The first heterozygous SHOX2 missense mutations were identified in a cohort of 378 patients with early-onset atrial fibrillation. Of these, a coding variant (SHOX2 c.849C>A, SHOX2 p.H283Q) and a 3’UTR variant (SHOX2 c.*28T>C) were shown to affect the regulation and function of SHOX2. The 3’UTR variant was identified in 15 of 378 patients (minor allele frequency 2%), but was also present in the general population without reported atrial fibrillation (MAF 0.7-0.9%), although it was significantly more frequent in patients compared to the control cohorts. The genetic variant created a functional miR-92b-5p binding site. This miRNA was also significantly lower expressed in carrier atrial fibrillation patients when compared to affected non-carriers. The association of SHOX2 with atrial fibrillation was confirmed by the identification of a heterozygous nonsense mutation (p.R194X) in a cohort of unrelated patients with familial atrial fibrillation that was absent in the control group. This variant co-segregated with the disease phenotype in the patient’s family in multiple affected members with complete penetrance. In addition, the SHOX2 missense variant p.G77D was identified in another cohort of atrial fibrillation patients. Atrial fibrillation and sinus node dysfunction frequently coexist with 40-70% of patients suffering from atrial fibrillation at the time of diagnosis of sinus node dysfunction; however, the molecular mechanisms linking both conditions remain elusive. Recently, we identified a functional missense mutation (p.P33R) in a patient with sinus node dysfunction, indicating for the first time a genetic link between sinus node dysfunction and atrial fibrillation involving SHOX2.
SHOX2