Mio Catia, Passon Nadia, Baldan Federica, Bregant Elisa, Monaco Elisabetta, Mancini Loretta, Demori Eliana, Damante Giuseppe
Department of Medicine (DAME), University of Udine, 33100, Udine, Italy.
Institute of Medical Genetics, ASUIUD University Hospital of Udine, 33100, Udine, Italy.
Eur J Med Genet. 2020 Apr;63(4):103843. doi: 10.1016/j.ejmg.2020.103843. Epub 2020 Jan 14.
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.
我们通过基于微阵列的比较基因组杂交技术（aCGH），鉴定出一个新生的44.7Kb的12p13.33间质性微缺失，该缺失仅涉及CACNA1C（MIM 114205）的第一个外显子。相关的主要表型特征为表达性语言障碍、震颤、精细运动技能延迟、肌张力减退和关节松弛。对我们的先证者与之前报道的20例患者的临床和基因组特征进行仔细比较后，我们提出CACNA1C单倍体不足是表达性语言延迟和运动技能损害的主要原因。CACNA1C的致病变异与多种临床表型相关，如 Timothy 综合征（TS，OMIM 601005）、Brugada 综合征（BRGDA3，OMIM 611875）以及各种神经精神疾病（双相情感障碍、重度抑郁症、精神分裂症、自闭症谱系障碍、精神病性表现）。在本报告中，我们描述了一个仅涉及一个编码基因的12p13.33微缺失，这与之前的研究形成对比，之前的研究大多得出结论，12p13.33亚端粒区域的多基因缺失是12p13.33单体患者最小临床表型的原因。当然，12p13.33中跨越多个兆碱基的更大缺失会导致更严重的表型，并伴有不同程度的畸形特征。
