Preclinical/Co-Clinical Section

摘要 临床外显子组测序和全基因组测序的引入改变了我们的能力 诊断疑似遗传病患者。临床外显子组测序确定了一个潜在的分子 至少25%-30%的疑似基因诊断患者的DNA损伤。基因组等新技术 测序、信使核糖核酸测序和代谢组谱分析正在继续提高这一诊断率。在……里面 此外，这些技术的引入导致了数百个新的疾病基因和 到已知基因诊断中的表型扩展。新疾病基因的不断发现导致了 结构、功能和机制的发现，指向个性化的管理方法和 心理治疗。此外，精确的基因诊断结束了昂贵的诊断奥德赛，促进了个性化 预防医学对诊断的长期并发症，使适当的预见性指导， 并为家庭遗传咨询提供便利。然而，高达70%的疑似遗传病患者 可能仍未确诊，因为他们的致病变异(S)尚未被发现，或者因为 基因组研究中发现的变异的临床意义尚不清楚。临床医生之间的协作 科学家和模型生物研究人员在推动这场革命中发挥了重要作用 基因组医学。模式生物，如果蝇和实验室老鼠，是帮助 在解释测序数据中发现的变异时。在某些情况下，模式生物提供了 支持表型与新疾病基因关联的关键数据。超越了对基因的建模 和表型，对模式生物，如苍蝇、老鼠和非人类灵长类动物的研究可能会提供信息 遗传性疾病患者的治疗管理。此外，这些模式生物提供了关键 用于生物标记物发现、药物筛选和评估特定基因治疗策略的资源。 我们之前在BCM的人类疾病精确建模方面的成功归功于强大的合作努力 本地临床医生、基因组科学家和模型生物科学家之间的合作，这是通过整合 基本活动、翻译活动、临床活动和诊断活动包含在BCM的DMHG中。这一整合具有 建立了产前、儿科和成人遗传学患者的临床和基因组信息流，并 研究参与者是贝勒遗传学实验室的遗传学家和各种基因发现项目。通过这样做， 我们已经建立了临床、临床前和模型生物体工作流程，并对其进行了建模 延伸到哺乳动物物种。我们的临床前/联合临床科将利用现有的基础设施 和专门知识，并通过以下目标将其推广到更广泛的社区：1)协调和审查 不同的提名，2)制定需要精确建模的临床问题，3)翻译临床 精确模型的意义。

ABSTRACT The introduction of clinical exome sequencing and whole genome sequencing has transformed our ability to diagnose patients with suspected genetic disease. Clinical exome sequencing identifies a potential molecular DNA lesion in at least 25-30% of patients with a suspected genetic diagnosis. New technologies such as genome sequencing, mRNA sequencing, and metabolomics profiling are continuing to increase this diagnostic rate. In addition, the introduction of these technologies has led to the discovery of hundreds of new disease genes and to phenotypic expansion within known genetic diagnoses. This continued discovery of new disease genes leads to structure, function and mechanistic discoveries that point to personalized approaches for management and therapy. Moreover, a precise genetic diagnosis ends the costly diagnostic odyssey, facilitates personalized preventive medicine for long-term complications of the diagnosis, enables appropriate anticipatory guidance, and facilitates genetic counseling for families. However, up to 70% of patients with suspected genetic disease remain undiagnosed likely because their disease-causing variant(s) has yet to be discovered or because the clinical significance of variants identified in genomic studies remains unclear. Collaborations between clinician scientists and model organism researchers have played a fundamental role in facilitating this revolution in genomic medicine. Model organisms, such as the fruity fly and laboratory mouse, are important tools for aiding in the interpretation of variants identified in sequencing data. In some cases, model organisms have provided key data supporting the association of a phenotype with a new disease gene. Beyond modeling the genotype and phenotype, studies in model organisms, such as fly, mouse, and non-human primates, may inform therapeutic management of patients with genetic disorders. In addition, these model organisms provide key resources for biomarker discovery, drug screens, and evaluation of genotype-specific therapeutic strategies. Our previous success in precision modeling of human disease at BCM is due to strong collaborative efforts between local clinicians, genome scientists, and model organism scientists that is afforded by the integration of basic, translational, clinical, and diagnostic activities housed within the DMHG at BCM. This integration has established a flow of clinical and genomic information from prenatal, pediatric and adult genetics patients and study participants to laboratory geneticists at Baylor Genetics and various gene discovery programs. In so doing, we have established and modeled the clinical, preclinical, and model organism workflow that we are now extending to mammalian species. Our Preclinical/Co-Clinical section will leverage this existing infrastructure and expertise and extend its use to the wider community through the following aims: 1) Coordinate and review variant nominations, 2) Formulate clinical questions requiring precision modeling, and 3) Translate clinical significance of precision models.