-causing mutations and pharmacogenomic variants are of primary interest for clinical whole-genome sequencing. However, estimating genetic liability for common complex diseases using established risk alleles might one day prove clinically useful.Methods:We compared polygenic scoring methods using a case–control data set with independently discovered risk alleles in the MedSeq Project. For eight traits of clinical relevance in both the primary-care and cardiomyopathy study cohorts, we estimated multiplicative polygenic risk scores using 161 published risk alleles and then normalized them using the population median estimated from the 1000 Genomes Project.Results:Our polygenic score approach identified the overrepresentation of independently discovered risk alleles in cases as compared with controls using a large-scale genome-wide association study data set. In addition to normalized multiplicative polygenic risk scores and rank in a population, the disease prevalence and proportion of heritability explained by known common risk variants provide important context in the interpretation of modern multilocus disease risk models.Conclusion:Our approach in the MedSeq Project demonstrates how complex trait risk variants from an individual genome can be summarized and reported for the general clinician and also highlights the need for definitive clinical studies to obtain reference data for such estimates and to establish clinical utility.Genet Med 17 7, 536–544.

Diagnostic yield and utility of neurovascular ultrasonography in the evaluation of patients with syncope.

OBJECTIVE To determine the diagnostic utility of neurovascular ultrasonography (transcranial Doppler and carotid ultrasonography) in patients with syncope. PATIENTS AND METHODS We retrospectively identified consecutive patients who underwent neurovascular ultrasonography for the diagnosis of syncope or presyncope at an academic hospital in 1997 and 1998. From medical records we abstracted patient demographic and clinical information, results and consequences of testing, and follow-up data for 3 years. RESULTS A total of 140 patients participated in the study. The median age of the study patients was 74 years (interquartile range, 66-80 years), and 49% were male. Severe extracranial or Intracranial cerebrovascular disease was found on neurovascular ultrasonography in 20 patients (14%; 95% confidence interval [CI], 9.5%-21%). Focal neurologic signs or symptoms or carotid bruits were found in 19 (95%) of 20 patients with positive test results compared with 46 (38%) of 120 patients without severe disease (P<.001). Ultrasonography identified cerebrovascular lesions that may have contributed to the syncopal process in only 2 (1.4%) of 140 patients (95% CI, 0.39%-5.1%), but the lesions were unlikely to have been the primary cause of syncope in either patient. CONCLUSION In this predominantly stroke-age population, neurovascular ultrasonography had a low yield for diagnosing vascular lesions that contributed to the pathophysiology of syncope. However, in patients with focal signs or symptoms or carotid bruits, it detected incidental lesions that typically require treatment or follow-up. In patients with syncope, neurovascular ultrasonography should be reserved for this subset. The data suggest enhancements to the American College of Physicians guideline for the use of neurovascular ultrasonography in patients with syncope.

A One-Page Summary Report of Genome Sequencing for the Healthy Adult

As genome sequencing technologies increasingly enter medical practice, genetics laboratories must communicate sequencing results effectively to nongeneticist physicians. We describe the design and delivery of a clinical genome sequencing report, including a one-page summary suitable for interpretation by primary care physicians. To illustrate our preliminary experience with this report, we summarize the genomic findings from 10 healthy participants in a study of genome sequencing in primary care.

Management of Incidental Findings in Clinical Genomic Sequencing

Genomic sequencing is becoming accurate, fast, and inexpensive, and is rapidly being incorporated into clinical practice. Incidental findings, which result in large numbers from genomic sequencing, are a potential barrier to the utility of this new technology due to their high prevalence and the lack of evidence or guidelines available to guide their clinical interpretation. This unit reviews the definition, classification, and management of incidental findings from genomic sequencing. The unit focuses on the clinical aspects of handling incidental findings, with an emphasis on the key role of clinical context in defining incidental findings and determining their clinical relevance and utility. Curr. Protoc. Hum. Genet. 77:9.23.1‐9.23.13.

