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Thompson B.A.,QIMR Berghofer Medical Research Institute | Thompson B.A.,University of Queensland | Spurdle A.B.,QIMR Berghofer Medical Research Institute | Plazzer J.-P.,Royal Melbourne Hospital | And 144 more authors.
Nature Genetics | Year: 2014

The clinical classification of hereditary sequence variants identified in disease-related genes directly affects clinical management of patients and their relatives. The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) undertook a collaborative effort to develop, test and apply a standardized classification scheme to constitutional variants in the Lynch syndrome-associated genes MLH1, MSH2, MSH6 and PMS2. Unpublished data submission was encouraged to assist in variant classification and was recognized through microattribution. The scheme was refined by multidisciplinary expert committee review of the clinical and functional data available for variants, applied to 2,360 sequence alterations, and disseminated online. Assessment using validated criteria altered classifications for 66% of 12,006 database entries. Clinical recommendations based on transparent evaluation are now possible for 1,370 variants that were not obviously protein truncating from nomenclature. This large-scale endeavor will facilitate the consistent management of families suspected to have Lynch syndrome and demonstrates the value of multidisciplinary collaboration in the curation and classification of variants in public locus-specific databases. © 2014 Nature America, Inc.


Lane W.J.,Harvard University | Westhoff C.M.,Brigham and Women's Hospital | Uy J.M.,Harvard University | Aguad M.,Harvard University | And 7 more authors.
Transfusion | Year: 2016

BACKGROUND There are 346 serologically defined red blood cell (RBC) antigens and 33 serologically defined platelet (PLT) antigens, most of which have known genetic changes in 45 RBC or six PLT genes that correlate with antigen expression. Polymorphic sites associated with antigen expression in the primary literature and reference databases are annotated according to nucleotide positions in cDNA. This makes antigen prediction from next-generation sequencing data challenging, since it uses genomic coordinates. STUDY DESIGN AND METHODS The conventional cDNA reference sequences for all known RBC and PLT genes that correlate with antigen expression were aligned to the human reference genome. The alignments allowed conversion of conventional cDNA nucleotide positions to the corresponding genomic coordinates. RBC and PLT antigen prediction was then performed using the human reference genome and whole genome sequencing (WGS) data with serologic confirmation. RESULTS Some major differences and alignment issues were found when attempting to convert the conventional cDNA to human reference genome sequences for the following genes: ABO, A4GALT, RHD, RHCE, FUT3, ACKR1 (previously DARC), ACHE, FUT2, CR1, GCNT2, and RHAG. However, it was possible to create usable alignments, which facilitated the prediction of all RBC and PLT antigens with a known molecular basis from WGS data. Traditional serologic typing for 18 RBC antigens were in agreement with the WGS-based antigen predictions, providing proof of principle for this approach. CONCLUSION Detailed mapping of conventional cDNA annotated RBC and PLT alleles can enable accurate prediction of RBC and PLT antigens from whole genomic sequencing data. © 2015 The Authors Transfusion published by Wiley Periodicals, Inc. on behalf of AABB.


PubMed | Laboratory for Molecular Medicine, Regeneron Pharmaceuticals, Regeneron Genetics Center and Geisinger Health System
Type: Journal Article | Journal: Science (New York, N.Y.) | Year: 2016

The DiscovEHR collaboration between the Regeneron Genetics Center and Geisinger Health System couples high-throughput sequencing to an integrated health care system using longitudinal electronic health records (EHRs). We sequenced the exomes of 50,726 adult participants in the DiscovEHR study to identify ~4.2 million rare single-nucleotide variants and insertion/deletion events, of which ~176,000 are predicted to result in a loss of gene function. Linking these data to EHR-derived clinical phenotypes, we find clinical associations supporting therapeutic targets, including genes encoding drug targets for lipid lowering, and identify previously unidentified rare alleles associated with lipid levels and other blood level traits. About 3.5% of individuals harbor deleterious variants in 76 clinically actionable genes. The DiscovEHR data set provides a blueprint for large-scale precision medicine initiatives and genomics-guided therapeutic discovery.


PubMed | Rady Childrens Institute for Genomic Medicine, University of Washington, Rti International, Laboratory for Molecular Medicine and 15 more.
Type: | Journal: Pediatrics | Year: 2017

The rapid development of genomic sequencing technologies has decreased the cost of genetic analysis to the extent that it seems plausible that genome-scale sequencing could have widespread availability in pediatric care. Genomic sequencing provides a powerful diagnostic modality for patients who manifest symptoms of monogenic disease and an opportunity to detect health conditions before their development. However, many technical, clinical, ethical, and societal challenges should be addressed before such technology is widely deployed in pediatric practice. This article provides an overview of the Newborn Sequencing in Genomic Medicine and Public Health Consortium, which is investigating the application of genome-scale sequencing in newborns for both diagnosis and screening.


