Abstracts

Rationale: GNB5 encodes guanine nucleotide-binding protein subunit beta-5 (Gß5).  Gß5 assists in the downregulation of  central nervous system G protein signaling. Pathogenic variants in GNB5 have recently been identified as a cause for an autosomal recessive neurodevelopmental disorder associated with sinus bradycardia in the neonatal period. Affected members of 4 of 9 reported families had seizures but the epileptology of this disorder has not been well characterised. Methods: Two individuals with GNB5 pathogenic variants and epilepsy were identified in a New Zealand and Australian cohort of developmental and epileptic encephalopathies (DEEs). The literature, GeneMatcher and Clinvar were searched for additional cases. Medical history, examination, MRI and EEG data were obtained for each patient together with their molecular data. Results: Six individuals (4 female) aged 2 to 24 years from 5 families were identified. Developmental progress was abnormal from birth (4/6), 1 month (1/6) and 3 months (1/6). Neonatal onset focal seizures evolved to epileptic spasms at 3 months in 2 children. The remaining 4 children presented with epileptic spasms: three at 3 months and one at 2 years. Later seizure types included tonic seizures (4/6), focal impaired awareness seizures (3/6), clonic seizures (1/6) or generalized tonic clonic seizures (1/6).  The initial EEG showed hypsarrhythmia (4) or burst suppression (2); later EEGs showed a slow background with multifocal epileptiform discharges. MRI was normal in 4 and showed atrophy in 2.Seizures were pharmacoresistant in all children. All individuals had profound intellectual disability with no speech or ambulation. Two required enteral feeding. All children had bradycardia with sinus pauses.Individuals all had biallelic pathogenic variants that were predicted by in silico tools to result in protein truncation. Four were homozygous for a frameshift (1), stop gain (2) or splicing variant (1), and two were compound heterozygous for a stop gain and splicing variant.   Conclusions: We describe the epilepsy phenotypes of GNB5 encephalopathy. Children have developmental delay from early in infancy and an epileptic encephalopathy characterized by epileptic spasms. All individuals had biallelic variants predicted to result in protein truncation whereas reported individuals without epilepsy and milder intellectual impairment had biallelic missense variants. Genotype-phenotype correlations are emerging as larger numbers of patients with GNB5 encephalopathy are recognized. Funding: Health Research Council of New ZealandCure Kids New ZealandNational Health and Medical Research Council of Australia