Gain-of-function mutations in SMAD4 cause a distinctive repertoire of cardiovascular phenotypes in patients with Myhre syndrome

Myhre syndrome is a rare, distinctive syndrome due to specific gain‐of‐function mutations in SMAD4. The characteristic phenotype includes short stature, dysmorphic facial features, hearing loss, laryngotracheal anomalies, arthropathy, radiographic defects, intellectual disability, and a more recently appreciated spectrum of cardiovascular defects with a striking fibroproliferative response to surgical intervention. We report four newly described patients with typical features of Myhre syndrome who had (i) a mildly narrow descending aorta and restrictive cardiomyopathy; (ii) recurrent pericardial and pleural effusions; (iii) a large persistent ductus arteriosus with juxtaductal aortic coarctation; and (iv) restrictive pericardial disease requiring pericardiectomy. Additional information is provided about a fifth previously reported patient with fatal pericardial disease. A literature review of the cardiovascular features of Myhre syndrome was performed on 54 total patients, all with a SMAD4 mutation. Seventy percent had a cardiovascular abnormality including congenital heart defects (63%), pericardial disease (17%), restrictive cardiomyopathy (9%), and systemic hypertension (15%). Pericarditis and restrictive cardiomyopathy are associated with high mortality (three patients each among 10 deaths); one patient with restrictive cardiomyopathy also had epicarditis. Cardiomyopathy and pericardial abnormalities distinguish Myhre syndrome from other disorders caused by mutations in the TGF‐β signaling cascade (Marfan, Loeys–Dietz, or Shprintzen–Goldberg syndromes). We hypothesize that the expanded spectrum of cardiovascular abnormalities relates to the ability of the SMAD4 protein to integrate diverse signaling pathways, including canonical TGF‐β, BMP, and Activin signaling. The co‐occurrence of congenital and acquired phenotypes demonstrates that the gene product of SMAD4 is required for both developmental and postnatal cardiovascular homeostasis.

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

BACKGROUND There are more than 300 known red blood cell (RBC) antigens and 33 platelet antigens that differ between individuals. Sensitisation to antigens is a serious complication that can occur in prenatal medicine and after blood transfusion, particularly for patients who require multiple transfusions. Although pre-transfusion compatibility testing largely relies on serological methods, reagents are not available for many antigens. Methods based on single-nucleotide polymorphism (SNP) arrays have been used, but typing for ABO and Rh-the most important blood groups-cannot be done with SNP typing alone. We aimed to develop a novel method based on whole-genome sequencing to identify RBC and platelet antigens. METHODS This whole-genome sequencing study is a subanalysis of data from patients in the whole-genome sequencing arm of the MedSeq Project randomised controlled trial (NCT01736566) with no measured patient outcomes. We created a database of molecular changes in RBC and platelet antigens and developed an automated antigen-typing algorithm based on whole-genome sequencing (bloodTyper). This algorithm was iteratively improved to address cis-trans haplotype ambiguities and homologous gene alignments. Whole-genome sequencing data from 110 MedSeq participants (30 × depth) were used to initially validate bloodTyper through comparison with conventional serology and SNP methods for typing of 38 RBC antigens in 12 blood-group systems and 22 human platelet antigens. bloodTyper was further validated with whole-genome sequencing data from 200 INTERVAL trial participants (15 × depth) with serological comparisons. FINDINGS We iteratively improved bloodTyper by comparing its typing results with conventional serological and SNP typing in three rounds of testing. The initial whole-genome sequencing typing algorithm was 99·5% concordant across the first 20 MedSeq genomes. Addressing discordances led to development of an improved algorithm that was 99·8% concordant for the remaining 90 MedSeq genomes. Additional modifications led to the final algorithm, which was 99·2% concordant across 200 INTERVAL genomes (or 99·9% after adjustment for the lower depth of coverage). INTERPRETATION By enabling more precise antigen-matching of patients with blood donors, antigen typing based on whole-genome sequencing provides a novel approach to improve transfusion outcomes with the potential to transform the practice of transfusion medicine. FUNDING National Human Genome Research Institute, Doris Duke Charitable Foundation, National Health Service Blood and Transplant, National Institute for Health Research, and Wellcome Trust.