Genetics of speech disorders

描述（由申请人提供）：本研究旨在通过应用新的基因发现方法（下一代外显子组测序，然后进行生物信息学基因过滤）来识别影响语音障碍（SSD）的基因。患有SSD的儿童在缺乏已知原因的情况下，很难说出别人容易理解的话。有证据表明，SSD是高度遗传的，但致病基因尚不清楚。近年来，对多个家族的SSD同胞子女的研究证实了一些候选区域，但也有证据表明SSD可能由不同家族的不同基因引起。为了推进我们的知识，常见疾病/罕见变异（CDRV）模型是基因识别的替代框架，使用一次仅关注一种遗传机制的方法。最近的见解，从语音研究的成年人谁在儿童时期有SSD，再加上外显子组为基础的基因发现方法，现在有可能确定因果基因在一个单一的扩展多代家庭。拟议的研究将确定多达两个这样的家庭，除了那些已经在目前的试点项目中确定的SSD单基因遗传的证据。表型分析和统计建模将提供SSD遗传模式的估计，并描述每个家族的相关性状。在每个家族中选择三个远缘的受影响成员进行外显子组测序。外显子组核苷酸序列将被过滤到具有新的非同义变体的候选基因的核心，所述新的非同义变体被测序的外显子组最大程度地共享，并且在拷贝数方面符合估计的遗传模式。如果每个家族保留一个以上的候选基因，则将选择具有最高基因座和/或功能相似性的候选基因用于在受影响和未受影响的对照中进行验证。这项研究具有现实的潜力，首次确定与SSD相关的单个或主要基因，并为未来研究其他SSD变体提供基础，并扩展到其他具有CDRV模式的交流和神经发育障碍，所有这些都具有比以前更高的效率和更低的成本。结果将流入一个更大的研究奋进，以确定其他罕见的变异与SSD的家庭，并创建一个基于生物学的SSD亚型分类。 公共卫生相关性：本计画应用医学遗传学中最新发展的方法--以外显子组为基础的基因发现，来找出家族性语音障碍的致病基因。这些发现将有助于更好地了解家族性言语声音障碍的遗传基础，并为其他家族性沟通和神经发育障碍的基因发现方法引入新的模型。这项工作与公共卫生直接相关，因为对言语声音障碍和其他沟通障碍的生物学原因的更好理解创建了基于生物学的亚型分类，导致更准确的诊断，促进了早期识别风险儿童，并激发了有关干预的新研究问题，包括早期干预。

DESCRIPTION (provided by applicant): This research aims to identify genes that influence speech sound disorder (SSD) by applying a newly available approach to gene discovery, next-generation exome sequencing followed by bioinformatic gene filtering. Children with SSD have difficulty producing speech that is readily understood by others, in the absence of known causes. There is evidence that SSD is highly heritable, but the causal genes are not yet known. Recent studies in child sib pairs with SSD from many families have confirmed a number of candidate regions, but there is evidence that SSD can result from different genes in different families. To advance our knowledge, the common disease/rare variant (CDRV) model is an alternative framework for gene identification, using approaches that focus on only one genetic mechanism at a time. Recent insights from speech studies in adults who had SSD during childhood, coupled with an exome-based gene discovery approach, now make it possible to identify causal genes in single extended multigenerational families. The proposed research will identify up to two such families with evidence of single-gene inheritance of SSD, in addition to those already ascertained in a current pilot project. Phenotyping and statistical modeling will provide an estimate of the mode of inheritance of SSD and characterize associated traits in each family. Three distantly related, affected members will be selected for exome sequencing in each family. Exomic nucleotide sequences will be filtered to a core of candidate genes with novel nonsynonymous variants that are maximally shared by the sequenced exomes and fit the estimated mode of inheritance in terms of copy numbers. If more than one candidate gene per family remains, the one with the highest locus and/or functional plausibility will be selected for validation in affected and unaffected controls. This research has the realistic potential to identify single or major genes associated with SSD for the first time and provide the basis for future studies investigating other SSD variants and, by extension, other communication and neuro-developmental disorders with a CDRV pattern, all with substantially higher efficiency and lower cost than previously possible. Results will flow into a larger research endeavor to identify other rare variants in families with SSD and create a biologically based SSD subtype classification. PUBLIC HEALTH RELEVANCE: This project applies a newly developed approach in medical genetics, exome-based gene discovery, toward identifying the causative gene(s) in familial speech sound disorder. The findings will contribute to a better understanding of the genetic basis of familial speech sound disorder and also introduce a new model of methods for gene discovery in other familial communication and, by extension, neurodevelopmental disorders. This work is directly relevant to public health because an improved understanding of the biologic causes of speech sound disorder and other communication disorders creates a biologically based subtype classification, leads to more accurate diagnoses, facilitates early identification of children at risk, and motivates new research questions about intervention including early intervention.