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

摘要 该项目的长期目标是确定危重病人出生缺陷的原因。 未确诊的婴儿，使用基因敲除小鼠内的胚胎表型管道 表型程序(KOMP2)，重点是植入后的发育致死率和 亚生存能力。这一类别的基因被直观地预测与先天性 异常，可能是显性疾病的浓缩。小鼠的单倍体必需基因 不能超过创始人阶段的很可能是富含人类单倍体不足的基因 对孟德尔疾病和发育障碍负责。通过这项建议， 研究人员将优先检查PLI得分较高的基因中的从头开始、LOF和其他变异 她之前发表的研究中死亡儿童的外显子组测序(ES)研究 (PMID：28973083)。然后，带有假定显性零等位基因的基因将与 国际小鼠已知的发育必需基因和亚活性基因 表型鉴定联盟(IMPC)数据集，以寻找表型相关性。调查员将 使用胚胎致死数据来详细分析未诊断的人类心血管疾病 具有早期致死性的表型。通过这个在基因组学领域获得职业提升的机会， 申请者主要是一名临床医生，他将学习比较老鼠和人类。 使用标准化表型术语的表型并使用由 IMPC加速发现罕见疾病。调查员期望获得技能和 评估发育必需的形态异常的实践经验 在狄金森博士团队的监督下进行的小鼠胚胎研究。工作范围，使用鼠标 为未诊断的遗传病患者寻找临床实用的胚胎数据已在 与KOMP2的项目目标完全一致。拟议的工作还将为 研究人员加快了她在儿童罕见疾病诊断方面的现有努力。

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.