When both copies of the RELN gene are affected (homozygous or biallelic variants)
Children with two altered copies of the RELN gene usually show a severe form of the condition.
The most common features include:
• Lissencephaly: the surface of the brain appears smoother than normal.
• Cerebellar hypoplasia: the cerebellum, which controls coordination and balance, is smaller and underdeveloped.
• Severe intellectual disability and global developmental delay.
• Epileptic seizures, often starting early in life.
• Low muscle tone (hypotonia).
• Structural changes in the hippocampus (an area involved in memory and learning).
• Abnormalities of the brainstem, which connects the brain with the spinal cord.
These signs reflect a serious syndromic brain development disorder affecting both the cortex and the cerebellum. It usually appears in early childhood and causes significant neurological disability.
When only one copy of the RELN gene is affected (heterozygous variants)
People who carry a single altered copy of RELN often have milder symptoms.
These may include:
• Focal epilepsy, especially a form called autosomal dominant lateral temporal epilepsy (ADLTE).
• Mild to moderate intellectual disability.
• Behavioral or emotional difficulties.
• Mild brain malformations, such as limited areas of lissencephaly (especially in the frontal or temporal regions).
• Autism spectrum disorder.
• Psychiatric conditions, such as schizophrenia in some individuals.
• Occasionally, generalized epilepsy.
These problems are usually less severe and often limited to epilepsy or mild learning and behavioral issues. Unlike the more severe form, the cerebellum is typically normal, and profound developmental delay is not seen.
Figure 1: Clinical and molecular spectrum associated with RELN variants, ranging from heterozygous (Het) milder phenotypes to homozygous (Hom) more severe ones. Within this spectrum are included neuropsychiatric comorbidities, which may occur as part of a complex phenotype or as isolated conditions.