Update on the Molecular Genetics of Timothy Syndrome.

Rosemary Bauer,Andy Golden,Katherine W Timothy

doi:10.3389/fped.2021.668546

Abstract

Timothy Syndrome (TS) (OMIM #601005) is a rare autosomal dominant syndrome caused by variants in CACNA1C, which encodes the α1C subunit of the voltage-gated calcium channel Cav1.2. 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 CACNA1C and differential expression of transcripts, and biophysical changes in mutant CACNA1C channels. Finally, we propose future research directions such as variant validation, in vivo modeling, and natural history characterization.

Highlights

Distinct Variants in the CACNA1C Gene Cause Timothy SyndromeTimothy Syndrome (TS) (OMIM #601005) is an ultra-rare, autosomal dominant syndrome that was independently recognized in three case reports in 1992 and 1995 [1,2,3] and given its name in 2004 when a mutation in the calcium channel gene CACNA1C (12p13.33) was revealed as the molecular cause [4]
We propose that cases previously designated cardiaconly TS” (COTS) be considered Atypical TS (ATS) to further differentiate them from non-syndromic Long QT Syndrome Type 8 (LQT8)
As one can see from the review of reported ATS variants, some are questionable as to whether they cause Timothy SyndromeTimothy Syndrome (TS)

Summary

Introduction

Timothy Syndrome (TS) (OMIM #601005) is an ultra-rare, autosomal dominant syndrome that was independently recognized in three case reports in 1992 and 1995 [1,2,3] and given its name in 2004 when a mutation in the calcium channel gene CACNA1C (12p13.33) was revealed as the molecular cause [4]. The molecular defect was first identified in 13 children with syndactyly of the fingers and/or toes, prolonged QT interval as detected by an ECG, and neurological characteristics similar to autism-spectrum disorders. Because this was the eighth LQT syndrome gene to be identified molecularly, it was called LQT8 [4]. The channel associates with an intracellular β subunit and an extracellular

Objectives

Findings

Conclusion