AUTHOR=Bauer Rosemary , Timothy Katherine W. , Golden Andy 

TITLE=Update on the Molecular Genetics of Timothy Syndrome

JOURNAL=Frontiers in Pediatrics

VOLUME=9

YEAR=2021

URL=https://www.frontiersin.org/journals/pediatrics/articles/10.3389/fped.2021.668546

DOI=10.3389/fped.2021.668546

ISSN=2296-2360

ABSTRACT=<p>Timothy Syndrome (TS) (OMIM #<ext-link ext-link-type="Omim" xlink:href="601005" xmlns:xlink="http://www.w3.org/1999/xlink">601005</ext-link>) is a rare autosomal dominant syndrome caused by variants in <italic>CACNA1C</italic>, which encodes the α1C subunit of the voltage-gated calcium channel Ca<sub>v</sub>1.2. 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 <italic>CACNA1C</italic> and differential expression of transcripts, and biophysical changes in mutant CACNA1C channels. Finally, we propose future research directions such as variant validation, <italic>in vivo</italic> modeling, and natural history characterization.</p>