CACNA1C-Related Disorders

Clinical characteristics: The first identified CACNA1C-related disorder, referred to as Timothy syndrome, consists of the combination of prolonged QT interval, autism, and cardiovascular malformation with syndactyly of the fingers and toes. Infrequent findings also include developmental and speech delay, seizures, and recurrent infections. With increased availability of molecular genetic testing, a wider spectrum of pathogenic variants and clinical findings associated with CACNA1C-related disorders has been recognized. Because CACNA1C is associated with calcium channel function, all individuals with a pathogenic variant in this gene are at risk for cardiac arrhythmia of a specific type. The clinical manifestations of a CACNA1C-related disorder include three phenotypes:

1. Timothy syndrome with or without syndactyly

2. QT prolongation (QTc >480 ms) and arrhythmias in the absence of other syndromic features

3. Short QT syndrome (QTc <350 ms) or Brugada syndrome with short QT interval

These three phenotypes can be separated into two broad categories on the basis of the functional consequences of the pathogenic variants in CACNA1C:

1. QT prolongation with or without a Timothy syndrome-associated phenotype associated with pathogenic variants inducing a gain of function at the cellular level (i.e., increased calcium current)

2. Short QT interval with or without Brugada syndrome EKG pattern associated with pathogenic variants causing loss of function (i.e., reduced calcium current)

Diagnosis/testing: The diagnosis of a CACNA1C-related disorder is established in a proband with suggestive findings and a heterozygous pathogenic variant in CACNA1C identified by molecular genetic testing.

Management: Treatment of manifestations: Treatment includes use of beta blockers and/or other antiarrhythmic drugs to maintain QT interval stability to prevent ventricular tachyarrhythmia. In some instances, pacemakers can be placed during the first days of life to control 2:1 atrioventricular block and resultant bradycardia, but an implantable cardioverter defibrillator to prevent sudden cardiac death should be considered in all affected persons. Standard care is recommended for cardiovascular malformations and extracardiac malformations such as syndactyly and hypoglycemia.

Prevention of primary manifestations: Arrhythmias must be prevented with the standard therapy. Because anesthesia is a known trigger for cardiac arrhythmia, close cardiac monitoring is warranted during surgery. Fever can be a trigger for arrhythmias in individuals with CACNA1C-related Brugada syndrome and requires aggressive treatment with standard antipyretic drugs.

Surveillance: Cardiac and neurologic evaluations every six to 12 months.

Agents/circumstances to avoid: Drugs reported to prolong QT interval; drugs and dietary practices that could lead to hypoglycemia.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of the older and younger at-risk relatives of a proband in order to identify as early as possible those who would benefit from a complete cardiac evaluation and institution of measures to prevent cardiac arrhythmias.

Genetic counseling: CACNA1C-related disorders are autosomal dominant disorders. Many individuals diagnosed with a CACNA1C-related disorder – particularly those individuals with Timothy syndrome – represent simplex cases (i.e., a single affected family member) and have the disorder as the result of a pathogenic variant that occurred de novo in the proband or in a mosaic parent. If a parent of the proband is affected and/or is known to be heterozygous for the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. If the proband has a known CACNA1C pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is greater than that of the general population because of the possibility of parental germline mosaicism. Once the CACNA1C pathogenic variant has been identified in an affected family member, prenatal testing and preimplantation genetic testing for a pregnancy at increased risk for a CACNA1C-related disorder are possible.