AKAP9-Related Channelopathy: Novel Pathogenic Variant and Review of the Literature

Figures

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  Figure 1. (A) ICU twelve-lead ECG showed a normal sinus rhythm, a normal PR interval at 160 milliseconds, a QRS complex, and a silent “prolonged” QTc interval of 436 milliseconds. (B) Repeated resting (left panel) and mental arithmetic stress ECG (right panel) showed QTc intervals of 400 and 457 milliseconds, respectively, which confirm the diagnosis of LQTS. (C) His father’s ECG at rest and during mental arithmetic stress showed a prolonged QTc of 460 (upper panel) and 485 milliseconds (lower panel).

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  Figure 2. (A) Sanger sequencing showing a frameshift AKAP9 variant c.7252_7255delGAAA p.(Glu2418Profs*5) in the propositus. (B) Familial segregation study showing the pathogenic AKAP9 frameshift variant was inherited from an apparently normal father. (C) MetaDome showing a graphic representation of the tolerance scores of the affected Glu2418 highly conserved among orthologs. (D) PyMOL showing the Yotiao 3D protein structure, the frameshift variant AKAP9: c.7252_7255delGAAA p.(Glu2418Profs*5) leading to the production of truncated Yotiao protein lacking the PKA-RII subunit binding domain, resulting in reduced PKA-dependent phosphorylation of the Ser27 located in the N terminus of IKs α-subunit KCNQ1, which gives rise to the prolonged QTc interval.