News Article | November 10, 2016
Site: www.eurekalert.org

A study published Nov. 9 in the journal Science Translational Medicine is the first to show that mutations in certain cancer and cardiovascular genes put individuals at an increased risk for dominantly inherited, actionable conditions, regardless of family medical history. The study, carried out in two separate populations of African-Americans and European-Americans, finds that individuals carrying these mutations are at higher risk for developing one of these cancer or cardiac syndromes, respectively. The new work, led by Robert C. Green, MD, MPH, of Brigham and Women's Hospital, Broad Institute and Harvard Medical School, has important implications for the use of genomic sequencing as a future clinical screening tool. "The field of clinical genetics has been uncertain about recommending genome screening in healthy individuals for two reasons. First, we do not know if those individuals will be at increased risk regardless of their family history. Second, we do not know if identifying individuals carrying these mutations will make a positive difference in their eventual clinical outcomes," said Green, senior author on the research. "This analysis addresses only the first of these questions, but demonstrates that in the aggregate, mutations in a subset of genes are associated with a substantial risk of developing the related condition." The study combined the work of investigators in genomics, informatics, molecular biology, epidemiology and statistics at multiple institutions to seek insights into a question that has been extremely difficult to answer. If people carry a genetic mutation, what are the chances that they will develop the related condition over a number of years? Addressing this question has been difficult because very few population-based cohorts have had both genetic sequencing and systematic medical testing recorded over time, and highly heritable conditions are relatively rare. To explore this question, the investigators used data previously collected in two longitudinal cohort studies that investigated heart disease but also collected data on cancer. Data were analyzed from 462 European-Americans from the Massachusetts-based Framingham Heart Study who had been followed for two decades, and 3,223 African-American participants in the Mississippi-based Jackson Heart Study who had been followed for a shorter period. The researchers screened participants for disease-causing mutations using a panel of 56 genes representing 24 hereditary cancer and cardiac syndromes while blinded to the clinical outcomes in these participants. The researchers also collected clinical and diagnostic test information on the participants while blinded to the genome sequencing results. The research team then analyzed whether those who carried the mutations went on to develop associated conditions (cancer, heart disease and high cholesterol) more frequently than those who did not carry the mutations. The results were highly significant, indicating that carrying a mutation in one of the 56 genes conferred greater risk of eventually developing an associated disease in both African-Americans and European-Americans. The risk differences were not thought to be due to racial differences, but rather to the fact that the European Americans in the Framingham study were followed longer than the African Americans in the Jackson study, and had more time to develop the clinical features associated with their genetic changes. Importantly, the study combined risks from very different mutations and very different genes into an "aggregate" estimation of the genetic penetrance (the likelihood that someone with a mutation will develop the condition). While these results establish that as group, those who carry one of these mutations have a higher risk to develop the related disease than those who do not, the results are less relevant to individuals within that population. Nevertheless, it is the first such study to attempt to estimate the effects of such aggregate penetrance within a group. "These populations are uniquely suited for a study like this because everyone in the Framingham and Jackson cohorts received regular EKGs, echocardiograms and lipid measurements, not just those who had medical problems," said Pradeep Natarajan, MD, MMSc, one of the lead authors based at Massachusetts General Hospital. "Data of this nature is not available from a typical health care system where only those who have come to medical attention get blood testing or certain types of diagnostic testing." Eventually, using an individual's genomic variants to predict and prevent future illness may become a routine part of health care. However, it remains to be seen whether identifying individuals with genetic mutations will result in sufficient clinical benefit to merit the risks and costs of downstream imaging studies or procedures. The authors caution that this study does not provide evidence that recognizing genetic mutations directly confers medical benefit. In seeking to explore the related question of clinical outcomes, Green and his team have also implemented a separate randomized clinical trial of medical sequencing called the MedSeq Project, and have organized a Consortium to track medical outcomes among any ostensibly healthy individuals who have been sequenced for predictive purposes. In addition to Natarajan, lead authors on the study included Alexander Bick, MD, PhD, of Massachusetts General Hospital, and Nina Gold, MD, of Boston Children's Hospital. The study involved screening thousands of variants from each person's genome, followed by rigorous manual classification of the variants, supervised by Heidi Rehm, PhD, FACMG, director of the Partners Laboratory for Molecular Medicine and a clinical molecular geneticist at Brigham and Women's Hospital and Harvard Medical School. The study also used sophisticated statistical modeling by simulation, designed by Peter Kraft, PhD, at the Harvard School of Public Health. Researchers from the University of Mississippi Medical Center contributed Jackson Heart Study data. This work was supported by the National Human Genome Research Institute, the Howard Hughes Medical Institute, the National Heart, Lung and Blood Institute and the National Institute on Minority Health and Health Disparities. Brigham and Women's Hospital (BWH) is a 793-bed nonprofit teaching affiliate of Harvard Medical School and a founding member of Partners HealthCare. BWH has more than 4.2 million annual patient visits and nearly 46,000 inpatient stays, is the largest birthing center in Massachusetts and employs nearly 16,000 people. The Brigham's medical preeminence dates back to 1832, and today that rich history in clinical care is coupled with its national leadership in patient care, quality improvement and patient safety initiatives, and its dedication to research, innovation, community engagement and educating and training the next generation of health care professionals. Through investigation and discovery conducted at its Brigham Research Institute (BRI), BWH is an international leader in basic, clinical and translational research on human diseases, more than 3,000 researchers, including physician-investigators and renowned biomedical scientists and faculty supported by nearly $666 million in funding. For the last 25 years, BWH ranked second in research funding from the National Institutes of Health (NIH) among independent hospitals. BWH is also home to major landmark epidemiologic population studies, including the Nurses' and Physicians' Health Studies and the Women's Health Initiative as well as the TIMI Study Group, one of the premier cardiovascular clinical trials groups. For more information, resources and to follow us on social media, please visit BWH's online newsroom.


