CACNA1C – Timothy syndrome

Timothy syndrome is a rare autosomal dominant multisystem disorder caused by gain-of-function mutations in the L-type calcium channel gene CACNA1C. Clinically, it presents with markedly prolonged QT interval, syndactyly, facial dysmorphism, seizures, immunodeficiency, neurodevelopmental delay and other systemic features (MONDO:0010979).

Genetic evidence supporting a definitive association includes over 40 unrelated probands harboring de novo heterozygous missense variants, notably recurrent p.Gly406Arg and p.Gly402Ser in exon 8/8A of CACNA1C (PMID:22106044, PMID:28371864). Additional familial mosaicism cases confirm autosomal dominant transmission with variable expressivity (PMID:23580742).

The variant spectrum centers on substitutions in transmembrane segments DIIS6 and DIVS6. Key mutations include c.1216G>A (p.Gly406Arg) and c.1204G>A (p.Gly402Ser), with emerging alleles such as c.4097_4101del (p.Leu1366fs) and c.1235G>T (p.Arg412Met). These cluster in regions critical for channel gating and inactivation.

Functional studies consistently demonstrate a gain-of-function mechanism: delayed voltage-dependent inactivation, increased late or window current, and negative shifts in activation. For instance, p.Gly406Arg channels exhibit slowed inactivation and persistent inward current ([PMID:23580742]), while p.Ile1166Thr increases window current and prolongs action potential duration in cellular models ([PMID:25260352]). An atypical p.Arg412Met variant similarly delays inactivation in patch-clamp assays ([PMID:36347939]).

No robust conflicting evidence has emerged; the phenotypic and molecular concordance across independent studies underpins a definitive gene–disease relationship. Exon usage (8 vs 8A) defines subtypes but does not alter the core gain-of-function pathogenic mechanism.

Given the weight of genetic and experimental data, CACNA1C is definitively implicated in Timothy syndrome. Genetic testing for CACNA1C exon 8/8A variants is essential for diagnosis and management of patients presenting with long QT and syndactyly. Key take-home: CACNA1C gain-of-function mutations are clinically diagnostically actionable in Timothy syndrome.

References

• American journal of medical genetics. Part A • 2012 • Long QT, syndactyly, joint contractures, stroke and novel CACNA1C mutation: expanding the spectrum of Timothy syndrome. PMID:22106044
• Circulation. Arrhythmia and electrophysiology • 2013 • Inhibition of late sodium current by mexiletine: a novel pharmotherapeutical approach in timothy syndrome. PMID:23580742
• PLoS one • 2014 • A CACNA1C variant associated with reduced voltage-dependent inactivation, increased CaV1.2 channel window current, and arrhythmogenesis. PMID:25184293
• Heart rhythm • 2015 • Novel Timothy syndrome mutation leading to increase in CACNA1C window current. PMID:25260352
• Scientific reports • 2022 • Increased CaV1.2 late current by a CACNA1C p.R412M variant causes an atypical Timothy syndrome without syndactyly. PMID:36347939
• Europace • 2018 • A multicentre study of patients with Timothy syndrome. PMID:28371864

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