编辑推荐：
一个研究合作团队利用新一代测序技术，鉴定了与一种罕见的儿童语言障碍临床相关的遗传变异。这项研究成果发表在9月16号的Journal of Neurodevelopmental Disorders杂志上。
儿童言语失用症（Childhood apraxia of speech, CAS）是一种罕见的、严重的持续性言语运动障碍，在一些患者中甚至影响到认知、语言和学习的过程。第一个被认为与CAS有因果关联的变异是一种在FOXP2上的杂合错义突变，FOXP2基因是FOX家族成员之一，在胎儿和成人大脑中高表达，参与人类语言功能的发育。
在这项研究中，威斯康星医学院的儿科学（基因组儿科学和生物信息学）助理教授Elizabeth Worthey博士，与威斯康星大学麦迪逊分校卫斯曼中心的Lawrence Shriberg医生及其他们的同事一起，采用Illumina Genome Analyzer IIx测序系统进行的全外显子测序（whole-exome sequencing, WES）技术来寻找与CAS相关的遗传变异。
与之前其它复杂神经发育疾病的外显子测序研究报道一样，这项研究是对这种具有多基因、通路和复杂关联的儿童语言障碍的异质性遗传起因的一个有力支持。研究也表明，外显子测序在儿童语言障碍疾病中的基因鉴定和个例临床诊断中具有潜在的应用价值。
早前的研究已经鉴定了几个与CAS相关的基因，在这项研究中，研究者测定了十个随机选择的儿童患者的序列，其中在八位被测者中鉴别出了临床上与CAS显著相关的变异。在一些病例中，发现患者在超过一个以上的基因中携带具有显然有害的变异。这项发现既证实了以前有关候选的关联基因的报道，也鉴定了新型的候选关联基因。
“这项研究用实例证明了全外显子测序对于诸如CAS这样复杂的神经发育障碍的研究潜力。检测个人基因的现行市场价远远超过了全外显子的价格，另一方面相比每次只研究一个基因，同时进行这些检测更具有时效性”Worthey医生说，“大部分具有复杂表型的患者很可能将会在多个基因被发现带有有害变异，单个基因检测将不可能鉴定这些病例。”
因此，对于表型明显的儿童言语运动障碍被测患者，下一代测序技术对于发现疾病基因变异和临床应用，很可能都会是一种节约成本和时间的方法。
生物通推荐原文摘要：Whole-exome sequencing supports genetic heterogeneity in childhood apraxia of speech
Background
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.
Methods
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.
Results
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.
Conclusions
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.
