Genetics of speech disorders

描述(申请人提供)：这项研究旨在通过应用一种新的基因发现方法来识别影响言语声音障碍(SSD)的基因，下一代外显子组测序随后进行生物信息基因过滤。患有SSD的儿童在没有已知原因的情况下，很难说出别人容易理解的语言。有证据表明，SSD是高度可遗传的，但其原因基因尚不清楚。最近对来自许多家庭的患有SSD的儿童同胞对的研究证实了一些候选区域，但有证据表明，SSD可以由不同家庭的不同基因引起。为了推进我们的知识，常见疾病/罕见变异(CDRV)模型是一种替代的基因识别框架，使用的方法一次只关注一种遗传机制。最近对童年时期患有SSD的成年人进行的言语研究，再加上基于外显子组的基因发现方法，现在使得在单个扩展的多代家庭中识别因果基因成为可能。这项拟议的研究将确定最多两个有单基因遗传证据的SSD家族，以及那些已经在目前的试点项目中确定的家族。表型分型和统计建模将提供对SSD遗传模式的估计，并描述每个家族中相关的特征。将在每个家族中选择三个远亲、受影响的成员进行外显子组测序。外显子核苷酸序列将被筛选到具有新的非同义变体的候选基因的核心，这些新的非同义变体被测序的外显子组最大限度地共享，并在拷贝数方面符合估计的遗传模式。如果每个家族仍有一个以上的候选基因，将选择具有最高基因座和/或功能可信度的基因在受影响和未受影响的对照中进行验证。这项研究具有首次识别与SSD相关的单个或主基因的现实潜力，并为未来研究其他SSD变种，进而研究其他具有CDRV模式的沟通和神经发育障碍提供了基础，所有这些都比以前可能的效率更高，成本更低。结果将流入一项更大的研究努力，以识别患有SSD的家族中的其他罕见变异，并创建基于生物学的SSD亚型分类。 公共卫生相关性：该项目应用医学遗传学中一种新开发的方法，基于外显子组的基因发现，来确定家族性语音障碍的致病基因(S)。这些发现将有助于更好地理解家族性语音障碍的遗传基础，并为其他家族沟通以及神经发育障碍的基因发现引入一种新的方法模型。这项工作与公共健康直接相关，因为对言语发音障碍和其他沟通障碍的生物原因的了解的提高创建了基于生物学的亚型分类，导致了更准确的诊断，有助于早期识别处于危险中的儿童，并引发了关于干预的新的研究问题，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.