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Philippakis A.A.,The Broad Institute of MIT and Harvard | Philippakis A.A.,Brigham and Women's Hospital | Philippakis A.A.,Harvard University | Azzariti D.R.,Molecular Partners | And 48 more authors.
Human Mutation | Year: 2015

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. © 2015 Wiley Periodicals, Inc.


PubMed | The Hospital for Sick Children, Baylor College of Medicine, Molecular Partners, Wellcome Trust Sanger Institute and 23 more.
Type: Journal Article | Journal: Human mutation | Year: 2015

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.


PubMed | University of Washington, University of Miami, Mayo Medical School, University of Rouen and 2 more.
Type: | Journal: Neurobiology of aging | Year: 2016

We aimed to identify new candidate genes potentially involved in early-onset Alzheimers disease (EOAD). Exome sequencing was conducted on 45 EOAD patients with either a family history of Alzheimers disease (AD, <65years) or an extremely early age at the onset (55years) followed by multiple variant filtering according to different modes of inheritance. We identified 29 candidate genes potentially involved in EOAD, of which the gene TYROBP, previously implicated in AD, was selected for genetic and functional follow-up. Using 3 patient cohorts, we observed rare coding TYROBP variants in 9 out of 1110 EOAD patients, whereas no such variants were detected in 1826 controls (p= 0.0001), suggesting that at least some rare TYROBP variants might contribute to EOAD risk. Overexpression of the p.D50_L51ins14 TYROBP mutant led to a profound reduction of TREM2 expression, a well-established risk factor for AD. This is the first study supporting a role for genetic variation in TYROBP in EOAD, with invitro support for a functional effect of the p.D50_L51ins14 TYROBP mutation on TREM2 expression.


Bose S.,Presidency University of India | Das K.,Hiroshima University | Torimoto J.,Project Genesis | Arima M.,Yokohama National University | Dunkley D.J.,Curtin University Australia
Lithos | Year: 2016

High-grade para- and orthogneissic rocks near the Chilka Lake granulite complex, northern part of the Eastern Ghats Belt show complex structural and petrological history. Based on field and petrographic characters, five (M1-M5) metamorphic events could be identified. The earliest metamorphic event (M1) produced amphibolite grade mineral assemblage which produced the peak granulite (M2) assemblages at 900-950°C, 8.5-9.0kbar. The third metamorphic event caused decompression of the deeper crust up to 700-800°C, 6.0-6.5kbar. This was followed by cooling (M4) and subsequent thermal overprinting (M5). Fluid-composition during M3 was dominated by high-density CO2 and changed to low-density mixed CO2-H2O during the M3. Zircon U-Pb SHRIMP data suggest 781±9Ma age for M3 event. Texturally constrained monazite U-Th-Pb EPMA data, on the other hand, yield a group age of 988±23Ma from grain interior, which can signifies the age of M2 event. Few spots with younger dates in the range of 550-500Ma are also noted. This interpretation changes the existing tectonothermal history of northern Eastern Ghats Belt. Our data show that the two adjacent crustal domains of the Eastern Ghats Belt show distinctly contrasting Neoproterozoic histories. While the central Domain 2 evolved through early anticlockwise P-T path culminating in ultrahigh temperature, the northern Domain 3 evolved through a clockwise P-T path. It appears that the Domain 3 was contiguous to East Antarctica and became part of the Eastern Ghats Belt during the assembly of Gondwana. The ca. 780Ma decompression event in the northern Eastern Ghats Belt opens up new possibilities for interpreting the breakup of Rodinia. © 2016 Elsevier B.V.


