Muhammad Arshad Rafiq, Tamara T Koopmann, Laura A Zahavich, Meena Fatah and Robert M Hamilton
Mutations of the gene encoding the L-type voltage gated calcium channel alpha-1C subunit (CACNA1C) underlie long QT phenotypes as part of Timothy syndrome. Milder phenotypes, as well as isolated cardiac phenotypes, including Brugada syndrome have been observed. To date, CACNA1C mutations have typically been missense mutations on limited number of sites that result in either gain of function (Timothy syndrome with a prolonged QT) or loss of function (short QT and/or Brugada pattern on ECG). We report a multiplex four-generation family with 3 individuals affected by QT prolongation, sudden cardiac death and conduction abnormalities, segregating with a novel heterozygous in-frame deletion mutation in exon 16 of CACNA1C resulting in a single amino acid deletion (p.Lys773del) discovered by using clinical gene panel testing at Invitae Corporation. Affected members are present in 3 consecutive generations (II, III and IV), and demonstrate only the cardiac rhythm phenotype segregating in an autosomal dominant fashion, with normal intellect, socialization and absence of syndactyly. The implicated in-frame deletion mutation of CACNA1C is absent from the exome aggregation consortium (ExAC) database, predicted to be disease causing by Mutation Taster, and removed an evolutionarily conserved lysine amino acid residue at position 773. Three-dimensional modelling demonstrated a marked effect of the mutation on the predicted protein structure.