LGI1

Chr 10ARAD

leucine rich glioma inactivated 1

Also known as: ADLTE, ADPAEF, ADPEAF, DEE121, EPITEMPIN, EPT, ETL1, IB1099

NCBI Gene: 9211 ENSG00000108231 UniProt: O95970 OMIM: 604619

The protein regulates voltage-gated potassium channels and serves as a ligand for ADAM22 to modulate synaptic transmission mediated by AMPA-type glutamate receptors. Mutations cause autosomal dominant familial temporal lobe epilepsy and autosomal recessive developmental and epileptic encephalopathy. This gene is highly constrained against loss-of-function variants, reflecting its critical role in neuronal function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismAR/ADLOEUF 0.192 OMIM phenotypes

Clinical Summary— LGI1

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Gene-Disease Validity (ClinGen)

autosomal dominant epilepsy with auditory features · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

70 unique Pathogenic / Likely Pathogenic· 253 VUS of 499 total submissions

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Clinical Trials

3 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — LGI1

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint

0.19LOEUF

pLI 0.999

Z-score 4.43

OE 0.04 (0.01–0.19)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint

2.78Z-score

OE missense 0.54 (0.47–0.62)

158 obs / 291.6 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios

LoF OE0.04 (0.01–0.19)

0≤0.351.4

Missense OE0.54 (0.47–0.62)

0≤0.61.4

Synonymous OE0.92

0≤1.21.6

LoF obs/exp: 1 / 24.8Missense obs/exp: 158 / 291.6Syn Z: 0.70

0.4487th %ile

GOF

0.4875th %ile

LOF

0.67top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 63% of P/LP variants are LoF · LOEUF 0.19

DN1 literature citation

Literature Evidence

DNHuman epilepsy-associated dominant-negative-truncated mutant LGI1 inhibited the seizure-induced suppression of phasic firing, increase of A-type K(+) current, and recruitment of Kv4.2 surface expression (in vivo and in vitro).PMID:22122031

LOFHaploinsufficiency of the leucine-rich glioma inactivated 1 (LGI1) gene is the major pathogenic basis for ADLTE, an inherited syndrome with no cure to date.PMID:29491011

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.