Clinical Guidance
The first CACNA1C-related disorder was referred to as Timothy syndrome , a condition with very high mortality with only a few individuals who reached reproductive age. Timothy syndrome consisted of the combination of prolonged QT interval, autism, and congenital heart defect with syndactyly of the fingers and toes; all these individuals had the same pathogenic variant, while a similar phenotype but without syndactyly was subsequently identified in association with comparable but distinct pathogenic variants . With the increased availability of molecular genetic testing, a wider spectrum of pathogenic variants and clinical findings associated with CACNA1C-related disorders have been recognized. Because CACNA1C is expressed at high levels both in the heart and in the central nervous system, pathogenic variants in CACNA1C can be associated with cardiac and/or neurologic manifestations. Review of the literature specifically focusing on the neurologic involvement in individuals with pathogenic variants in CACNA1C showed that intellectual disability is the most frequent phenotype (89%), followed by hypotonia (55.5%) ataxia (52%), seizures (37.9%), and autism (29%). Therefore, the clinical manifestations include a spectrum of nonsyndromic and syndromic phenotypes, which generally correlate with the impact of the pathogenic variant on calcium current (see and ): • Classic Timothy syndrome (prolonged QT interval, autism, and congenital heart defect) with or without syndactyly • CACNA1C-related neurodevelopmental disorder, in which the features tend to favor one or more of the following: developmental delay/ intellectual disability, hypotonia, epilepsy, and/or ataxia Note: For this phenotype, gain-of-function, neutral effect, and loss-of-function pathogenic variants have all been reported in affected individuals . • Nonsyndromic long QT syndrome (rate-corrected QT [QTc] interval 480 ms) • Short QT syndrome (QTc 350 ms), with risk of sudden death • Brugada syndrome (ST segment elevation in right precordial leads [V1-V2]) with short QT interval The clinical phenotype associated with large deletions/duplications is less defined, as few individuals with this phenotype have been reported . Table 2. CACNA1C-Related Disorders: Frequency of Select Features by Type of Pathogenic Variant
Variant Type | Feature | Frequency |
|---|
Nearly all | Common | Infrequent Gain-of- function pathogenic |
variants | Cardiac | QTc prolongation |
Cardiovascular malformations | Neurologic | Seizures |
Other | Typical craniofacial features | Cutaneous syndactyly |
variants1 | Cardiac | Short QT syndrome |
Sudden death | Neurologic |
Source: GeneReviews — "CACNA1C-Related Disorders"
