Sick Sinus Syndrome and Neurodevelopmental Delay in an Infant Due to Altered G-Protein Signalling

Background: Sick sinus syndrome (SSS) is a rare disease in childhood that may present with sinus bradycardia or arrest, ectopic, or nodal rhythms or profound bradycardia following a period of tachycardia. In most cases, SSS results from cardiac surgery or structural heart disease. However, SSS caused by pathogenic genetic variants has also been described.

Method: We present a male infant with biallelic GNB5 variants associated with SSS and neurodevelopmental delay.

Results: At the age of 8 weeks, the patient was referred to our department with failure to thrive and frequent short runs of narrow-complex tachycardia combined with episodes of bradycardia. The initial ECGs were suspicious for an ectopic atrial focus, so that focal atrial tachycardia was the primary diagnosis. Echocardiography documented normal cardiac anatomy and function. Pharmacotherapy with beta-blockers and class Ic antiarrhythmics was commenced and successfully controlled tachycardia. The child was readmitted at the age of 4 months as repeated the Holter ECG monitoring showed intermittent sinus arrests with pauses up to 4 seconds. Antiarrhythmic medication was discontinued. At that time, clinical examination revealed visual impairment with nystagmus and muscular hypotonia. He also presented with seizures (blank stare and lip smacking). Sleep EEG showed sharp slow waves, so that antiepileptic medication was commenced. The phenotypic spectrum, including cardiac, neurologic, and ophthalmologic abnormalities, was suggestive of an underlying syndromic disorder. Exome sequencing showed two pathogenic variants in GNB5 independently inherited from the unaffected parents. GNB5 encodes a G-protein subunit. Biallelic loss of GNB5 results in autonomic dysfunction and has a direct impact on the control of heart rate by augmentation of the cholinergic response. Sinus bradycardia with sinus arrests necessitated pacemaker implantation at the age of 13 months. At the latest follow-up, the child presented in good general condition but mental retardation and poor feeding with gastric reflux require continued medical care.

Conclusion: Tachycardia–bradycardia syndrome associated with global neurodevelopmental delay, seizures, nystagmus and muscular hypotonia should raise suspicion of a genetic syndrome. In addition to previously described genes encoding for ion channel subunits, genetic variants encoding for G-protein subunits are a possible cause. Pacemaker implantation is highly recommended in patients with documented progressive bradycardia.

Publication History

Article published online:
12 February 2022