SEQuencing a Baby for an Optimal Outcome (SEQaBOO)

 描述(由申请人提供)：SEQABO(为婴儿测序以获得最佳结果)将把高通量基因组方法转化为常规的新生儿听力损失筛查(HL)。该项目将招募大约500名没有通过初始新生儿听力筛查的新生儿及其父母进行基因组序列分析。直到最近，对没有明显解剖畸形的先天性缺陷的临床诊断，如听力损失，都受到了极大的限制。今天，先天性HL和其他微小的出生缺陷在新生儿中得到承认，从而可以进行早期干预，限制终身残疾。发展 新一代DNA测序技术的发展为致力于改善出生缺陷新生儿生活的研究人员和临床医生提供了一个新的机会，以调查是否可以更准确和有效地确定先天性缺陷的遗传病因，以及改进的基因诊断是否会转化为更好的临床护理。在这个项目中，我们旨在通过评估先天性HL新生儿基因组数据的临床影响来应对这一挑战。对于通过外显子组测序未发现致病突变的新生儿，将使用替代基因组方法来全面探索整个基因组的突变谱。将开发分析管道，以提供对基因组变异的自动化和准确的临床解释。在适当的时候，遗传信息将被返还给父母和医生，以便进行早期干预。尽管HL是在新生儿早期确诊的，不会危及生命，但它需要家人和患者进行多次调整，以优化生活质量。在某些情况下，植入人工耳蜗可以将听力恢复到接近正常的水平。其他治疗先天性HL的干预措施正在开发中。由于先天性HL有许多不同的病因，从基因突变到病毒感染，我们推测适当的治疗方法可能会根据确切的病因而有所不同。HL的遗传原因是高度异质性的，已经确定了&gt；115基因的突变。在这项提案中，我们将检验这一假设，即迅速发现新生儿HL的确切原因将有助于管理和治疗干预。我们每年都会对儿童群体进行调查，以确定总体健康状况，除了听力状况外，还包括语言和语言的发展，以及父母对基因组测序的态度。综上所述，我们将分析和组装基因组数据集，进行通过新生儿筛查可识别的HL的临床基因组研究，并探索将基因组测序整合到新生儿筛查中的意义。所有这些都将为基因组测序对先天性HL新生儿的护理和管理带来的影响提供信息，并使我们能够调查与我们的社会接受这项新技术以实现新生儿的“最佳结果”相关的因素。

 DESCRIPTION (provided by applicant): SEQaBOO (SEQuencing a Baby for an Optimal Outcome) will translate high-throughput genomic approaches into routine newborn screening for hearing loss (HL). The project will enroll approximately 500 newborns that do not pass their initial newborn hearing screen and their parents for genomic sequence analysis. Until recently, clinical diagnosis of congenital defects without an overt anatomical malformation, such as hearing loss, was profoundly limited. Today, congenital HL and other subtle birth defects are recognized in newborns, allowing early interventions that limit life-long disabilities. Development of next generation DNA sequencing technologies provides a new opportunity for researchers and clinicians dedicated to improving the lives of newborns with birth defects to investigate whether genetic etiologies of congenital defects can be more accurately and efficiently defined and whether improved genetic diagnosis translates into superior clinical care. In this project we aim to address this challenge by assessing the clinical impact of genomic data in newborns with congenital HL. For newborns in whom no pathogenic mutation is identified via exome sequencing, alternative genomic approaches will be used to explore comprehensively the full mutational spectrum across the genome. Analytic pipelines will be developed to provide automated and accurate clinical interpretation of genomic variants. When appropriate, genetic information will be returned to parents and physicians for early intervention purposes. Although diagnosed in the early neonatal period and not life threatening, HL requires a number of adjustments by the family and patient to optimize quality of life. In some instances, cochlear implants can restore hearing to near normal levels. Other therapeutic interventions for congenital HL are under development. As there are a remarkable number of different etiologies of congenital HL that range from genetic mutation to viral infection, we surmise that appropriate therapies may vary depending on precise etiology. Genetic causes of HL are highly heterogeneous and mutations in >115 genes have already been identified. In this proposal, we will test the hypothesis that rapid discovery of the exact cause of a newborn's HL will benefit management and therapeutic interventions. Annually we will survey the cohort of children to ascertain general health, including speech and language development in addition to hearing status, and parental attitudes on genomic sequencing. In sum, we will analyze and assemble genomic datasets, perform clinical genomic research of HL identifiable through newborn screening and explore implications of integration of genomic sequencing into newborn screening. All of this will inform the impact of genomic sequencing on the care and management of newborns with congenital HL and allow us to investigate factors associated with our society's acceptance of this new technology for "optimal outcome" of a newborn baby.