Speech and language disorders are known to have a substantial genetic contribution. Although frequently examined as components of other conditions, research on the genetic basis of linguistic differences as separate phenotypic subgroups has been limited so far. Here, we performed an in-depth characterization of speech and language disorders in 52 143 individuals, reconstructing clinical histories using a large-scale data-mining approach of the electronic medical records from an entire large paediatric healthcare network. The reported frequency of these disorders was the highest between 2 and 5 years old and spanned a spectrum of 26 broad speech and language diagnoses. We used natural language processing to assess the degree to which clinical diagnoses in full-text notes were reflected in ICD-10 diagnosis codes. We found that aphasia and speech apraxia could be retrieved easily through ICD-10 diagnosis codes, whereas stuttering as a speech phenotype was coded in only 12% of individuals through appropriate ICD-10 codes. We found significant comorbidity of speech and language disorders in neurodevelopmental conditions (30.31%) and, to a lesser degree, with epilepsies (6.07%) and movement disorders (2.05%). The most common genetic disorders retrievable in our analysis of electronic medical records were STXBP1 (n = 21), PTEN (n = 20) and CACNA1A (n = 18). When assessing associations of genetic diagnoses with specific linguistic phenotypes, we observed associations of STXBP1 and aphasia (P = 8.57 × 10-7, 95% confidence interval = 18.62-130.39) and MYO7A with speech and language development delay attributable to hearing loss (P = 1.24 × 10-5, 95% confidence interval = 17.46-infinity). Finally, in a sub-cohort of 726 individuals with whole-exome sequencing data, we identified an enrichment of rare variants in neuronal receptor pathways, in addition to associations of UQCRC1 and KIF17 with expressive aphasia, MROH8 and BCHE with poor speech, and USP37, SLC22A9 and UMODL1 with aphasia. In summary, our study outlines the landscape of paediatric speech and language disorders, confirming the phenotypic complexity of linguistic traits and novel genotype-phenotype associations. Subgroups of paediatric speech and language disorders differ significantly with respect to the composition of monogenic aetiologies.

中文翻译：

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儿科言语和语言障碍的临床和遗传谱。


众所周知，言语和语言障碍具有很大的遗传贡献。尽管经常作为其他条件的组成部分进行检查，但迄今为止，关于语言差异作为单独表型亚群的遗传基础的研究一直有限。在这里，我们对 52 143 人的言语和语言障碍进行了深入表征，使用来自整个大型儿科医疗保健网络的电子病历的大规模数据挖掘方法重建临床病史。这些疾病的报道频率在 2 至 5 岁之间最高，涵盖 26 种广泛的言语和语言诊断。我们使用自然语言处理来评估全文笔记中的临床诊断在 ICD-10 诊断代码中的反映程度。我们发现失语症和言语失用症可以通过 ICD-10 诊断代码轻松检索，而口吃作为一种言语表型的个体只有 12% 通过适当的 ICD-10 代码进行编码。我们发现神经发育疾病 （30.31%） 存在言语和语言障碍的显著共病，在较小程度上，与癫痫 （6.07%） 和运动障碍 （2.05%） 存在显著的共病。在我们对电子病历的分析中，可检索到的最常见的遗传疾病是 STXBP1 （n = 21） 、PTEN （n = 20） 和 CACNA1A （n = 18）。在评估遗传诊断与特定语言表型的关联时，我们观察到 STXBP1 和失语症 （P = 8.57 × 10-7,95% 置信区间 = 18.62-130.39） 和 MYO7A 与听力损失引起的言语和语言发育延迟的关联 （P = 1.24 × 10-5,95% 置信区间 = 17.46-无穷大）。 最后，在具有全外显子组测序数据的 726 个个体的亚队列中，除了 UQCRC1 和 KIF17 与表达性失语症、MROH8 和 BCHE 与言语障碍以及 USP37、SLC22A9 和 UMODL1 与失语症的关联外，我们还确定了神经元受体通路中罕见变异的丰富。总之，我们的研究概述了儿科言语和语言障碍的前景，证实了语言特征的表型复杂性和新的基因型-表型关联。儿科言语和语言障碍的亚组在单基因病因的组成方面存在显著差异。