Genetic Candidate Variants in Two Multigenerational Families with Childhood Apraxia of Speech

Childhood apraxia of speech (CAS) is a severe and socially debilitating form of speech sound disorder with suspected genetic involvement, but the genetic etiology is not yet well understood. Very few known or putative causal genes have been identified to date, e.g., FOXP2 and BCL11A. Building a knowledge base of the genetic etiology of CAS will make it possible to identify infants at genetic risk and motivate the development of effective very early intervention programs. We investigated the genetic etiology of CAS in two large multigenerational families with familial CAS. Complementary genomic methods included Markov chain Monte Carlo linkage analysis, copy-number analysis, identity-by-descent sharing, and exome sequencing with variant filtering. No overlaps in regions with positive evidence of linkage between the two families were found. In one family, linkage analysis detected two chromosomal regions of interest, 5p15.1-p14.1, and 17p13.1-q11.1, inherited separately from the two founders. Single-point linkage analysis of selected variants identified CDH18 as a primary gene of interest and additionally, MYO10, NIPBL, GLP2R, NCOR1, FLCN, SMCR8, NEK8, and ANKRD12, possibly with additive effects. Linkage analysis in the second family detected five regions with LOD scores approaching the highest values possible in the family. A gene of interest was C4orf21 (ZGRF1) on 4q25-q28.2. Evidence for previously described causal copy-number variations and validated or suspected genes was not found. Results are consistent with a heterogeneous CAS etiology, as is expected in many neurogenic disorders. Future studies will investigate genome variants in these and other families with CAS.儿童言语失用症（Childhood apraxia of speech, CAS）是一种严重且会对社交功能造成障碍的语音障碍，疑似与遗传因素相关，但目前其遗传病因学尚未被充分阐明。截至目前，仅发现极少数已被证实或推定的致病基因，例如叉头框P2（FOXP2）与B细胞淋巴瘤/白血病11A（BCL11A）。构建CAS遗传病因学知识库，将能够精准识别携带遗传风险的婴幼儿，并推动高效极早期干预方案的研发。本研究对两个携带家族性CAS的大型多代家系开展了CAS遗传病因学分析，采用的互补基因组学方法包括马尔可夫链蒙特卡洛连锁分析（Markov chain Monte Carlo linkage analysis）、拷贝数分析（copy-number analysis）、血缘同一性共享分析（identity-by-descent sharing），以及带变异过滤的外显子组测序（exome sequencing with variant filtering）。两个家系的阳性连锁区域未发现重叠。在其中一个家系中，连锁分析检测到两个感兴趣的染色体区域：5p15.1-p14.1与17p13.1-q11.1，分别由该家系的两名创始者独立遗传。针对筛选出的变异开展单点连锁分析，鉴定出钙黏蛋白18（CDH18）作为核心候选基因，此外还包括肌球蛋白10（MYO10）、黏连蛋白加载因子NIPBL（NIPBL）、胰高血糖素样肽2受体（GLP2R）、核受体辅抑制因子1（NCOR1）、滤泡素（FLCN）、Smith-Magenis综合征染色体区域8蛋白（SMCR8）、有丝分裂激酶NEK8（NEK8）以及锚蛋白重复域12（ANKRD12），上述基因可能存在加性效应。对第二个家系开展的连锁分析检测到五个染色体区域，其对数似然比分数（LOD scores）接近该家系可达到的最高值。该家系的候选基因为4号染色体开放阅读框21（ZGRF1，C4orf21），位于4q25-q28.2区域。本研究未发现此前报道的致病性拷贝数变异，以及已验证或推定致病基因的相关证据。研究结果支持CAS病因具有异质性，这与多数神经源性疾病的特征相符。未来的研究将对上述家系及其他CAS家系中的基因组变异展开进一步探究。