Genetic causes of developmental speech sound disorder in families

描述(申请人提供)：沟通障碍在儿童中很常见，可能会持续到成年，并被认为会导致无处不在的终生残疾。三种沟通障碍，言语发音障碍、阅读障碍和语言障碍，在严重残疾的人中经常被观察到是三重障碍。语音障碍首先在儿童早期被诊断出来，很可能构成了三级缺陷的基石，尽管这些并存疾病的确切生物学根源尚不清楚。患有最严重形式的语音障碍的人会一直持续到成年，无论是否有其他合并症，在学习成绩方面都表现出最大的不足。求学期间的困难实际上影响了职业生涯的实现和维持，这些人往往具有更高的失业率和更低的收入潜力。在以前的工作中，我们已经证明了言语声音障碍有遗传基础，并在家庭中聚集，特别是在患有严重语言障碍的儿童中。使用我们的24年纵向数据数据库，我们建议寻找受影响的家庭，然后对父母和受影响的孩子进行完整的外显子组测序，平均覆盖&gt；50X。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具有生物学意义的变异。这种方法在未解决的隐性和显性孟德尔疾病中取得了惊人的成功，这些疾病在家族中传播，但在罕见疾病的零星病例中也是如此。在医学遗传学中，翻译的第一步是找到临床上可操作的变种，这些变种可以得到验证，并发展成诊断工具。十年前，鉴定出一种高渗透性、离散的遗传变异 在FOXP2中，单一家庭是言语和语言障碍领域的第一步。在我们目前的计划中，我们正在将搜索范围扩大到整个编码蛋白质的外显子组的水平，而不是从单个基因开始。我们的设计是基于对两个没有显示FOXP2突变的家族的外显子组的检查，以及大量的支持文献，表明该基因的突变在语音障碍中并不典型。将在这个家庭的所有成员中输入大约250万个标记。利用250万个标记和三人组的外显组数据，外显组信息将被赋予所有家庭成员。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异的分离，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。使用这些新发现的变异进行早期诊断，并将语音障碍分成更同质的类别，其中的子集可以主动作为强化行为或其他治疗的靶点，最终可能是可行的。

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.