钙调蛋白结合转录激活因子1(CAMTA1)在脑中高表达,在细胞周期调控中起作用。细胞分化,调节长期记忆,和初步发展,成熟,和小脑神经元的存活。人类神经表型的存在,包括小脑功能障碍与可变的认知和行为异常(CECBA),与CAMTA1变体相关,进一步支持了它在大脑功能中的作用。在这项研究中,我们在表型和分子鉴定了具有23种新CAMTA1变异体(移码-7,无义-6,剪接-1,起始密码子-1,错义-5和基因内缺失-3)的最大个体队列(n=26),并将这些发现与以前报道的所有病例(共53例)进行了比较.我们表明,最显着的表型发现是发育迟缓/智力障碍,步态不稳定或不协调,低张力,行为问题,和眼睛异常。此外,构音障碍的发病率很高,书写困难症,小头畸形,胃肠道异常,睡眠困难,和非特异性脑MRI发现;其中一些报道不足。该队列中超过三分之一的变体是从无症状或轻度受影响的父母遗传的,这表明外显率和表达能力降低。我们的队列提供了CECBA个体中表型和基因型谱的全面表征,大量数据将有助于为这些个体提供咨询和制定管理计划和监测建议。
Calmodulin-binding transcriptional activator 1 (CAMTA1) is highly expressed in the brain and plays a role in cell cycle regulation, cell differentiation, regulation of long-term memory, and initial development, maturation, and survival of cerebellar neurons. The existence of human neurological phenotypes, including cerebellar dysfunction with variable cognitive and behavioral abnormalities (CECBA), associated with CAMTA1 variants, has further supported its role in brain functions. In this study, we phenotypically and molecularly characterize the largest cohort of individuals (n = 26) with 23 novel CAMTA1 variants (frameshift-7, nonsense-6, splicing-1, initiation codon-1, missense-5, and intragenic deletions-3) and compare the findings with all previously reported cases (total = 53). We show that the most notable phenotypic findings are developmental delay/intellectual disability, unsteady or uncoordinated gait,
hypotonia, behavioral problems, and eye abnormalities. In addition, there is a high incidence of dysarthria, dysgraphia, microcephaly, gastrointestinal abnormalities, sleep difficulties, and nonspecific brain MRI findings; a few of which have been under-reported. More than one third of the variants in this cohort were inherited from an asymptomatic or mildly affected parent suggesting reduced penetrance and variable expressivity. Our cohort provides a comprehensive characterization of the spectrum of phenotypes and genotypes among individuals with CECBA and the large data will facilitate counseling and formulating management plans and surveillance recommendations for these individuals.