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患者出生缺陷的原因， 未确诊的婴儿，使用基因敲除小鼠中的胚胎表型管道 表型分析计划（KOMP2），重点关注着床后发育致死率， 亚生存能力。这类基因被直观地预测与先天性 异常，可能富集显性疾病。小鼠中的单倍必需基因 不能超越创始人阶段的人可能富含人类单倍不足基因 导致孟德尔疾病和发育障碍。通过这项提案， 研究者将优先考虑从pLI得分高的基因中的从头、LoF和其他变异， 她先前发表的研究中对已故儿童的外显子组测序（ES）研究 (PMID：28973083）。具有假定的显性无效等位基因的基因将与 国际小鼠中已知的发育必需基因和亚活力基因 表型分析联盟（IMPC）数据集，以发现表型相关性。研究者将 使用胚胎致死数据来特别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在基因组学方面职业发展的机会， 主要是临床医生的申请人将学习比较小鼠和人类 使用标准化的表型术语，并利用由 IMPC加速发现罕见疾病研究者期望获得技能， 实践经验，以评估发育必需的形态异常 在迪金森博士团队的监督下，工作范围，使用鼠标 胚胎数据，以寻找临床效用的患者与未确诊的遗传条件是在 与KOMP 2的项目目标完全一致。拟议的工作还将编写 研究人员加速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.