To explore the clinical characteristics of intellectual developmental disorder with cardiac arrhythmia syndrome (IDDCA) in a family caused by GNB5 gene variation and to review the literature.

The clinical and genetic data of an infant with IDDCA, who visited Shenzhen Children′s Hospital in September 2018, were collected and analyzed. His parents′ and brother′s gene analysis was also done by the next-generation sequencing and confirmed by Sanger sequencing. Related literature up to March 2020 was searched in Online Mendelian Inheritance in Man (OMIM), PubMed, CNKI and Wanfang databases with “GNB5” “IDDCA” “LADCI” “intellectual developmental disorder with cardial arrhythmia” “language delay and attention deficit-hyperactivity disorder or cognitive impairment with or without cardiac arrhythmia” as the key words. The related papers were retrieved and analyzed to summarize the clinical and genetic characteristics of this disorder.

The proband was an 11-month-old boy who presented with mental and motor developmental retardation, accompanied with convulsion and muscle weakness. Sinus arrest was also detected. His electroencephalogram (EEG) and flash visual evoked potential (FVEP) were both abnormal. Genetic analysis identified the homozygous frameshift variation of GNB5 gene (c.136delG, p.Glu46Argfs*8) in this infant and heterozygous variation in his parents, confirmed the diagnosis of IDDCA. The same GNB5 variation was identified in his brother, who was 4 years and 8 months old and had developed the similar clinical manifestations after birth. There were only 7 papers reporting this disease in the literature review, with a total of 27 patients from 14 families. Including these 2 cases, there were 29 patients in total, whose age of diagnosis ranged from 5.5 months to 23 years. Among all the patients, 20 cases (69%) were diagnosed as IDDCA, while 8 cases (28%) as LADCI; and 11 (38%) were males while 18 (62%) females. Regarding the clinical features, 66% (19/29) had mental retardation, 41% (12/29) had seizures, 79% (23/29) developed language delay and 62%（18/29） had sinus node dysfunction. Genetic tests showed that 4 patients from 3 families had complex heterozygous variation, and 25 patients (86%) from 12 families had homozygous variation. Seventeen patients from 8 families were consanguineous. Among the total 12 variations, there were 4 nonsense, 3 frameshift, 2 missense and 2 shear mutations, and 1 shear disorder caused by synonymous mutation.

IDDCA caused by GNB5 gene variations mainly manifests as general developmental delay or severe mental retardation, and sinus node dysfunction. GNB5 associated syndromes have phenotypic heterogeneity and are inherited in an autosomal recessive manner.

Epilepsy; Genes, GNB5; Mental retardation; Sick sinus syndrome