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| Early onset or syndromic epilepsy v8.41 | LGI1 | Arina Puzriakova Publications for gene: LGI1 were set to 15079010; 11810107; 22496201 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v8.40 | LGI1 | Arina Puzriakova Phenotypes for gene: LGI1 were changed from Epilepsy, familial temporal lobe, 1 600512 to Epilepsy, familial temporal lobe, 1, OMIM:600512; developmental and epileptic encephalopathy, MONDO:0100620 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v8.39 | LGI1 | Arina Puzriakova Tag Q3_25_MOI tag was added to gene: LGI1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v8.39 | LGI1 |
Ida Ertmanska changed review comment from: Comment on mode of inheritance: As reviewed previously, 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'.; to: 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'. |
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| Early onset or syndromic epilepsy v8.39 | LGI1 |
Ida Ertmanska changed review comment from: 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 AR 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.; to: 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. |
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| Early onset or syndromic epilepsy v8.38 | LGI1 |
Ida Ertmanska changed review comment from: 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). 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 AR 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.; to: 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 AR 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. |
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| Early onset or syndromic epilepsy v8.38 | LGI1 |
Ida Ertmanska edited their review of gene: LGI1: Added comment: Comment on mode of inheritance: As reviewed previously, 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'.; Changed publications to: 26773249, 40455867, 41000458 |
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| Early onset or syndromic epilepsy v8.38 | LGI1 |
Ida Ertmanska changed review comment from: 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). 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 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 (variable penetrance, estimated at 60% by ClinGen). LGI1 is associated with AR 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.; to: 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). 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 AR 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. |
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| Early onset or syndromic epilepsy v8.38 | LGI1 |
Ida Ertmanska changed review comment from: 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). 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 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 (variable penetrance, estimated at 60% by ClinGen). LGI1 is associated with AR 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); to: 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). 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 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 (variable penetrance, estimated at 60% by ClinGen). LGI1 is associated with AR 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. |
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| Early onset or syndromic epilepsy v8.38 | LGI1 | Ida Ertmanska reviewed gene: LGI1: Rating: GREEN; Mode of pathogenicity: None; Publications: 40455867, 41000458; Phenotypes: Epilepsy, familial temporal lobe, 600512, developmental and epileptic encephalopathy MONDO:0100620; Mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.191 | LGI1 | Rebecca Foulger Source Wessex and West Midlands GLH was added to LGI1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.190 | LGI1 | Rebecca Foulger Source NHS GMS was added to LGI1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.189 | LGI1 | Rebecca Foulger reviewed gene: LGI1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy v1.188 | LGI1 | Tracy Lester reviewed gene: LGI1: Rating: GREEN; Mode of pathogenicity: ; Publications: 11810107; Phenotypes: Epilepsy, familial temporal lobe, 600512; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy | LGI1 | Sarah Leigh commented on LGI1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy | LGI1 | Sarah Leigh classified LGI1 as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Early onset or syndromic epilepsy | LGI1 | Sarah Leigh Added gene to panel | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||