Pathogenic variants in the RELN gene cause a multisystem disorder (Fig1)
The clinical features most commonly associated with homozygous RELNgene mutations are:
• Lissencephaly
• Cerebellar hypoplasia
• Severe intellectual disability
• Global developmental delay
• Epileptic seizures
• Hypotonia
• Abnormality of the hippocampus
• Abnormality of the brainstem
These features reflect a severe, syndromic neuronal migration disorder with both cortical and cerebellar involvement, typically presenting in early childhood and associated with profound neurological impairment. On the other hand, heterozygous pathogenic variants are associated more often to clinical features such as:
• Focal epilepsy, especially ADLTE
• Mild to moderate intellectual disability
• Behavioral abnormalities
• Mild cortical malformations (e.g., frontotemporal or temporal-predominant lissencephaly)
• ASD
• Psychiatric symptoms (e.g., schizophrenia)
• Generalized epilepsy, in some cases
These features are generally less severe, often limited to epilepsy or mild cognitive/behavioral dysfunction, and do not include cerebellar hypoplasia or the profound global developmental delay seen in biallelic cases. Intellectual disability, epilepsy/seizures, and cortical malformations can be seen in both homozygous and heterozygous individuals, but the severity and associated findings (notably cerebellar hypoplasia) distinguish the biallelic from the monoallelic forms.
Figure 1: Clinical and molecular spectrum associated with RELNvariants, 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.