RELN – Autosomal Dominant Epilepsy with Auditory Features

Heterozygous variants in the secreted extracellular matrix protein RELN have been established as a cause of Autosomal dominant epilepsy with auditory features, also known as ADLTE. This syndrome is characterized by focal seizures with auditory auras, episodes of aphasia, and secondary bilateral tonic–clonic seizures, typically beginning in adolescence.

In a collaborative Italian cohort of 40 families, 7 unrelated pedigrees harbored heterozygous RELN mutations in 28 affected individuals, with seizure onset at a mean age of 20 years and auditory auras in ~71% of cases ([PMID:28142128]). Clinical features were indistinguishable from LGI1-related ADLTE, with prominent left temporal EEG abnormalities and good response to antiepileptic drugs in most patients.

Whole-exome sequencing and SNP-array linkage in 13 initial ADLTE families identified 3 co-segregating RELN missense mutations; subsequent screening of 15 additional small families found 4 more, totaling 7/40 (17.5%) families with RELN mutations ([PMID:26046367]). Co-segregation was also confirmed in an independent nuclear family with a c.6631C>T (p.Arg2211Cys) variant in both the proband and her affected mother ([PMID:32723706]).

The variant spectrum in ADLTE is dominated by heterozygous missense changes clustered in Reelin repeat domains, including the exemplar c.6631C>T (p.Arg2211Cys), which markedly reduces protein secretion and alters temporal lobe structure on MRI ([PMID:32723706]). No recurrent founder alleles have been reported.

Functional studies demonstrate that pathogenic RELN mutations impair trafficking through the secretory pathway, leading to autophagy-mediated degradation of mutant proteins and decreased extracellular Reelin levels in cell models. Autophagosome markers LC3 and p62 are elevated in cells expressing mutant RELN, and small-molecule correctors partially rescue secretion ([PMID:34508592]).

No studies have refuted the RELN–ADLTE association, and the clinical spectrum remains consistent across cohorts. Additional evidence, including detailed electrophysiological and imaging correlates, further supports the diagnostic utility of RELN genetic testing in lateral temporal epilepsy.

Together, these genetic and experimental data fulfill criteria for a Strong ClinGen gene–disease association. Heterozygous RELN variants should be considered in patients with auditory-feature focal epilepsy, enabling accurate diagnosis, family counseling, and potential therapeutic targeting of Reelin secretion pathways.

References

• Epilepsy & behavior • 2017 • The clinical phenotype of autosomal dominant lateral temporal lobe epilepsy related to reelin mutations PMID:28142128
• American Journal of Human Genetics • 2015 • Heterozygous reelin mutations cause autosomal-dominant lateral temporal epilepsy PMID:26046367
• Epileptic Disorders • 2020 • Autosomal dominant lateral temporal lobe epilepsy associated with a novel reelin mutation PMID:32723706
• Human Molecular Genetics • 2022 • Epilepsy-causing Reelin mutations result in impaired secretion and intracellular degradation of mutant proteins PMID:34508592

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