Genetic causes of developmental speech sound disorder in families

家族发育性言语障碍的遗传原因

基本信息

批准号：
8446613
负责人：
SUDHA K IYENGAR
金额：
$ 64.95万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-26 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8446613
关键词：
3 year old 6 year old Academic achievement Adult Affect Algorithms Alleles Behavioral Bioinformatics Biological Candidate Disease Gene Categories Characteristics Child Clinical Code Communication impairment Comorbidity Complex Data Databases Development Diagnosis Diagnostic Disabled Children Disease Early Diagnosis Education Family Family member Future Gene Frequency Genes Genetic Genomics Genotype Goals Impairment Individual Knowledge Language Language Disorders Lead Literature Maps Medical Medical Genetics Methods Minor Molecular Molecular Abnormality Mutation Nature Neighborhoods Neurodevelopmental Disorder Nuclear Family Parents Participant Phenotype Plant Roots Population Predisposition Prevalence Productivity Property Proteins Rare Diseases Reading Reading Disorder Reporting Research Resolution Running Sampling Schools Services Siblings Special Education Speech Speech Delay Speech Disorders Speech Sound Structure Symptoms Techniques Testing Translations Unemployment Ursidae Family Variant Vertebral column Work base career cost cost effective density design disability early childhood exome genetic linkage analysis genetic variant genome-wide innovation member novel population based proband scaffold segregation tool transmission process

项目摘要

DESCRIPTION (provided by applicant): Communication Disorders are common in children, may persist into adulthood, and are recognized as causing pervasive and lifelong disabilities. Three communication disorders, speech sound disorder, reading disorder and language impairment, are often observed as a triumvirate in individuals who have severe disability. Speech sound disorder is diagnosed first in early childhood, and likely forms the cornerstone of the tri-level deficit, although the exact biological root of these comorbidities is unknown. Individuals with the most severe forms of speech sound disorder that persist into adulthood, with or without other comorbidities, show the greatest shortfalls in terms of academic achievements. Difficulties during the scholastic years effectively influence the realization and sustenance of professional careers, and these individuals tend to have higher unemployment rates, and lower earning potential. In previous work, we have shown that speech sound disorder has a genetic basis and clusters in families, particularly among children affected with severe forms of the disorder. Using our database of 24-year longitudinal data, we propose to find families with affecteds followed by whole exome sequencing of two parents and affected children at an average coverage of >50X. We will use state-of-the-art statistical and bioinformatic methods to find biologically meaningful variants that cause speech sound disorder. This approach has been spectacularly successful for unsolved recessive and dominant Mendelian diseases that run in families, but also among sporadic cases of rare diseases. In medical genetics, the first step towards translation is finding clinically actionable variants that can be validated, and developed into diagnostic tools. A decade ago, identification of a highly penetrant, discrete genetic variant in FOXP2 in a single family was the first step for the field of speech and language disorders. In our current plan, we are scaling the search neighborhood to the level of the entire protein-coding exome, rather than starting with single genes. Our design is based on examination of exomes of two families which do not show mutations in FOXP2, and a vast supporting literature that suggests that mutations in this gene are not typical in speech sound disorder. Approximately 2.5 million markers will be typed in all members of the family. Using the scaffold of the 2.5 million markers, and exome data from the trio, exomic information will be imputed in all family members. We will use this information to confirm segregation of variants in affected and unaffected individuals, and examine modes of inheritance. This suite of techniques will allow us to identify new genes for speech sound disorder. It may ultimately be feasible to use these newly identified variants for early diagnosis, and to subtype speech sound disorders into more homogeneous categories, subsets of which could proactively be targeted for intensive behavioral or other therapy. PUBLIC HEALTH RELEVANCE: Communication disorders are highly prevalent in the US with approximately 42 million people (1 in 6) reporting some type of communication disorder. Of these the three most common are Speech Sound Disorder (SSD), Reading Disorder (RD) and Language Impairment (LI), and these bear high societal and personal costs. The research in this application will help us (a) discover novel loci specific to severe SSD, (b) clarify subtypes f SSD, and (c) lead to development of new statistical strategies for complex disorders that may universally be applicable to RD and LI and other unsolved neurodevelopmental disorders.

描述（由申请人提供）：沟通障碍在儿童中很常见，可能会持续到成年，并被认为会导致普遍存在和终身残疾。在患有严重残疾的个体中，经常将三种沟通障碍，言语障碍，阅读障碍和语言障碍视为trium绕。语音障碍在幼儿时期首先被诊断出来，并可能构成三级赤字的基石，尽管这些合并症的确切生物学根源尚不清楚。具有最严重形式的言语障碍形式的人在成年后，有或没有其他合并症，在学术成就方面表现出最大的缺陷。学术时期的困难有效地影响了职业职业的实现和维持，这些人往往具有较高的失业率和较低的收入潜力。在先前的工作中，我们已经表明，语音障碍在家庭中具有遗传基础和簇，尤其是在受到严重疾病形式的儿童中。使用我们的24年纵向数据的数据库，我们建议找到患有受影响的家庭，然后对两个父母和受影响的孩子进行整个外显子组测序，平均覆盖范围> 50倍。我们将使用最先进的统计和生物信息学方法来找到引起言语障碍的生物学意义变体。对于在家庭中运行的未解决的隐性和占主导地位的孟德尔疾病而言，这种方法在罕见疾病的零星病例中取得了成功。在医学遗传学中，迈向翻译的第一步是找到可以验证并发展为诊断工具的临床可行变体。十年前，鉴定高度渗透物，离散的遗传变异在FOXP2中，一个家庭是言语和语言障碍领域的第一步。在当前的计划中，我们将搜索邻域扩展到整个蛋白质编码外显子的水平，而不是从单个基因开始。我们的设计基于对两个不显示FOXP2突变的家族的外体的检查，以及大量的支持文献，表明该基因中的突变在语音障碍中并不典型。大约有250万个标记将在家庭的所有成员中输入。使用250万个标记的脚手架和三人组的外显子数据，所有家庭成员都将估算外观信息。我们将使用这些信息来确认受影响和未受影响的个体中变体的隔离，并检查继承模式。这套技术将使我们能够识别出言语障碍的新基因。最终将这些新确定的变体用于早期诊断可能是可行的，并将亚型语音疾病分为更均匀的类别，这些类型的子集可以主动针对强化行为或其他治疗。公共卫生相关性：在美国，沟通障碍非常普遍，大约有4200万人（六分之一）报告某种类型的沟通障碍。其中最常见的三个是言语障碍（SSD），阅读障碍（RD）和语言障碍（LI），这些言论障碍（LI）具有很高的社会和个人成本。本应用程序中的研究将帮助我们（a）发现针对严重SSD的新颖基因座，（b）澄清子类型F SSD，以及（c）导致开发新的复杂疾病统计策略，以普遍适用于RD和Li和其他未解决的神经发育障碍。