Genetic causes of developmental speech sound disorder in families

描述（由申请人提供）：沟通障碍在儿童中很常见，可能持续到成年，并被认为是导致普遍和终身残疾的原因。三种沟通障碍，语音障碍，阅读障碍和语言障碍，经常被观察到作为一个严重残疾的个人三巨头。言语声音障碍首先在儿童早期被诊断出来，并且可能形成三水平缺陷的基石，尽管这些合并症的确切生物学根源尚不清楚。患有最严重形式的言语声音障碍并持续到成年的个体，无论是否有其他合并症，在学术成就方面表现出最大的不足。在校期间的困难实际上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。在以前的工作中，我们已经表明，语音障碍具有遗传基础和家族聚集性，特别是在患有严重形式的疾病的儿童中。使用我们的24年纵向数据库，我们建议在平均覆盖率>50X的情况下，通过对双亲和受影响儿童的全外显子组测序来寻找受影响的家庭。我们将使用最先进的统计和生物信息学方法来寻找导致语音障碍的生物学上有意义的变体。这种方法在家族遗传的隐性和显性孟德尔遗传病以及罕见病的散发病例中非常成功。在医学遗传学中，翻译的第一步是找到可以验证的临床可行的变体，并开发成诊断工具。十年前，一种高度渗透的离散遗传变异的鉴定 FOXP2基因在一个家族中的发现是语言障碍领域的第一步。在我们目前的计划中，我们正在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。我们的设计是基于对两个家族的外显子组的检查，这两个家族没有显示FOXP2的突变，以及大量的支持文献，这些文献表明该基因的突变在言语声音障碍中并不典型。大约250万个标记将在家庭的所有成员中进行分型。使用250万个标记的支架和来自三人组的外显子组数据，将外显子组信息插补到所有家族成员中。我们将使用这些信息来确认受影响和未受影响个体的变异分离，并检查遗传模式。这套技术将使我们能够识别语音障碍的新基因。它可能最终是可行的，使用这些新发现的变体进行早期诊断，并将言语声音障碍亚类到更同质的类别，其中的子集可以主动针对强化行为或其他治疗。

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.