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.

中文翻译：

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CAMTA1相关疾病：26个新个体的表型和分子特征及文献综述

钙调蛋白结合转录激活因子 1 (CAMTA1) 在大脑中高表达，在细胞周期调节、细胞分化、长期记忆调节以及小脑神经元的初始发育、成熟和存活中发挥作用。人类神经表型的存在，包括与CAMTA1变异相关的伴有可变认知和行为异常的小脑功能障碍 (CECBA)，进一步支持了其在大脑功能中的作用。在这项研究中，我们从表型和分子上表征了最大的一组个体（n  = 26），具有 23 个新的CAMTA1变体（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) 并将研究结果与所有先前报告的病例进行比较（总数 = 53）。我们发现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、肌张力低下、行为问题和眼睛异常。此外，构音障碍、书写困难、小头畸形、胃肠道异常、睡眠困难和非特异性脑部MRI表现的发生率也很高；其中一些未得到充分报道。该队列中超过三分之一的变异是从无症状或轻度受影响的父母遗传的，表明外显率降低和表达性可变。我们的队列提供了 CECBA 个体表型和基因型谱的全面特征，大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。