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An integrated clinical program and crowdsourcing strategy for genomic sequencing and Mendelian disease gene discovery.

ABSTRACT: Despite major progress in defining the genetic basis of Mendelian disorders, the molecular etiology of many cases remains unknown. Patients with these undiagnosed disorders often have complex presentations and require treatment by multiple health care specialists. Here, we describe an integrated clinical diagnostic and research program using whole-exome and whole-genome sequencing (WES/WGS) for Mendelian disease gene discovery. This program employs specific case ascertainment parameters, a WES/WGS computational analysis pipeline that is optimized for Mendelian disease gene discovery with variant callers tuned to specific inheritance modes, an interdisciplinary crowdsourcing strategy for genomic sequence analysis, matchmaking for additional cases, and integration of the findings regarding gene causality with the clinical management plan. The interdisciplinary gene discovery team includes clinical, computational, and experimental biomedical specialists who interact to identify the genetic etiology of the disease, and when so warranted, to devise improved or novel treatments for affected patients. This program effectively integrates the clinical and research missions of an academic medical center and affords both diagnostic and therapeutic options for patients suffering from genetic disease. It may therefore be germane to other academic medical institutions engaged in implementing genomic medicine programs.

SUBMITTER: Haghighi A

PROVIDER: S-EPMC6089983 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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An integrated clinical program and crowdsourcing strategy for genomic sequencing and Mendelian disease gene discovery.

Haghighi Alireza A Krier Joel B JB Toth-Petroczy Agnes A Cassa Christopher A CA Frank Natasha Y NY Carmichael Nikkola N Fieg Elizabeth E Bjonnes Andrew A Mohanty Anwoy A Briere Lauren C LC Lincoln Sharyn S Lucia Stephanie S Gupta Vandana A VA Söylemez Onuralp O Sutti Sheila S Kooshesh Kameron K Qiu Haiyan H Fay Christopher J CJ Perroni Victoria V Valerius Jamie J Hanna Meredith M Frank Alexander A Ouahed Jodie J Snapper Scott B SB Pantazi Angeliki A Chopra Sameer S SS Leshchiner Ignaty I Stitziel Nathan O NO Feldweg Anna A Mannstadt Michael M Loscalzo Joseph J Sweetser David A DA Liao Eric E Stoler Joan M JM Nowak Catherine B CB Sanchez-Lara Pedro A PA Klein Ophir D OD Perry Hazel H Patsopoulos Nikolaos A NA Raychaudhuri Soumya S Goessling Wolfram W Green Robert C RC Seidman Christine E CE MacRae Calum A CA Sunyaev Shamil R SR Maas Richard L RL Vuzman Dana D

NPJ genomic medicine 20180813

Despite major progress in defining the genetic basis of Mendelian disorders, the molecular etiology of many cases remains unknown. Patients with these undiagnosed disorders often have complex presentations and require treatment by multiple health care specialists. Here, we describe an integrated clinical diagnostic and research program using whole-exome and whole-genome sequencing (WES/WGS) for Mendelian disease gene discovery. This program employs specific case ascertainment parameters, a WES/W ...[more]

PMID: 30131872

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Project description:Antibiotic misuse is a public health problem due to the appearance of resistant strains in almost all human pathogens, making infectious diseases more difficult to treat. The search for solutions requires the development of new antimicrobials as well as novel strategies, including increasing social awareness of the problem. The Small World Initiative (SWI) and the Tiny Earth (TE) network are citizen science programs pursuing the discovery of new antibiotics from soil samples and the promotion of scientific culture. Both programs aim to bring scientific culture and microbiological research closer to pre-university students through a crowdsourcing strategy and a Service Learning (SL) educational approach, with a 2-fold objective: to encourage students to pursue careers in science and to involve them in the discovery of soil microorganisms producing new antimicrobials. SWI and TE projects were put into practice in Spain under the common name MicroMundo. MicroMundo@Valencia was implemented at the Universitat de València (UV) during the academic years 2017-2018 and 2018-2019. It trained 140 university students to disseminate this initiative into 23 high/secondary schools, and one primary school, involving about 900 people (teachers and students) as researchers. A total of 7,002 bacterial isolates were obtained from 366 soil samples and tested for antibiosis at UV and high/secondary school centers. About 1 or 7% of them produced inhibition halos for the Escherichia coli or Bacillus cereus target strains, respectively. Geolocation of sampling sites by an application developed ad hoc and Kriging analysis also allowed detection of soil foci of antibiotic-producing bacteria. Evaluation of the project by university, high/secondary, and primary school students revealed their strong positive perception and their increased interest in science, as a consequence of acquiring new scientific and pedagogical concepts and skills that they were able to pass on to other classmates, younger students, or relatives. To further expand the dissemination of the project in the Valencian Community, diverse extramural activities deemed to include a gender perspective and aimed at different age groups, were also carried out, obtaining very satisfactory results, increasing sensitivity and awareness to the global antibiotic crisis.

Dataset Information

An integrated clinical program and crowdsourcing strategy for genomic sequencing and Mendelian disease gene discovery.

Publications

An integrated clinical program and crowdsourcing strategy for genomic sequencing and Mendelian disease gene discovery.

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