Bauer Rosemary, Timothy Katherine W, Golden Andy
Laboratory of Biochemistry and Genetics, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States.
Timothy Syndrome Alliance, Gloucestershire, United Kingdom.
Front Pediatr. 2021 May 17;9:668546. doi: 10.3389/fped.2021.668546. eCollection 2021.
Timothy Syndrome (TS) (OMIM #601005) is a rare autosomal dominant syndrome caused by variants in , which encodes the α1C subunit of the voltage-gated calcium channel Ca1.2. TS is classically caused by only a few different genetic changes and characterized by prolonged QT interval, syndactyly, and neurodevelopmental delay; however, the number of identified TS-causing variants is growing, and the resulting symptom profiles are incredibly complex and variable. Here, we aim to review the genetic and clinical findings of all published case reports of TS to date. We discuss multiple possible mechanisms for the variability seen in clinical features across these cases, including mosaicism, genetic background, isoform complexity of and differential expression of transcripts, and biophysical changes in mutant CACNA1C channels. Finally, we propose future research directions such as variant validation, modeling, and natural history characterization.
蒂莫西综合征（TS）（OMIM #601005）是一种罕见的常染色体显性综合征，由编码电压门控钙通道Ca1.2的α1C亚基的 中的变异引起。经典的TS仅由少数几种不同的基因变化引起，其特征为QT间期延长、并指畸形和神经发育迟缓；然而，已鉴定的导致TS的变异数量正在增加，其产生的症状表现极其复杂且多变。在此，我们旨在回顾迄今为止所有已发表的TS病例报告的遗传学和临床研究结果。我们讨论了这些病例临床特征中所见变异性的多种可能机制，包括嵌合体、遗传背景、 的异构体复杂性和转录本的差异表达，以及突变型CACNA1C通道的生物物理变化。最后，我们提出了未来的研究方向，如变异验证、 建模和自然病史特征描述。
