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
