Prevalence
RELN-related disorders are extremely rare, with only a limited number of families reported worldwide.
Clinical spectrum and molecular characteristics
Mutations in the RELNgene are linked to a broad range of neurodevelopmental and neuropsychiatric disorders, most prominently LCH, ADLTE, and an increased susceptibility to autism spectrum disorder (ASD) and schizophrenia.
LCH
Lissencephaly is a severe malformation of the cerebral cortex characterized by a smooth brain surface due to impaired neuronal migration, resulting in a thickened cortex with absent or reduced gyri and sulci. In the context of RELN-related disorders, lissencephaly is most commonly associated with cerebellar hypoplasia, a distinct syndrome caused by biallelic loss-of-function (LoF) mutations in RELN. This includes often abnormalities of the hippocampus and brainstem. Clinically, it manifests as profound global developmental delay, severe intellectual disability, and refractory epilepsy.
ADLTE
Autosomal dominant lateral temporal lobe epilepsy is a genetically heterogeneous, focal epilepsy syndrome characterized by recurrent focal seizures, most commonly presenting with auditory auras (such as simple or complex auditory hallucinations, sounds, or aphasia), and sometimes accompanied by other sensory symptoms (visual, vertigo, déjà-vu) or focal impaired awareness. Seizures typically begin in adolescence or early adulthood, and are usually well controlled with standard antiseizure medications. Interictal EEG frequently shows focal epileptiform discharges over the temporal regions, with a left-sided predominance, while conventional brain MRI is typically normal. Heterozygous mutations in the RELN gene account for approximately 17.5% of ADLTE families who do not have LGI1 mutations, that results clinically indistinguishable, with incomplete penetrance and variable expressivity even within families.
ASD and psychiatric comorbidities
Some heterozygous carriers may remain asymptomatic, while others show variable expressivity including different neuropsychiatric manifestations, such as ASD and schizophrenia.
Genetic Counselling
The inheritance pattern is autosomal recessive for LCH and autosomal dominant for ADLTE.
For biallelic (recessive) cases, the recurrence risk for siblings is 25%.
For heterozygous (dominant) variants confirmed de novo, the recurrence risk is low (<1%), though slightly higher than in the general population due to the possibility of parental germline mosaicism. Otherwise If either parent carries the variant, even if asymptomatic due to incomplete penetrance or variable expressivity, the recurrence risk for siblings is 50% at each pregnancy.
Management
Treatment is symptomatic and multidisciplinary.
RELN