Timothy Syndrome and Brugada Syndrome via the CACNA1C Gene

Timothy syndrome is characterized by physical malformations, neurological and developmental defects, including syndactyly, heart QT-prolongation and arrhythmias, developmental delay and autism spectrum disorders. Timothy syndrome is also called Long QT syndrome with syndactyly or long QT syndrome (LQT8) (Krause et al. 2011). Two forms of Timothy syndrome have been described: the classic type (type 1) and a second form caused by mutations in an alternatively spliced form (type 2). Type 1 includes all of the characteristic features described above. Type 2, or the atypical type, causes a more severe form of long QT syndrome and a greater risk of arrhythmia and sudden death. Unlike the classic type, the atypical type does not appear to cause webbing of the fingers or toes.

Brugada syndrome (BrS) is a potentially life-threating rhythm disorder characterized by ST segment elevation on ECG. Other findings may include right bundle branch block, first degree AV block, and intraventricular conduction delay. Brugada syndrome is treatable with preventive measures such as reducing fever, avoiding certain medications and using implantable cardiac defibrillator (Francis and Antzelevitch 2005).

CACNA1C-related Timothy and Brugada syndrome are inherited in an autosomal dominant manner. The majority of causative mutations in CACNA1C are missense mutations. CACNA1C encodes the Alpha-1C subunit of the cardiac L-type calcium channel which is important for excitation and contraction of the heart. Mutations in CACNA1C are responsible for all reported cases of Timothy syndrome. Most cases of Timothy syndrome are not inherited from an affected parent, but occur for the first time in a family due to a spontaneous de novo change in the CACNA1C gene (Splawski et al. 2005). Mutations in at least 7 genes (CACNA1C, CACNB2, GPD1L, KCNE3, SCN1B, SCN3B and SCN5A) influencing sodium and calcium currents in the heart are associated with BrS and account for at least 26%-41% of cases of Brugada syndrome. Most patients with Brugada syndrome have inherited a disease-causing mutation from a parent as de novo mutations in BrS are rare (Hedley et al. 2009).

Sequencing analysis should yield positive results for nearly 100% of individuals with Timothy syndrome type 1 (Splawski et al 2004). The detection rates for Timothy syndrome type 2 and Brugada syndrome via CACNA1C cannot be estimated because only a small number of patients have been reported. Analytical sensitivity should be high because all mutations reported are detectable by sequencing.

This test provides full coverage of all coding exons of the CACNA1C gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).