Shen L.,Massachusetts Eye and Ear Infirmary | Diroma M.A.,University of Bari | Gonzalez M.,Project Genesis | Navarro-Gomez D.,Massachusetts Eye and Ear Infirmary | And 11 more authors.
Human Mutation | Year: 2016

MSeqDR is the Mitochondrial Disease Sequence Data Resource, a centralized and comprehensive genome and phenome bioinformatics resource built by the mitochondrial disease community to facilitate clinical diagnosis and research investigations of individual patient phenotypes, genomes, genes, and variants. A central Web portal (https://mseqdr.org) integrates community knowledge from expert-curated databases with genomic and phenotype data shared by clinicians and researchers. MSeqDR also functions as a centralized application server for Web-based tools to analyze data across both mitochondrial and nuclear DNA, including investigator-driven whole exome or genome dataset analyses through MSeqDR-Genesis. MSeqDR-GBrowse genome browser supports interactive genomic data exploration and visualization with custom tracks relevant to mtDNA variation and mitochondrial disease. MSeqDR-LSDB is a locus-specific database that currently manages 178 mitochondrial diseases, 1,363 genes associated with mitochondrial biology or disease, and 3,711 pathogenic variants in those genes. MSeqDR Disease Portal allows hierarchical tree-style disease exploration to evaluate their unique descriptions, phenotypes, and causative variants. Automated genomic data submission tools are provided that capture ClinVar compliant variant annotations. PhenoTips will be used for phenotypic data submission on deidentified patients using human phenotype ontology terminology. The development of a dynamic informed patient consent process to guide data access is underway to realize the full potential of these resources. © 2016 Wiley Periodicals, Inc.


Gonzalez M.,Project Genesis | Falk M.J.,Children's Hospital of Philadelphia | Gai X.,Massachusetts Eye and Ear Infirmary | Postrel R.,Project Genesis | And 4 more authors.
Human Mutation | Year: 2015

Next-generation sequencing has led to an unparalleled pace of Mendelian disease gene discovery in recent years. To address the challenges of analysis and sharing of large datasets, we had previously introduced the collaborative web-based GEM.app software [Gonzalez et al., ]. Here, we are presenting the results of using GEM.app over nearly 3 years and introducing the next generation of this platform. First, GEM.app has been renamed to GENESIS since it is now part of "The Genesis Project" (501c3), a not-for-profit foundation that is committed to providing the best technology to enable research scientists and to connecting patients and clinicians to genomic information. Second, GENESIS (GEM.app) has grown to nearly 600 registered users from 44 countries, who have collectively achieved 62 gene identifications or published studies that have expanded phenotype/genotype correlations. Our concept of user-driven data sharing and matchmaking is now the main cause for gene discoveries within GENESIS. In many of these findings, researchers from across the globe have been connected, which gave rise to the genetic evidence needed to successfully pinpoint-specific gene mutations that explained patients' disease. Here, we present an overview of the various novel insights that have been made possible through the data-sharing capabilities of GENESIS/GEM.app. © 2015 Wiley Periodicals, Inc.


Horga A.,University College London | Tomaselli P.J.,University College London | Gonzalez M.A.,University of Miami | Gonzalez M.A.,Project Genesis | And 9 more authors.
Neurology | Year: 2016

Objective: To describe the genetic and clinical features of a simplex patient with distal hereditary motor neuropathy (dHMN) and lower limb spasticity (Silver-like syndrome) due to a mutation in the sigma nonopioid intracellular receptor-1 gene (SIGMAR1) and review the phenotypic spectrum of mutations in this gene. Methods: We used whole-exome sequencing to investigate the proband. The variants of interest were investigated for segregation in the family using Sanger sequencing. Subsequently, a larger cohort of 16 unrelated dHMN patients was specifically screened for SIGMAR1 mutations. Results: In the proband, we identified a homozygous missense variant (c.194T>A, p.Leu65Gln) in exon 2 of SIGMAR1 as the probable causative mutation. Pathogenicity is supported by evolutionary conservation, in silico analyses, and the strong phenotypic similarities with previously reported cases carrying coding sequence mutations in SIGMAR1. No other mutations were identified in 16 additional patients with dHMN. Conclusions: We suggest that coding sequence mutations in SIGMAR1 present clinically with a combination of dHMN and pyramidal tract signs, with or without spasticity, in the lower limbs. Preferential involvement of extensor muscles of the upper limbs may be a distinctive feature of the disease. These observations should be confirmed in future studies. © 2016 American Academy of Neurology.

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