Early onset or syndromic epilepsy

Gene: LGI1

Green List (high evidence)

Comment on mode of inheritance: Monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), which presents with later-onset and incomplete penetrance (e.g. PMID: 26773249 - cohort of 26 patients, average onset of epilepsy at 16.83 years).
Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including seizures from birth, infantile lethality and severe developmental delay. There are at least 5 unrelated individuals reported with biallelic variants in LGI1, with infantile onset developmental and epileptic encephalopathy (PMID:40455867 Hirano et al., 2025; PMID:41000458 Mouhi et al., 2025). Hence, the MOI should be updated from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal'.

Created: 7 Oct 2025, 10:39 a.m. | Last Modified: 7 Oct 2025, 11:02 a.m.

Panel Version: 8.39

As reviewed previously, monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF), also known as familial temporal lobe epilepsy. The LGI1-ADEAF association is Definitive in ClinGen, with penetrance estimated at 60% (https://search.clinicalgenome.org/CCID:005280) Individuals with monoallelic variants present with later-onset epilepsy and incomplete penetrance (e.g. PMID: 26773249 - cohort of 26 patients, average onset of epilepsy at 16.83 years).

Recent evidence identifies cases with biallelic LGI1 variants, presenting with a more severe phenotype, including infantile lethality and severe intellectual disability:

PMID: 40455867 Hirano et al., 2025
Report of 6 cases from 4 consanguineous unrelated families (Saudi Arabian, Pakistani, Jordanian, Turkish). All affected individuals presented with drug-resistant neonatal/infantile-onset seizures, as well as intellectual disability (mild in P4, severe ID in 5 other patients), delayed motor milestones. P2 died at age 9 months due to status epilepticus; P3 died of unknown cause at 4yo; patients 1A-C died of respiratory failure aged 11-24yo. Seq method: Trio WES (all), Sanger confirmation (with exception of P3).
Variants:
P1A-C: c.143G>T p.(Cys48Phe) – Revel 0.93, not in gnomAD v4
P2: c.931C>T p.(Arg311*) - not in gnomAD v4
P3: c.1570T>C p.(Ser524Pro) – Revel 0.67, 1 allele in gnomAD v4 (exome only)
P4: c.1672T>G p.(Ter558GlyextTer23) – not in gnomAD v4

Additional functional evidence from PMID:40455867:
Expressed wild-type LGI1 (WT) or newly identified LGI1 variants in HEK293T cells - secretion levels of LGI1 variants Cys48Phe and Ter558GlyextTer23 were somewhat reduced, while Arg311* and Ser524Pro levels were significantly reduced.
Cell surface binding to ADAM22 in COS-7 cells (ADAM22 serves as a receptor for LGI1) - Arg311* and Ser524Pro did not show any binding, Cys48Phe and Ter558GlyextTer23 retained good binding activity.
The functional impact of the variants on LGI1 function correlates well with the severity of clinical presentation.

PMID: 41000458 Mouhi et al., 2025
Consanguineous Moroccan family, siblings with epileptic encephalopathy due to a homozygous variant within the LGI1 gene: c.245T>C (p.Ile82Thr) - Method: WES +Sanger; Revel = 0.97, not in gnomAD v4
Proband VI.1: seizures from birth, generalised clonic seizures, focal and generalised tonicoclonic seizures. Severe developmental delay at 4yo. Repeated EEG showed abnormal background activity.
Younger brother (IV.2): seizures from the 1st week of life, died at the age of 11 months after repeated pulmonary infections.
c.245T>C (p.Ile82Thr) also reported in a het state in PMID 24206907 – patient with autosomal dominant epilepsy with auditory aura.
Paternal cousin heterozygous for the variant experienced moderate focal epilepsy; het parents unaffected.

LGI1 is associated with AD Epilepsy, familial temporal lobe, 1 (600512) in OMIM - accessed 7th Oct 2025.

Based on the recent evidence, the MOI should be changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal.

Created: 7 Oct 2025, 10:16 a.m. | Last Modified: 7 Oct 2025, 10:51 a.m.

Panel Version: 8.39

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Phenotypes
Epilepsy, familial temporal lobe, 600512; developmental and epileptic encephalopathy MONDO:0100620

Publications

• 26773249
• 40455867
• 41000458

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

Green List (high evidence)

AD familial lobe epilepsy type 1. Kalachiov et al, 2002 - het variants detected in each of the 5 families. Brodtkorb et al, 2002 & Gu et al 2002 - het missense variant identified. Berkovic et al 2004 - in affected members in 2 of 4 families - het mutations identified. Fanciulli et al, 2012 - het 81kb del including first 4 exons of gene in affected members of a 3 generation Italian family. On HGMD pro lots of missense, nonsense, splicing snall dels and ins and gross del reported in patients with an epilepsy phenotype.

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

Panel Version: 1.188

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Epilepsy, familial temporal lobe, 600512

Publications

• 11810107

Associated with relevant phenotype in OMIM and as possible Gen2Phen gene. At least 11 variants reported

Created: 9 Apr 2018, 9:47 a.m.

Green List (high evidence)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Epilepsy, familial temporal lobe, 1

Publications

• Berkovic et al (2004) Neurology 62: 1115-1119

Variants in this GENE are reported as part of current diagnostic practice

Green List (high evidence)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Epilepsy, familial temporal lobe, 1

Publications

• Berkovic et al (2004) Neurology 62: 1115-1119

Variants in this GENE are reported as part of current diagnostic practice

Green List (high evidence)

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Epilepsy, familial temporal lobe, 1

Publications

• Berkovic et al (2004) Neurology 62: 1115-1119

Variants in this GENE are reported as part of current diagnostic practice

Green List (high evidence)

Comment when marking as ready: Promoted to green as clearly associated with the phenotype in OMIM

Created: 12 Jun 2017, 9:59 a.m.

Add to the panel following expert review (Prof. Sisodiya). Gene clearly associated with the phenotype in OMIM

Created: 12 Jun 2017, 9:57 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Epilepsy, familial temporal lobe, 1 600512

Comment on list classification: The reviewers later agreed by email that this should be red. It is a possible DD gene.

Created: 29 Jan 2016, 11:39 a.m.

Red List (low evidence)

Causes older-onset focal seizures; i.e. different phenotype.

Created: 12 Nov 2015, 2:17 p.m.

Phenotypes
Epilepsy, familial temporal lobe, 1

Publications

• Berkovic et al (2004) Neurology 62: 1115-1119