GNB5-Related Neurodevelopmental Disorder

Clinical characteristics: GNB5-related neurodevelopmental disorder (GNB5-NDD) is characterized by a spectrum of neurodevelopmental phenotypes that range from severe-to-profound intellectual disability (ID; 31/41 reported individuals), to mild-to-moderate ID (5/41), to normal intellect with severe language disorder (5/41, one extended family). A unique and specific feature of GNB5-NDD – regardless of neurodevelopmental phenotype – is nearly universal bradycardia caused by sinoatrial node dysfunction (sick sinus syndrome). Most individuals with severe and profound ID have a developmental and epileptic encephalopathy with focal seizures or epileptic spasms, as well as visual impairment (central or retinal) with nystagmus, difficulty feeding, and gastroesophageal reflux disease. The risk of early mortality is increased.

Diagnosis/testing: The diagnosis of GNB5-NDD is established in a proband with suggestive clinical findings and biallelic pathogenic variants in GNB5 identified by molecular genetic testing.

Management: Treatment of manifestations: Management by multidisciplinary specialists including a general pediatrician, developmental pediatrician, pediatric neurologist, speech-language pathologist, orthopedist, physical medicine and rehabilitation specialist, physical therapist, occupational therapist, pediatric ophthalmologist, and pediatric cardiologist is recommended.

Surveillance: Routine follow up by multidisciplinary care providers based on individual needs and circumstances.

Agents/circumstances to avoid: Use parasympathomimetics with extreme caution because of the potential to cause asystole. It is best to avoid other drugs that can potentiate bradycardia, particularly beta blockers.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of at-risk neonates (if prenatal testing was not performed) in order to identify as early as possible those who warrant developmental assessment (and monitoring) and evaluation by a pediatric cardiologist.

Genetic counseling: GNB5-NDD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a GNB5 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the GNB5 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.