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：
8554297
负责人：
SUDHA K IYENGAR
金额：
$ 61.7万
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/8554297
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 exome sequencing 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.

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的终身残疾。三种沟通障碍，即语音障碍、阅读障碍和语言障碍，通常在严重残疾的个体中被视为三巨头。言语障碍首先在儿童早期被诊断出来，并且可能构成三级缺陷的基石，尽管这些合并症的确切生物学根源尚不清楚。患有最严重的言语声音障碍并持续到成年的个体，无论有或没有其他合并症，在学业成绩方面表现出最大的差距。学业期间的困难有效地影响了职业生涯的实现和维持，这些人往往失业率较高，收入潜力较低。在之前的工作中，我们已经证明言语障碍具有遗传基础并在家庭中聚集，特别是在患有严重障碍的儿童中。利用我们的 24 年纵向数据数据库，我们建议找到受影响的家庭，然后对两位父母和受影响的儿童进行全外显子组测序，平均覆盖率 > 50 倍。我们将使用最先进的统计和生物信息学方法来寻找导致言语障碍的具有生物学意义的变异。这种方法对于未解决的家族遗传性隐性和显性孟德尔疾病以及罕见疾病的散发病例取得了巨大成功。在医学遗传学中，转化的第一步是找到可以验证的临床上可行的变异，并将其开发为诊断工具。十年前，鉴定出一种高渗透性、离散的遗传变异 FOXP2 在单一家庭中的研究是言语和语言障碍领域的第一步。在我们当前的计划中，我们将搜索邻域扩展到整个蛋白质编码外显子组的水平，而不是从单个基因开始。我们的设计基于对两个未显示 FOXP2 突变的家族的外显子组的检查，以及大量支持文献表明该基因的突变在言语声音障碍中并不典型。大约 250 万个标记将在所有家庭成员中被输入。使用 250 万个标记的支架和来自三人组的外显子组数据，外显子组信息将被推算到所有家庭成员中。我们将利用这些信息来确认受影响和未受影响个体中变异的分离，并检查遗传模式。这套技术将使我们能够识别言语障碍的新基因。最终可能可以使用这些新发现的变异进行早期诊断，并将言语声音障碍分为更同质的类别，其中的子集可以主动针对强化行为或其他治疗。