KCNJ5 – Long QT Syndrome

KCNJ5 (HGNC:6266) has been reported in heterozygous autosomal dominant cases of Long QT Syndrome ([MONDO:0002442]). One individual with periodic paralysis carried the variant c.1159G>C (p.Gly387Arg) which segregated with disease in his affected mother (PMID:33199157). The same variant was previously identified in two unrelated families with familial LQTS or Andersen–Tawil syndrome, suggesting allelic overlap (PMID:33199157). However, a comprehensive reappraisal of LQTS genes classified KCNJ5 among those with limited or disputed evidence for LQTS causation, without supportive larger case series or robust segregation (PMID:31983240).

Functional studies in Xenopus oocytes indicate that the p.Gly387Arg mutant Kir3.4 channel exhibits loss-of-function effects, impairing inward rectifier currents that could influence cardiac repolarization (PMID:33199157). No cardiac‐specific animal models or rescue experiments have been reported, and experimental evidence remains limited. Taken together, the small number of probands, minimal segregation data, and reclassification as limited evidence underscore that KCNJ5 testing for clinical LQTS decision-making is not currently supported without new corroborative data.

References

• Circulation • 2020 • An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome PMID:31983240
• 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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