Waisman Center, University of Wisconsin-Madison, 1500 Highland Avenue, Madison, WI, 53705, USA.
J Neurodev Disord. 2013 Oct 2;5(1):29. doi: 10.1186/1866-1955-5-29.
Childhood apraxia of speech (CAS) is a rare, severe, persistent pediatric motor speech disorder with associated deficits in sensorimotor, cognitive, language, learning and affective processes. Among other neurogenetic origins, CAS is the disorder segregating with a mutation in FOXP2 in a widely studied, multigenerational London family. We report the first whole-exome sequencing (WES) findings from a cohort of 10 unrelated participants, ages 3 to 19 years, with well-characterized CAS.
As part of a larger study of children and youth with motor speech sound disorders, 32 participants were classified as positive for CAS on the basis of a behavioral classification marker using auditory-perceptual and acoustic methods that quantify the competence, precision and stability of a speaker's speech, prosody and voice. WES of 10 randomly selected participants was completed using the Illumina Genome Analyzer IIx Sequencing System. Image analysis, base calling, demultiplexing, read mapping, and variant calling were performed using Illumina software. Software developed in-house was used for variant annotation, prioritization and interpretation to identify those variants likely to be deleterious to neurodevelopmental substrates of speech-language development.
Among potentially deleterious variants, clinically reportable findings of interest occurred on a total of five chromosomes (Chr3, Chr6, Chr7, Chr9 and Chr17), which included six genes either strongly associated with CAS (FOXP1 and CNTNAP2) or associated with disorders with phenotypes overlapping CAS (ATP13A4, CNTNAP1, KIAA0319 and SETX). A total of 8 (80%) of the 10 participants had clinically reportable variants in one or two of the six genes, with variants in ATP13A4, KIAA0319 and CNTNAP2 being the most prevalent.
Similar to the results reported in emerging WES studies of other complex neurodevelopmental disorders, our findings from this first WES study of CAS are interpreted as support for heterogeneous genetic origins of this pediatric motor speech disorder with multiple genes, pathways and complex interactions. We also submit that our findings illustrate the potential use of WES for both gene identification and case-by-case clinical diagnostics in pediatric motor speech disorders.
儿童言语运动障碍（CAS）是一种罕见的、严重的、持续的儿科运动言语障碍，伴有感觉运动、认知、语言、学习和情感过程的缺陷。在其他神经遗传起源中，CAS 是在一个广泛研究的、多代伦敦家族中与 FOXP2 突变分离的疾病。我们报告了来自一个有 10 名年龄在 3 至 19 岁之间、具有明确 CAS 特征的非相关参与者队列的首次全外显子组测序（WES）结果。
作为儿童和青少年运动言语障碍的更大研究的一部分，根据听觉感知和声学方法对 32 名参与者进行了行为分类标记，这些方法可量化说话者言语、韵律和声音的能力、精度和稳定性。使用 Illumina Genome Analyzer IIx 测序系统对 10 名随机选择的参与者进行 WES。使用 Illumina 软件进行图像分析、碱基调用、多路分解、读取映射和变异调用。使用内部开发的软件对变体进行注释、优先级排序和解释，以确定那些可能对言语语言发展的神经发育基质有害的变体。
在潜在的有害变体中，总共在 5 条染色体（Chr3、Chr6、Chr7、Chr9 和 Chr17）上出现了具有临床报告意义的发现，其中包括与 CAS 强烈相关的 6 个基因（FOXP1 和 CNTNAP2）或与具有与 CAS 重叠表型的疾病相关的基因（ATP13A4、CNTNAP1、KIAA0319 和 SETX）。总共 10 名参与者中有 8 名（80%）在这 6 个基因中的一个或两个基因中具有临床报告意义的变体，其中 ATP13A4、KIAA0319 和 CNTNAP2 的变体最为普遍。
与其他复杂神经发育障碍的新兴 WES 研究报告的结果类似，我们对 CAS 的首次 WES 研究的发现被解释为支持这种儿科运动言语障碍的多种基因、途径和复杂相互作用的异质性遗传起源的支持。我们还提出，我们的发现说明了 WES 用于儿科运动言语障碍的基因鉴定和逐个病例临床诊断的潜力。
