Identification of a Novel Genetic Variant Responsible for Familial Atrial Fibrillation

Atrial fibrillation (AF) is the most common cardiac arrhythmia. Although familial AF frequently follows an autosomal dominant inheritance pattern, the genetic mechanisms remain incompletely defined. We sought to identify the causal variant within a previously established linkage region on chromosome 10q22-q24.

Additional recombination events and fine mapping reduced the original linkage interval to 0.8 Mb. Targeted sequencing of the locus was performed in affected and unaffected family members. Patient-specific human induced pluripotent stem cells (hiPSCs) were differentiated into atrial cardiomyocytes to assess gene expression and ion channel function.

Refinement of the locus identified 3 genes (KCNMA1; DLG5; and POLR3A). A novel 15-kb tandem duplication within intron 1 of KCNMA1 segregated with disease in 6 families and was absent in controls and population databases. Patient-derived hiPSC atrial cardiomyocytes demonstrated reduced KCNMA1 and POLR3A mRNA and protein expression, accompanied by decreased paxilline-sensitive outward current.

We identified a rare intronic structural variant in KCNMA1 associated with familial AF. The variant segregates with disease and is associated with reduced KCNMA1 expression and BK channel activity in patient-specific cardiomyocytes. These findings implicate the 10q22-q24 locus and highlight the potential contribution of noncoding structural variation to inherited atrial arrhythmia.