Genetics of speech disorders

言语障碍的遗传学

• 批准号: 8248738
• 负责人: Beate Peter
• 金额: $ 15.6万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2014-03-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8248738
• 关键词: Adult; Affect; Base Sequence; Biochemical; Bioinformatics; Blood; Candidate Disease Gene; Characteristics; Child; Childhood; Classification; Code; Communication; Communication impairment; Complex; Coupled; DNA; Data; Databases; Diagnosis; Disease; Disease model; Distant; Early identification; Early treatment; Evaluation; Exons; Family; Family member; Future; Genes; Genetic; Genetic Heterogeneity; Genetic Variation; Genome; Genomics; Heterogeneity; Individual; Intervention; Knowledge; Measures; Medical Genetics; Methods; Modeling; Neurodevelopmental Disorder; Pattern; Phenotype; Pilot Projects; Positioning Attribute; Procedures; Production; Public Health; RNA Splicing; Rare Diseases; Recording of previous events; Recruitment Activity; Research; Research Personnel; Resources; Risk; Saliva; Science; Sequence Analysis; Severities; Site; Speech; Speech Disorders; Speech Sound; Statistical Models; Time; Universities; Validation; Variant; Washington; Work; base; cost; data sharing; developmental disease; disorder subtype; exome; gene discovery; improved; inclusion criteria; insight; kindred; member; next generation; novel; proband; public health relevance; segregation; trait; transmission process

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.

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以及生物信息学基因过滤来识别影响言语障碍（SSD）的基因。在没有已知原因的情况下，患有 SSD 的儿童很难说出容易被他人理解的语言。有证据表明 SSD 具有高度遗传性，但致病基因尚不清楚。最近对许多家庭患有 SSD 的儿童同胞对进行的研究已经证实了许多候选区域，但有证据表明 SSD 可能是由不同家庭的不同基因引起的。为了增进我们的知识，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。最近对童年时期患有 SSD 的成年人进行的言语研究得出的见解，加上基于外显子组的基因发现方法，现在可以识别单个大的多代家庭中的因果基因。除了当前试点项目中已确定的家族外，拟议的研究还将鉴定最多两个具有 SSD 单基因遗传证据的此类家族。表型和统计模型将提供 SSD 遗传模式的估计，并表征每个家族的相关性状。每个家庭将选择三名远亲受影响的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核心，这些变体由已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。如果每个家族保留了多个候选基因，则将选择具有最高位点和/或功能合理性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 相关的单个或主要基因的现实潜力，并为未来研究其他 SSD 变体以及进一步研究具有 CDRV 模式的其他沟通和神经发育障碍的研究提供基础，所有这些都比以前可能具有更高的效率和更低的成本。结果将进入更大规模的研究工作，以确定 SSD 家族中的其他罕见变异，并创建基于生物学的 SSD 亚型分类。 公共健康相关性：该项目应用了医学遗传学中新开发的方法，即基于外显子组的基因发现，以识别家族性言语障碍的致病基因。这些发现将有助于更好地理解家族言语障碍的遗传基础，并为其他家族沟通乃至神经发育障碍的基因发现引入一种新的方法模型。这项工作与公共卫生直接相关，因为对言语障碍和其他沟通障碍的生物学原因的更好的理解创建了基于生物学的亚型分类，导致更准确的诊断，有助于早期识别处于危险中的儿童，并激发了有关干预（包括早期干预）的新研究问题。