Division of Pediatric Cardiology, University of Utah, Salt Lake City, Utah, USA.
Genome Medical, San Francisco, California, USA.
Mol Genet Genomic Med. 2021 Jun;9(6):e1673. doi: 10.1002/mgg3.1673. Epub 2021 Apr 1.
Pathogenic variants in the L-type Ca channel gene CACNA1C cause a multi-system disorder that includes severe long QT syndrome (LQTS), congenital heart disease, dysmorphic facial features, syndactyly, abnormal immune function, and neuropsychiatric disorders, collectively known as Timothy syndrome. In 2015, a variant in CACNA1C (p.R518C) was reported to cause cardiac-only Timothy syndrome, a genetic disorder with a mixed phenotype of congenital heart disease, hypertrophic cardiomyopathy (HCM), and LQTS that lacked extra-cardiac features. We have identified a family harboring the p.R518C pathogenic variant with a wider spectrum of clinical manifestations.
A four-generation family harboring the p.R518C pathogenic variant was reviewed in detail. The proband and his paternal great-uncle underwent comprehensive cardiac gene panel testing, and his remaining family members underwent cascade testing for the p.R518C pathogenic variant.
In addition to displaying cardinal features of CACNA1C disorders including LQTS, congenital heart disease, HCM, and sudden cardiac death, family members manifested atrial fibrillation and sick sinus syndrome.
Our report expands the cardiac phenotype of CACNA1C variants and reflects the variable expressivity of mutations in the L-type Ca channel.
L 型钙通道基因 CACNA1C 的致病变体导致多系统疾病，包括严重的长 QT 综合征（LQTS）、先天性心脏病、面部畸形、并指畸形、免疫功能异常和神经精神障碍，统称为 Timothy 综合征。2015 年，报道了 CACNA1C（p.R518C）变体导致仅心脏 Timothy 综合征，这是一种具有先天性心脏病、肥厚型心肌病（HCM）和 LQTS 混合表型的遗传疾病，缺乏心脏外特征。我们已经确定了一个携带 p.R518C 致病变体的家族，其临床表现范围更广。
详细回顾了一个携带 p.R518C 致病变体的四代家族。先证者和他的叔祖父接受了全面的心脏基因 panel 检测，其余家庭成员接受了 p.R518C 致病变体的级联检测。
除了显示 CACNA1C 疾病的主要特征，包括 LQTS、先天性心脏病、HCM 和心源性猝死外，家族成员还表现出心房颤动和病态窦房结综合征。
我们的报告扩展了 CACNA1C 变体的心脏表型，并反映了 L 型钙通道突变的可变表达性。
