Optimizing Genetic Testing for Deafness for Clinical Diagnostics

描述(由申请人提供)：在这项目标驱动的提案中，我们将为临床医生提供全面的耳聋基因测试，每人不超过500美元。这一倡议背后的驱动力是听力障碍的频率。作为最常见的感觉障碍，每500名新生儿中就有1人被诊断为此病，50%的八旬老人被诊断为此病(Morton Ann N Y Acad Sci1991)。有57个基因与非综合征性听力损失(NSHL)有关，这也是一种非常不同的特征，给诊断带来了巨大的挑战。目前针对耳聋的基因检测策略是不充分的。对于大多数人来说，只有一小部分基因被纳入，选择标准通常反映：1)作为耳聋原因的高患病率(即GJB2)；2)与另一个可识别的特征(如SLC26A4和扩大的前庭导水管)的关联；或3)可识别的听觉轮廓(如WFS1所见的低频听力损失)(Hilgert等人Mut Res 2009)。然而，最近出现的强大的DNA靶标浓缩和测序技术，使提供有效和经济的全面耳聋基因测试成为可能。我们已经证明，在一个平台(称为耳镜)上同时分析所有耳聋基因是可能的(Sheeller等人2010年的PNAS)。与这一努力相关的是，我们还验证了Audiogene是一种表型工具，它使用患者听力图来预测ADNSHL的遗传原因(Hildebrand等人Genet Med 2008年；Hildebrand等人喉镜2009年)。在这些发现的基础上，在这项提案中，我们将完成两个具体目标。具体目标1：为耳聋基因测试提供全面、高通量、低成本的DNA序列生成和分析目标1：通过使用靶向序列浓缩和大规模平行测序，为耳聋基因测试提供全面、高通量、低成本的DNA序列分析成为可能，其灵敏度和特异性可与桑格测序相媲美。具体目标2：通过扩展和改进我们开发的名为Audiogene Goal 2的平台，优化基于机器学习的听力数据的音频分析和表型数据的表型过滤：作为一种现象组工具，一个基于大量听力数据的机器学习软件系统可以用于根据听力数据预测和消除导致耳聋的特定基因或基因变异。这些特定目标的实现将改变聋人和重听者的临床评估，使基因测试成为继病史、体检和听力学评估之后最重要的诊断测试。 与公共健康相关：在这项目标驱动的提案中，我们将向临床医生提供全面的耳聋基因检测，每人不超过500美元。实现这一目标将改变聋人和重听人的临床评估，使基因测试成为继病史和体检之后最重要的诊断测试。

DESCRIPTION (provided by applicant): In this goal-driven proposal, submitted in response to Funding Opportunity Announcement (FOA) Number PAR-11-003, we will make comprehensive genetic testing for deafness available to clinicians for under $500 per person. The driving force behind this initiative is the frequency of hearing impairment. As the most common sensory impairment, it is diagnosed in 1 of every 500 newborns and 50% of octogenarians (Morton Ann N Y Acad Sci 1991). With 57 genes implicated in nonsyndromic hearing loss (NSHL), it is also an extremely heterogeneous trait and presents a tremendous challenge to diagnosis. Current strategies for genetic testing for deafness are inadequate. For most, only a minority of genes is included, with selection criteria typically reflecting: 1) high prevalence as a cause of deafness (i.e. GJB2); 2) association with another recognizable feature (i.e. SLC26A4 and enlarged vestibular aqueduct); or 3) a recognizable audioprofile (i.e. low frequency hearing loss as seen with WFS1) (Hilgert et al Mut Res 2009). The recent advent of powerful DNA target enrichment and sequencing technologies, however, makes it possible to provide comprehensive genetic testing for deafness that is efficient and cost-effective. We have shown that it is possible to analyze all deafness genes simultaneously on a single platform (called OtoSCOPE) (Shearer et al PNAS 2010). Related to this endeavor, we have also validated AudioGene as a phenotypic tool that uses patient audiograms to predict the genetic cause of ADNSHL (Hildebrand et al Genet Med 2008; Hildebrand et al Laryngoscope 2009). Building on these findings, in this proposal we will complete two specific aims. Specific Aim 1: To provide comprehensive, high-throughput, low-cost DNA sequence generation and analysis for deafness genetic testing Goal 1: Comprehensive, high-throughput, low-cost DNA sequence analysis for genetic testing for deafness is possible at sensitivities and specificities comparable to Sanger sequencing by using targeted sequence enrichment followed by massively parallel sequencing. Specific Aim 2: To optimize both machine learning-based audioprofiling of audiometric data and phenotypic filtering of genotypic data by expanding and improving the platform we have developed called AudioGene Goal 2: As a phenome tool, a machine-learning software system trained on an extensive set of audiometric data can be used to predict and to eliminate specific genes or gene variants as causes of deafness based on audiometric data. Achieving these specific aims will change the clinical evaluation of deaf and hard-of-hearing persons by making genetic testing the most important diagnostic test after a history, physical examination and audiological assessment. PUBLIC HEALTH RELEVANCE: In this goal-driven proposal, submitted in response to Funding Opportunity Announcement (FOA) Number PAR-11-003, we will make comprehensive genetic testing for deafness available to clinicians for under $500 per person. Achieving this goal will change the clinical evaluation of deaf and hard-of-hearing persons by making genetic testing the most important diagnostic test after a history and physical exam.