Elucidation of as a Novel Long-QT Syndrome-Susceptibility Gene.

BACKGROUND

Long-QT syndrome (LQTS) is characterized by QT prolongation and increased risk for syncope, seizures, and sudden cardiac death. The majority of LQTS stems from pathogenic mutations in , , or . However, ≈10% of patients with LQTS remain genetically elusive. We utilized genome sequencing to identify a novel LQTS genetic substrate in a multigenerational genotype-negative LQTS pedigree.

METHODS

Genome sequencing was performed on 5 affected family members. Only rare nonsynonymous variants present in all affected family members were considered. The candidate variant was characterized functionally in patient-derived induced pluripotent stem cell and gene-edited, variant corrected, isogenic control induced pluripotent stem cell-derived cardiomyocytes.

RESULTS

A missense variant (p.G6S) was identified in -encoded α-1,2-glucosyltransferase B protein. ALG10B (alpha-1,2-glucosyltransferase B protein) is a known interacting protein of -encoded K11.1 (HERG [human Ether-à-go-go-related gene]). Compared with isogenic control, ALG10B-p.G6S induced pluripotent stem cell-derived cardiomyocytes showed (1) decreased protein expression of ALG10B (p.G6S, 0.7±0.18, n=8 versus control, 1.25±0.16, n=9; <0.05), (2) significant retention of HERG in the endoplasmic reticulum (<0.0005), and (3) a significantly prolonged action potential duration confirmed by both patch clamp (p.G6S, 531.1±38.3 ms, n=15 versus control, 324.1±21.8 ms, n=13; <0.001) and multielectrode assay (<0.0001). Lumacaftor-a compound known to rescue HERG trafficking-shortened the pathologically prolonged action potential duration of ALG10B-p.G6S induced pluripotent stem cell-derived cardiomyocytes by 10.6% (n=31 electrodes; <0.001).

CONCLUSIONS

Here, we demonstrate that ALG10B-p.G6S downregulates ALG10B, resulting in defective HERG trafficking and action potential duration prolongation. Therefore, is a novel LQTS-susceptibility gene underlying the LQTS phenotype observed in a multigenerational pedigree. ALG10B mutation analysis may be warranted, especially in genotype-negative patients with an LQT2-like phenotype.