What are GABRG2-related disorders? 

GABRG2-related neurodevelopmental disorders are caused by genetic variants in the GABRG2 gene. They are genetic epilepsy syndromes characterized by febrile and non-febrile seizures and developmental delay. The symptoms a child experiences and the severity of their condition can vary widely.  

What causes GABRG2-related disorders? 

The gene GABRG2 is responsible for instructing the brain to make a protein that is involved with regulating the excitability of neurons. Children with GABRG2-related neurodevelopmental disorders have a pathogenic variant (“mutation”) in the gene GABRG2. The genetic mutation may affect the ion channel in different ways for each child. In most cases, the GABRG2 mutation leads to decreased activity of the ion channel. In other cases, the mutation may lead to overactivity of the ion channel.

In many children with GABRG2-related neurodevelopmental disorders, the pathogenic GABRG2 variant occurred spontaneously (de novo) and was not inherited from either parent. However, there are cases where the pathogenic GABRG2 variant was inherited from either an affected or asymptomatic parent.

In rare cases, the pathogenic GABRG2  variant has been passed on from an asymptomatic parent due to parental mosaicism. Just like a mosaic piece of art, in which each tile is different, a mosaic parent has distinct cell types. Most cells of a mosaic parent do not carry the pathogenic GABRG2 variant. However, a small proportion of cells do carry the pathogenic GABRG2 variant in very low levels that may be difficult or impossible to detect.

Signs and symptoms of GABRG2-Related Disorders 

Children with GABRG2-related disorders typically experience febrile or fever-sensitive seizures and delays in achieving developmental milestones within the first three years of life. However, the spectrum of GABRG2-related neurodevelopmental disorders can range from mild to severe.  

• Mild disorders – Children have febrile seizures (seizures that are brought on by a fever) in infancy or early childhood. These seizures usually stop by age 6, although some individuals continue to have febrile or afebrile seizures later in life. Some individuals may have normal development and intellectual ability, while others will have mild to moderate developmental delay and intellectual disability. In mild cases, there may be a family history of febrile seizures in siblings or parents, suggesting the genetic mutation was inherited from a parent.
• Moderate disorders – Children may have both fever-induced and unprovoked seizures and normal development or mild/moderate developmental delays.
• Severe disorders – Children have developmental and epileptic encephalopathy (a disease of the brain that alters brain function or structure) characterized by difficult-to-treat seizures typically occurring within the first year of life. They may experience multiple seizure types, including febrile seizures, and may receive a clinical diagnosis of Dravet syndrome. Severely affected children typically have moderate to profound developmental delays in gross motor, fine motor and language function. Some individuals with GABRG2-related developmental and epileptic encephalopathy may also have moderate to profound intellectual disability, low muscle tone (hypotonia), variable movement disorders, and ocular abnormalities. In most children with a more severe presentation of GABRG2-related neurodevelopmental disorder, the genetic mutation is spontaneous (de novo) and was not inherited from either parent. However, there are reports of rare cases where significantly affected children inherited the pathogenic GABRG2 variant from either an asymptomatic parent or a parent with a personal history of seizures. A family history of epilepsy may suggest an inherited  GABRG2  variant.