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。临床外显子组测序鉴定了一种潜在的分子 至少25-30%的疑似遗传诊断患者存在DNA损伤。基因组等新技术 测序、mRNA测序和代谢组学分析正在继续提高这一诊断率。在 此外，这些技术的引入导致发现了数百种新的疾病基因， 到已知遗传诊断中的表型扩张。新的疾病基因的不断发现导致 结构，功能和机械的发现，指向个性化的管理方法， 疗法此外，精确的基因诊断结束了昂贵的诊断之旅， 对诊断的长期并发症进行预防性治疗，能够提供适当的预期指导， 并为家庭提供遗传咨询。然而，高达70%的疑似遗传病患者 仍然未被诊断，可能是因为他们的致病变异尚未被发现，或者因为 在基因组研究中鉴定的变体的临床意义仍然不清楚。临床医生之间的合作 科学家和模式生物研究人员在促进这场革命中发挥了重要作用， 基因组医学模式生物，如果蝇和实验室小鼠，是帮助 在测序数据中鉴定的变体的解释中。在某些情况下，模式生物提供了 支持表型与新疾病基因相关的关键数据。除了对基因型进行建模 和表型，在模式生物，如苍蝇，小鼠和非人类灵长类动物的研究，可以告知 遗传病患者的治疗管理。此外，这些模式生物提供了关键的 生物标志物发现、药物筛选和基因型特异性治疗策略评估的资源。 我们之前在人类疾病精确建模方面的成功归功于强大的合作努力 当地临床医生，基因组科学家和模式生物科学家之间的联系， 基本的，翻译，临床和诊断活动在DMHG内。这种整合 建立了来自产前、儿科和成人遗传学患者的临床和基因组信息流， 研究参与者在贝勒遗传学实验室遗传学家和各种基因发现计划。在这样做时， 我们已经建立并模拟了临床，临床前和模式生物的工作流程，我们现在正在 延伸到哺乳动物物种。我们的临床前/协同临床部分将利用现有的基础设施 和专业知识，并通过以下目标将其应用于更广泛的社区：1）协调和审查 变体提名，2）制定需要精确建模的临床问题，以及3）翻译临床 精确模型的重要性。

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.