Early onset or syndromic epilepsy

Gene: RELN

Green List (high evidence)

Biallelic variants in RELN are associated with 'lissencephaly with cerebellar hypoplasia' (MONDO:0019450) with 'Definitive' rating by the Brain Malformations GCEP expert panel in ClinGen. Seizures are recorded as part of this phenotype in majority of the cases.

Monoallelic variants in RELN are associated with 'complex neurodevelopmental disorder' (MONDO:0100038) with 'Disputed' rating by the Intellectual Disability and Autism GCEP expert panel in ClinGen. However, this phenotype did not include the cases with autosomal-dominant lateral temporal epilepsy reported in PMID:26046367.

As there are sufficient monoallelic and biallelic cases reported with epilepsy as part of this phenotype, this gene can remain green with 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' as the MOI.

Created: 20 Oct 2025, 4:20 p.m. | Last Modified: 20 Oct 2025, 4:20 p.m.

Panel Version: 8.47

Comment on phenotypes: Both monoallelic and biallelic variants in this gene have been associated with relevant phenotypes in OMIM (MIMs #257320 & #616436, OMIM records were accessed on 20 October 2025).

Created: 20 Oct 2025, 4:15 p.m. | Last Modified: 20 Oct 2025, 4:16 p.m.

Panel Version: 8.47

Monoallelic variants:

PMID:26046367 (2015) reported the identification of seven different heterozygous missense variants in RELN gene in seven unrelated families with autosomal-dominant lateral temporal epilepsy. These variants were identified by performing SNP-array linkage analysis and whole-exome sequencing. Of these seven variants, six of these are either absent or present with a very low allele frequency in gnomAD v4.1.0. However, c.2015C>T (p.Pro672Leu) variant is present in gnomAD with higher allele frequency.

Biallelic variants:

PMID:10973257 (2000) reported two unrelated consanguineous pedigrees segregating an autosomal recessive form of lissencephaly associated with severe abnormalities of the cerebellum, hippocampus, and brainstem. They were identified with homozygous variants in RELN gene and had seizures.

PMID:27000652 (2016) reported a Moroccan female patient with lissencephaly and with homozygous RELN variant. This patient presented with neonatal seizures that were controlled with medication.

PMID:35769015 (2022) reported the identification of biallelic RELN variants in seven patients from four unrelated families and monoalellic RELN variants from 13 individuals from seven families with frontotemporal or temporal-predominant lissencephaly. Five patients from three different families with biallelic variants presented with seizures as part of the phenotype, while detailed phenotypic information was not available in two patients from the first family with biallelic variants. However, seizure was only reported in three of 13 individuals with monoallelic variants (all three are unrelated).

Created: 20 Oct 2025, 4:12 p.m. | Last Modified: 20 Oct 2025, 4:13 p.m.

Panel Version: 8.45

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Lissencephaly 2 (Norman-Roberts type), OMIM:257320; Norman-Roberts syndrome, MONDO:0009760; {Epilepsy, familial temporal lobe, 7}, OMIM:616436; familial temporal lobe epilepsy 7, MONDO:0014639

Publications

• 10973257
• 26046367
• 27000652
• 35769015

Green List (high evidence)

AR Lissencephaly 2 and AD familial temporal lobe epilepsy 7 (ETL7). AR Lissencephaly - Hong et al 2000 - 2 consang families (British and Saudi Arabian) - aff family members were found to have had hom RELN variants. Zaki et al 2007 - consang Egyptian marriage - hom apparantly balanced reciprocal translocation in 2 aff sibs - disrupts the RELN gene. All affecteds had seizures. ETL7 - charecterised by focal seizures. Dazzo et al, 2015 - 7 unrelated families of Italian descent - 7 diff het variants. Functional studies not performed but 3D modelling predicts mutations would result in structural defects and protein misfolding which could lead to degredation of the altered proteins. Aff individuals from 4 families had reduced up to 50%) serum levels of the main 310-kD reelin isform compared to controls - poss due to impaired secretion of the altered proteins from hepatocytes. On HGMD Pro - other associations include Hypogonadotrophic hypogonadism and Autism spectrum disorder. Obvioulsy assoc with seizures, but not the case for all variants.

Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.

Panel Version: 1.188

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Lissencephaly 2 (Norman-Roberts type), 257320; {Epilepsy, familial temporal lobe, 7}, 616436

Publications

• 7682675

I don't know

Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: John Taylor and Helen Lord. Suggested gene rating: Green.

Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.

Panel Version: 1.189

Comment on mode of inheritance: Updated MOI from monoallelic to 'BOTH monoallelic and biallelic' based on papers reporting seizures as part of AR lissencephaly phenotype: PMID:17431900 (Zaki et al 2007) and PMID:10973257 (Hong et al, 2000).

Created: 11 Jul 2019, 8:58 a.m. | Last Modified: 11 Jul 2019, 8:58 a.m.

Panel Version: 1.153

Associated with {Epilepsy, familial temporal lobe, 7} 616436 in OMIM and not in Gen2Phen. At least 4 missense variants identified in unrelated families.

Created: 23 Jul 2018, 1:56 p.m.

Comment on phenotypes: Biallelic variants are associated with Lissencephaly 2 (Norman-Roberts type) 257320

Created: 23 Jul 2018, 1:49 p.m.

Comment on mode of inheritance: Biallelic variants are associated with Lissencephaly 2 (Norman-Roberts type) 257320.

Created: 23 Jul 2018, 1:47 p.m.