We identified a de novo 44.7 Kb interstitial 12p13.33 micro-deletion that involves solely the first exon of the CACNA1C (MIM 114205), using microarray-based comparative genomic hybridization (aCGH). The associated main phenotype is characterized by expressive language impairment, tremors, fine motor-skills delay, muscular hypotonia, and joint laxity. A careful comparison between the clinical and genomic characteristics between our proband and 20 previously reported patients, led us to propose CACNA1C haploinsufficiency as the main cause of both expressive language delay and motor-skills impairment. Pathogenic variants of CACNA1C have been associated to a plethora of clinical phenotypes, such as Timothy syndrome (TS, OMIM 601005), Brugada syndrome (BRGDA3, OMIM 611875) and a variety of neuropsychiatric disorders (bipolar disorder, major depression, schizophrenia, autism spectrum disorder, psychotic manifestations). In this report we describe a 12p13.33 micro-deletion involving one coding gene only, in contrast with previous studies that mostly concluded that a multi-genes deletion in the 12p13.33 sub-telomeric region is responsible of the minimum clinical phenotype of patients with 12p13.33 monosomy. Certainly, larger deletions spanning multiple Mb in 12p13.33 are responsible for more severe phenotypes, associated to a variable degree of dysmorphic features.

我们使用基于微阵列的比较基因组杂交（aCGH），确定了仅涉及CACNA1C（MIM 114205）的第一个外显子的从头开始的44.7 Kb间隙微缺失。相关的主要表型的特征是表达性语言障碍，震颤，精细的运动技能延迟，肌张力低下和关节松弛。在先证者和20位先前报告的患者之间的临床和基因组特征之间进行仔细比较，使我们提出CACNA1C单倍体功能不足是表达语言延迟和运动技能受损的主要原因。CACNA1C的致病变异与多种临床表型有关，例如蒂莫西综合征（TS，OMIM 601005），布鲁格达综合征（BRGDA3，OMIM 611875）和各种神经精神疾病（双相情感障碍，重度抑郁症，精神分裂症，自闭症谱系障碍，精神病表现） ）。在本报告中，我们描述了仅涉及一个编码基因的12p13.33微缺失，与先前的研究相反，该研究大多得出结论，即12p13.33亚端粒区域中的多基因缺失是造成患者最低临床表型的原因与12p13.33 monosomy。当然，跨越12p13.33中多个Mb的较大缺失会导致更严重的表型，这与可变程度的畸形特征相关。