KOMP2 Administrative Supplement-Using Mouse Essentiality Screen to Identify Disease Genes Causing Severe Human Phenotypes With Early Lethality

KOMP2 行政补充 - 使用小鼠必需性筛选来识别导致早期致死性严重人类表型的疾病基因

• 批准号: 10166090
• 负责人: Mary E Dickinson
• 金额: $ 24.33万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-28 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10166090
• 关键词: Address; Administrative Supplement; Alleles; Cardiovascular system; Categories; Child; Clinical; Congenital Abnormality; Critical Illness; Data; Data Set; Development; Diagnosis; Disease; Embryo; Essential Genes; Family; Future; Genes; Genetic; Genetic Diseases; Genomics; Goals; Human; Infant; International; Intuition; Knockout Mice; Knowledge; Learning; Medical; Mendelian disorder; Molecular Diagnosis; Morphology; Mus; Patients; Phenotype; Publishing; Rare Diseases; Research; Research Personnel; Resolution; Risk; Standardization; Supervision; Translating; Variant; Work; career; congenital anomaly; congenital heart disorder; design; developmental disease; disease diagnosis; exome sequencing; experience; genetic variant; genomic data; implantation; loved ones; malformation; programs; skills; tool; transmission process

ABSTRACT The long-term goal of this project is to determine the cause of birth defects in critically-ill undiagnosed infants, using the embryonic phenotyping pipeline within the Knockout Mouse Phenotyping Program (KOMP2), with focus on post-implantation developmental lethality and sub-viability. Genes in this category are intuitively predicted to be associated with congenital anomalies, with likely enrichment for dominant disorders. The haplo-essential genes in mice that cannot go beyond the founder stage are likely enriched for human haploinsufficient genes responsible for Mendelian diseases and developmental disorders. Through this proposal, the investigator will prioritize de novo, LoF and other variants in genes with high pLI score from exome sequencing (ES) studies of the deceased children from her previously published study (PMID: 28973083). The genes with putative dominant null alleles will then be intersected with the known developmental essential and subviable genes in the International Mouse Phenotyping Consortium (IMPC) dataset to find phenotypic correlations. The investigator will use the embryonic lethal data to particularly analyze undiagnosed human cardiovascular phenotypes with early lethality. Through this opportunity for career enhancement in genomics, the applicant who is primarily a clinician, will learn to compare the mouse and human phenotypes using standardized phenotype terms and to utilize automated tools designed by IMPC to accelerate discovery of rare diseases. The investigator anticipates acquiring skills and hands-on experience to evaluate morphological abnormalities in developmental essential mouse embryos under the supervision of Dr. Dickinson's team. The scope of work, using mouse embryonic data to find clinical utility for patients with undiagnosed genetic conditions is in complete alignment with the project goals of KOMP2. The proposed work will also prepare the investigator to accelerate her existing efforts on rare disease diagnoses in children.

抽象的 该项目的长期目标是确定重症患者出生缺陷的原因 未确诊的婴儿，使用基因敲除小鼠内的胚胎表型分析管道 表型分析计划 (KOMP2)，重点关注植入后发育致死率和 亚生存能力。直观地预测此类基因与先天性相关 异常，可能会丰富显性疾病。小鼠中的单倍体必需基因 无法超越创始人阶段 可能富含人类单倍体基因不足 负责孟德尔疾病和发育障碍。通过这项提案， 研究人员将优先考虑 de novo、LoF 和具有高 pLI 评分的基因中的其他变异 根据她之前发表的研究，对已故儿童进行外显子组测序 (ES) 研究 （PMID：28973083）。然后将具有假定显性无效等位基因的基因与 国际小鼠中已知的发育必需基因和亚活性基因 表型联盟 (IMPC) 数据集用于查找表型相关性。调查员将 利用胚胎致死数据专门分析未确诊的人类心血管疾病 具有早期致死性的表型。通过这个基因组学职业提升的机会， 主要是临床医生的申请人将学习比较小鼠和人类 使用标准化表型术语并利用由 IMPC 旨在加速罕见疾病的发现。研究者期望获得技能和 评估发育必需的形态异常的实践经验 在迪金森博士团队的监督下研究小鼠胚胎。工作范围，使用鼠标 胚胎数据可为未确诊遗传性疾病的患者寻找临床实用性 与 KOMP2 的项目目标完全一致。拟议的工作还将准备 调查员加快其现有的儿童罕见疾病诊断工作。