Variant Synonymizer: Platform to identify mutations defined in different ways is available now!

VarSy

Over 2,000 gene–disease validation summaries are now available—no login required!

Browse Summaries

AKAP9 – Long QT syndrome

Heterozygous AKAP9 variants have been reported in three unrelated LQTS type 11 probands: a 3-year-old male with c.4021C>A (p.Gln1341Lys) (PMID:36395689), a 10-year-old female and two unaffected relatives carrying c.11487_11489del (p.Thr3830ValfsTer12) (PMID:38585551), and a 47-year-old male with a novel frameshift c.7252_7255del (p.Glu2418ProfsTer5) (PMID:36421840). Segregation was demonstrated in two affected relatives. However, a recent evidence-based reappraisal classified AKAP9 as a limited/disputed LQTS gene based on sparse case numbers and variable pathogenicity assertions (PMID:31983240).

Functional assays of the p.Ser1570Leu variant show disrupted binding of AKAP9 (Yotiao) to the KCNQ1 channel, loss of cAMP-induced phosphorylation of IKs, and prolonged simulated ventricular action potentials, consistent with delayed repolarization (PMID:18093912).

Key Take-home: AKAP9 currently has limited clinical validity for LQTS and should be interpreted with caution in diagnostic testing.

References

  • Stem cell research • 2022 • Reprogramming of a human induced pluripotent stem cell line (ZZUSAHi004-A) from a long QT syndrome patient with a heterozygous AKAP9 (c.4021C>A) mutant PMID:36395689
  • Molecular syndromology • 2024 • A Novel Variant in AKAP9 Gene, a Controversial Gene, in Long QT Syndrome. PMID:38585551
  • Circulation • 2020 • An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome. PMID:31983240
  • Proceedings of the National Academy of Sciences of the United States of America • 2007 • Mutation of an A-kinase-anchoring protein causes long-QT syndrome. PMID:18093912

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

Three unrelated probands, two small pedigrees, limited segregation, and a disputed classification in a recent reappraisal

Genetic Evidence

Limited

3 probands with heterozygous AKAP9 variants, segregation in 2 relatives, variant classes include missense and frameshift ([PMID:36395689], [PMID:38585551])

Functional Evidence

Moderate

Cellular assays demonstrate disrupted Yotiao–KCNQ1 interaction and loss of I(Ks) response for p.Ser1570Leu consistent with delayed repolarization ([PMID:18093912])