Abstract Body: Background
GNB2 encodes β2 subunits of guanine nucleotide-binding proteins, consisting of α, β and γ subunits. Gβ2γ2 dimer opens G-protein-coupled potassium channel (GIRK), resulting in outward K+ current. In GNB2, five mutations associated with neurodevelopmental disorders and one gain of function mutation linked to sick sinus syndrome have been previously described. The gain of function mutation has been shown to induce prolonged hyperpolarization in pacemaker cells, leading to slowing of the heart rate, and thus underlying the pathology of sick sinus syndrome.
Hypothesis
Loss of function and gain of function mutations in GNB2 lead to neurodevelopmental disorders and sick sinus syndrome, respectively, although the substitutions in the protein sequence are in close proximity to one another.
Case Presentation
A 17 year old male patient presented with symptoms of fatigue, shortness of breath, and episodes of near-syncope. Initial investigations revealed atrial fibrillation with slow ventricular conduction, necessitating the implantation of a dual-chamber pacemaker. Family history revealed a similar condition in the patient’s mother, who also had atrial fibrillation with slow ventricular conduction and had previously undergone dual-chamber pacemaker implantation. The patient’s brother exhibited intermittent 2nd degree AV block with occasional pauses and episodes of complete AV block alternating with slow conducting atrial fibrillation, requiring pacemaker therapy as well.
Methods
We performed whole exome sequencing (WES) for proband, mother, father and brother. Data was processed and analyzed by Gennext. Variant filtering was performed using HPO term-based gene lists, following ACMG/AMP guidelines. Novel candidate and previously reported variants were analyzed and compared by DynaMut2 to assess their impact on protein stability.
Results
We identified a novel heterozygous variant NM_005273.4(GNB2):c.233A>G(p.Lys78Arg) in the affected family members. Protein stability analysis revealed a distinct pattern differentiating the two disorders: mutations associated with neurodevelopmental disorders were found to be destabilizing, while those linked to cardiac disorders were stabilizing.
Conclusion
The novel missense variant in GNB2 represents the second mutation reported in the literature to be associated with sick sinus syndrome, further highlighting its pleiotropic effects, which include both neurodevelopmental and cardiac disorders.