Heart and Brain: Homozygous Mutations of GNB5 Gene in Two Siblings with Early Onset Sinus Node Dysfunction and Severe Neurological Symptoms

Heart rhythm disorders with normal cardiac morphology combined with severe congenital neurological dysfunction are rarely found in genetic syndromes.

We report two sons of parents from Afghanistan presenting with bradycardia due to early onset sinus node dysfunction requiring pacemaker implantation in the first months of life. Without previous heart arrest or hypoxic -ischemic events, severe neurological symptoms manifested in the further course: marked combined developmental delay, muscular hypotonia, epilepsy (myoclonic and generalized tonic-clonic seizures in the older boy, respectively West syndrome in the younger) and secondary microcephaly. Brain MRI did not show any abnormalities. Additionally, gastro-esophageal reflux and visual impairment were diagnosed. Somewhat later central hypoventilation repeatedly caused respiratory insufficiency requiring mechanical ventilation during pneumonias. At the age of 7 years the younger boy died after aspiration, apnea and prolonged, ineffective resuscitation.

Whole exome sequencing demonstrated homozygous truncating mutations of GNB5 gene in both boys confirmed by sanger sequencing and found as heterozygous variants at the parents. This autosomal-recessive multisystem syndrome caused by GNB5 mutations was first published in 9 individuals from 6 families in 2016. A genotype-phenotype correlation probably exists with more severe symptoms caused by loss of function mutations. GNB5 gene encodes for G protein beta subunit 5 which is involved in inhibitory G protein signalling and plays a crucial role for parasympathetic control of heart rate.

In summary, we report two new cases of GNB5 gene mutations associated with severe cardiac and neurological symptoms possibly including central hypoventilation as additional autonomous dysfunction. This case report expands the phenotypic spectrum associated with homozygous truncation of GNB5.

Zeichen einer autonomen Dysfunktion. Diese Kasuistik erweitert das phänotypische Spektrum bei homozygoten trunkierenden Mutationen im GNB5 Gen.

Deutscher Titel: Herz und Hirn: Homozygote Mutationen im GNB5 Gen bei zwei Geschwistern mit congenitalem Sinusarrestsyndrom und schweren neurologischen Symptomen

No conflict of interest has been declared by the author(s).