KCNJ5 – Andersen-Tawil syndrome

Andersen-Tawil syndrome is a rare autosomal dominant channelopathy characterized by episodic flaccid paralysis and ventricular arrhythmias. A heterozygous KCNJ5 variant, c.1159G>C (p.Gly387Arg), was identified in a proband with familial periodic paralysis and inherited from his affected mother (PMID:33199157), and this same allele was previously reported in two unrelated cases of Andersen-Tawil syndrome or familial long QT syndrome. In Xenopus oocytes, Kir3.4 p.Gly387Arg exerts a dominant-negative inhibition on Kir2.1-mediated inward rectifier currents, providing a mechanistic link to the periodic paralysis and cardiac phenotype (PMID:24574546). However, the c.1159G>C allele occurs at a frequency of 0.21–0.25% in East Asian populations, indicating incomplete penetrance. While segregation and functional studies support pathogenicity, the elevated carrier frequency and limited number of affected families temper the overall clinical validity. Key take-home: KCNJ5 p.Gly387Arg can underlie Andersen-Tawil syndrome in a subset of patients, but cautious interpretation is required due to reduced penetrance.

References

• Brain & development • 2021 • Familial periodic paralysis associated with a rare KCNJ5 variant that supposed to have incomplete penetrance. PMID:33199157
• Neurology • 2014 • A Kir3.4 mutation causes Andersen-Tawil syndrome by an inhibitory effect on Kir2.1. PMID:24574546

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