CACNA2D1 – Short QT syndrome

CACNA2D1 has been implicated in Short QT syndrome through a single case report of a heterozygous c.2264G>C (p.Ser755Thr) variant in a patient presenting with a QT interval of 317 ms (QTc 329 ms) and malignant tachyarrhythmias (PMID:21383000). This variant exhibited autosomal dominant transmission in one family without additional segregation data (PMID:21383000). Functional analysis in HEK-293 cells co-expressing Ca(v)1.2α1 and Ca(v)β2b subunits demonstrated that p.Ser755Thr reduced barium currents by more than 70% compared with wild type, consistent with a loss-of-function mechanism affecting cardiac repolarization (PMID:21383000). No further CACNA2D1 variants have been reported in SQTS cohorts, and additional cases or segregation studies are lacking. Although the robust in vitro deficit supports a pathogenic role, the current evidence is limited to a single proband and functional assay. Key Take-home: The p.Ser755Thr loss-of-function variant in CACNA2D1 is a candidate diagnostic marker for Short QT syndrome pending replication in additional families.

References

• European heart journal • 2011 • Identification of a novel loss-of-function calcium channel gene mutation in short QT syndrome (SQTS6). PMID:21383000

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