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，并且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，通常在严重残疾的个体中被观察到为三巨头。语音障碍首先在儿童早期被诊断出来，并可能形成三级缺陷的基础，尽管这些合并症的确切生物学根源尚不清楚。患有最严重的语音障碍的人，无论有无其他合并症，都会持续到成年，在学术成就方面表现出最大的不足。求学期间的困难有效地影响了职业生涯的实现和维持，这些人往往有较高的失业率和较低的收入潜力。在之前的工作中，我们已经表明语音障碍具有遗传基础和家族聚集性，特别是在患有严重语音障碍的儿童中。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，然后对父母和受影响的孩子进行全外显子组测序，平均覆盖率为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语音障碍的生物学上有意义的变异。这种方法在未解决的隐性和显性孟德尔家族疾病，以及罕见疾病的散发病例中取得了惊人的成功。在医学遗传学中，翻译的第一步是找到临床可操作的变异，这些变异可以被验证，并发展成诊断工具。十年前，发现了一种高度渗透的，离散的基因变异

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.