Model organisms contribute to diagnosis and discovery in the undiagnosed diseases network: current state and a future vision.
Model organisms contribute to diagnosis and discovery in the undiagnosed diseases network: current state and a future vision.
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DOI：
10.1186/s13023-021-01839-9
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发表时间：
2021-05-07
影响因子：
3.7
通讯作者：
Westerfield M
中科院分区：
文献类型：
--
作者：
Baldridge D;Wangler MF;Bowman AN;Yamamoto S;Undiagnosed Diseases Network;Schedl T;Pak SC;Postlethwait JH;Shin J;Solnica-Krezel L;Bellen HJ;Westerfield M
测序成本的降低导致了基因和基因组数据的爆炸式增长。这些数据揭示了数千种候选的人类疾病变体。然而，确定哪些变异导致表型和疾病仍然具有挑战性。取得了重大进展，包括由美国国立卫生研究院（NIH）资助的未确诊疾病网络（UDN）取得的进展。然而，还有6000 - 13000个额外的疾病基因有待鉴定。罕见病及其遗传基础的不断发现为受影响的患者（全世界有4亿多罕见病患者）带来了益处，也促进了对更常见疾病机制的了解。利用模式生物的平台可以发现新的基因-疾病关系，帮助建立变异致病性，并经常导致探索病理生理学的潜在机制，从而提出新的治疗方法。UDN的模式生物筛选中心（MOSC）是一个独特的资源，致力于利用模式生物的信息学和功能研究，包括蠕虫（秀丽隐杆线虫），果蝇（果蝇）和斑马鱼（Danio rerio），以帮助诊断。MOSC直接有助于诊断具有挑战性的病例，包括具有复杂多器官表型的多例患者。此外，moc为基础科学家和临床医生如何合作推动诊断提供了一个框架。定制的实验计划考虑到患者的表现，特定的基因和变异，以及每个模型生物分析的适当性。moc还为更广泛的科学界生产生物信息学和实验工具和试剂。MOSC成功的两个重要因素是：(1)具有变异生物信息学和人类及模式生物遗传学专业知识的多学科团队，以及(2)与临床团队持续沟通的机制。在此，我们就模式生物在继续发现疾病基因方面的核心作用提供立场声明，我们主张继续和扩大mosc类型的研究实体，作为一个模式生物网络（MON），通过向NIH提交的拨款申请、专注于特定罕见疾病的家庭团体、其他慈善组织、行业合作伙伴关系和其他支持来源来资助。
Decreased sequencing costs have led to an explosion of genetic and genomic data. These data have revealed thousands of candidate human disease variants. Establishing which variants cause phenotypes and diseases, however, has remained challenging. Significant progress has been made, including advances by the National Institutes of Health (NIH)-funded Undiagnosed Diseases Network (UDN). However, 6000–13,000 additional disease genes remain to be identified. The continued discovery of rare diseases and their genetic underpinnings provides benefits to affected patients, of whom there are more than 400 million worldwide, and also advances understanding the mechanisms of more common diseases. Platforms employing model organisms enable discovery of novel gene-disease relationships, help establish variant pathogenicity, and often lead to the exploration of underlying mechanisms of pathophysiology that suggest new therapies. The Model Organism Screening Center (MOSC) of the UDN is a unique resource dedicated to utilizing informatics and functional studies in model organisms, including worm (Caenorhabditis elegans), fly (Drosophila melanogaster), and zebrafish (Danio rerio), to aid in diagnosis. The MOSC has directly contributed to the diagnosis of challenging cases, including multiple patients with complex, multi-organ phenotypes. In addition, the MOSC provides a framework for how basic scientists and clinicians can collaborate to drive diagnoses. Customized experimental plans take into account patient presentations, specific genes and variant(s), and appropriateness of each model organism for analysis. The MOSC also generates bioinformatic and experimental tools and reagents for the wider scientific community. Two elements of the MOSC that have been instrumental in its success are (1) multidisciplinary teams with expertise in variant bioinformatics and in human and model organism genetics, and (2) mechanisms for ongoing communication with clinical teams. Here we provide a position statement regarding the central role of model organisms for continued discovery of disease genes, and we advocate for the continuation and expansion of MOSC-type research entities as a Model Organisms Network (MON) to be funded through grant applications submitted to the NIH, family groups focused on specific rare diseases, other philanthropic organizations, industry partnerships, and other sources of support.
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影响因子：
13.6
作者：
Bangi, Erdem;Ang, Celina;Cagan, Ross L.
通讯作者：
Cagan, Ross L.
影响因子：
3.3
作者：
Corsi AK;Wightman B;Chalfie M
通讯作者：
Chalfie M
影响因子：
64.8
作者：
Dickinson ME;Flenniken AM;Ji X;Teboul L;Wong MD;White JK;Meehan TF;Weninger WJ;Westerberg H;Adissu H;Baker CN;Bower L;Brown JM;Caddle LB;Chiani F;Clary D;Cleak J;Daly MJ;Denegre JM;Doe B;Dolan ME;Edie SM;Fuchs H;Gailus-Durner V;Galli A;Gambadoro A;Gallegos J;Guo S;Horner NR;Hsu CW;Johnson SJ;Kalaga S;Keith LC;Lanoue L;Lawson TN;Lek M;Mark M;Marschall S;Mason J;McElwee ML;Newbigging S;Nutter LM;Peterson KA;Ramirez-Solis R;Rowland DJ;Ryder E;Samocha KE;Seavitt JR;Selloum M;Szoke-Kovacs Z;Tamura M;Trainor AG;Tudose I;Wakana S;Warren J;Wendling O;West DB;Wong L;Yoshiki A;International Mouse Phenotyping Consortium;Jackson Laboratory;Infrastructure Nationale PHENOMIN, Institut Clinique de la Souris (ICS);Charles River Laboratories;MRC Harwell;Toronto Centre for Phenogenomics;Wellcome Trust Sanger Institute;RIKEN BioResource Center;MacArthur DG;Tocchini-Valentini GP;Gao X;Flicek P;Bradley A;Skarnes WC;Justice MJ;Parkinson HE;Moore M;Wells S;Braun RE;Svenson KL;de Angelis MH;Herault Y;Mohun T;Mallon AM;Henkelman RM;Brown SD;Adams DJ;Lloyd KC;McKerlie C;Beaudet AL;Bućan M;Murray SA
通讯作者：
Murray SA
影响因子：
64.5
作者：
Bellen HJ;Yamamoto S
通讯作者：
Yamamoto S
影响因子：
9.8
作者：
Boycott KM;Rath A;Chong JX;Hartley T;Alkuraya FS;Baynam G;Brookes AJ;Brudno M;Carracedo A;den Dunnen JT;Dyke SOM;Estivill X;Goldblatt J;Gonthier C;Groft SC;Gut I;Hamosh A;Hieter P;Höhn S;Hurles ME;Kaufmann P;Knoppers BM;Krischer JP;Macek M Jr;Matthijs G;Olry A;Parker S;Paschall J;Philippakis AA;Rehm HL;Robinson PN;Sham PC;Stefanov R;Taruscio D;Unni D;Vanstone MR;Zhang F;Brunner H;Bamshad MJ;Lochmüller H
通讯作者：
Lochmüller H