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Early onset or syndromic epilepsy v8.47 RELN Achchuthan Shanmugasundram commented on gene: RELN: 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.
Early onset or syndromic epilepsy v8.47 RELN Achchuthan Shanmugasundram changed review comment from: Comment on phenotypes: Both monoallelic and biallelic variants in this gene has been associated with relevant phenotypes in OMIM (MIMs #257320 & #616436, OMIM records were accessed on 20 October 2025).; to: 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).
Early onset or syndromic epilepsy v8.47 RELN Achchuthan Shanmugasundram Added comment: Comment on phenotypes: Both monoallelic and biallelic variants in this gene has been associated with relevant phenotypes in OMIM (MIMs #257320 & #616436, OMIM records were accessed on 20 October 2025).
Early onset or syndromic epilepsy v8.47 RELN Achchuthan Shanmugasundram Phenotypes for gene: RELN were changed from Lissencephaly 2 (Norman-Roberts type), OMIM:257320; {Epilepsy, familial temporal lobe, 7}, OMIM:616436 to 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
Early onset or syndromic epilepsy v8.46 RELN Achchuthan Shanmugasundram Publications for gene: RELN were set to 26046367; 17431900; 10973257
Early onset or syndromic epilepsy v8.45 RELN Achchuthan Shanmugasundram changed review comment from: 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).; to: 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).
Early onset or syndromic epilepsy v8.45 RELN Achchuthan Shanmugasundram reviewed gene: RELN: Rating: GREEN; Mode of pathogenicity: None; Publications: 10973257, 26046367, 27000652, 35769015; 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; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v2.502 RELN Sarah Leigh Phenotypes for gene: RELN were changed from {Epilepsy, familial temporal lobe, 7} 616436 to Lissencephaly 2 (Norman-Roberts type), OMIM:257320; {Epilepsy, familial temporal lobe, 7}, OMIM:616436
Early onset or syndromic epilepsy v2.501 RELN Sarah Leigh Publications for gene: RELN were set to 26046367
Early onset or syndromic epilepsy v1.191 RELN Rebecca Foulger Source Wessex and West Midlands GLH was added to RELN.
Early onset or syndromic epilepsy v1.190 RELN Rebecca Foulger Source NHS GMS was added to RELN.
Early onset or syndromic epilepsy v1.189 RELN Rebecca Foulger edited their review of gene: RELN: Added comment: 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. ; Changed rating: AMBER
Early onset or syndromic epilepsy v1.188 RELN Tracy Lester reviewed gene: RELN: Rating: GREEN; Mode of pathogenicity: ; Publications: 7682675; Phenotypes: Lissencephaly 2 (Norman-Roberts type), 257320, {Epilepsy, familial temporal lobe, 7}, 616436; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early onset or syndromic epilepsy v1.153 RELN Rebecca Foulger Added comment: 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).
Early onset or syndromic epilepsy v1.153 RELN Rebecca Foulger Mode of inheritance for gene: RELN was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early onset or syndromic epilepsy RELN Sarah Leigh commented on gene: RELN
Early onset or syndromic epilepsy RELN Sarah Leigh classified RELN as Green List (high evidence)
Early onset or syndromic epilepsy RELN Sarah Leigh Added gene to panel