Bettinelli A.L.,Ochsner Clinic Foundation | Mulder T.J.,Ochsner Clinic Foundation | Funke B.H.,Laboratory for Molecular Medicine | Lafferty K.A.,Laboratory for Molecular Medicine | And 2 more authors.
American Journal of Medical Genetics, Part A | Year: 2013

Ebstein anomaly is a rare congenital heart defect that most often occurs sporadically within a kindred. Familial cases, although reported, are uncommon. At this time, the genetic etiology of Ebstein anomaly is not fully elucidated. Here, we describe clinical and molecular investigations of a rare case of familial Ebstein anomaly in association with a likely pathogenic mutation of the MYH7 gene. The severity of presentation varies, and Ebstein anomaly can be observed in association with such other heart defects as ventricular septal defect and left ventricular (LV) hypertrabeculation, as seen in our family of study. In our family of study, the 31-year-old father and four of his children have been diagnosed with Ebstein anomaly. Genetic testing revealed that the father was heterozygous for the Glu1220del variant detected in exon 27 of the MYH7 gene. The MYH7 gene encodes the β-myosin heavy chain and is expressed in cardiac muscle. DNA sequencing of three of his affected children confirmed that they carried the same variant while the fourth affected child was not available for testing. This is the first report of familial Ebstein anomaly associated with the Glu1220del mutation of the MYH7 gene. The mutation segregates with disease in a family with autosomal dominant transmission of congenital heart defects including Ebstein anomaly and other associated cardiovascular defects including LV hypertrabeculation and ventricular septal defect. © 2013 Wiley Periodicals, Inc.


McLaughlin H.M.,Laboratory for Molecular Medicine | McLaughlin H.M.,Lansdowne Partners | Kelly M.A.,Lansdowne Partners | Hawley P.P.,Boston Childrens Hospital Boston | And 7 more authors.
BMC Medical Genetics | Year: 2013

Background: Variants in the desmin gene (DES) are associated with desminopathy; a myofibrillar myopathy mainly characterized by muscle weakness, conduction block, and dilated cardiomyopathy. To date, only ~50 disease-associated variants have been described, and the majority of these lead to dominant-negative effects. However, the complete genotypic spectrum of desminopathy is not well established.Case presentation: Next-generation sequencing was performed on 51 cardiac disease genes in a proband with profound skeletal myopathy, dilated cardiomyopathy, and respiratory dysfunction. Our analyses revealed compound heterozygous DES variants, both of which are predicted to lead to a loss-of-function. Consistent with recessive inheritance, each variant was identified in an unaffected parent.Conclusions: This case report serves to broaden the variant spectrum of desminopathies and provides insight into the molecular mechanisms of desminopathy, supporting distinct dominant-negative and loss-of-function etiologies. © 2013 McLaughlin et al.; licensee BioMed Central Ltd.


Olive M.,U.S. National Institutes of Health | Harten I.,Benaroya Research Institute | Harten I.,University of Washington | Mitchell R.,Harvard University | And 18 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2010

OBJECTIVE-: Children with Hutchinson-Gilford progeria syndrome (HGPS) exhibit dramatically accelerated cardiovascular disease (CVD), causing death from myocardial infarction or stroke between the ages of 7 and 20 years. We undertook the first histological comparative evaluation between genetically confirmed HGPS and the CVD of aging. METHODS AND RESULTS-: We present structural and immunohistological analysis of cardiovascular tissues from 2 children with HGPS who died of myocardial infarction. Both had features classically associated with the atherosclerosis of aging, as well as arteriolosclerosis of small vessels. In addition, vessels exhibited prominent adventitial fibrosis, a previously undescribed feature of HGPS. Importantly, although progerin was detected at higher rates in the HGPS coronary arteries, it was also present in non-HGPS individuals. Between the ages of 1 month and 97 years, progerin staining increased an average of 3.34% per year (P<0.0001) in coronary arteries. CONCLUSION-: We find concordance among many aspects of cardiovascular pathology in both HGPS and geriatric patients. HGPS generates a more prominent adventitial fibrosis than typical CVD. Vascular progerin generation in young non-HGPS individuals, which significantly increases throughout life, strongly suggests that progerin has a role in cardiovascular aging of the general population. © 2010 American Heart Association, Inc.

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