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| Intellectual disability v9.117 | LGI1 |
Ida Ertmanska changed review comment from: 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 'BIALLELIC, 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; not associated with intellectual disability). 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 'BIALLELIC, autosomal or pseudoautosomal'. |
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| Intellectual disability v9.117 | LGI1 |
Ida Ertmanska changed review comment from: 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'.; 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 'BIALLELIC, autosomal or pseudoautosomal'. |
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| Intellectual disability v9.117 | LGI1 | Ida Ertmanska edited their review of gene: LGI1: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v9.117 | LGI1 | Arina Puzriakova Mode of inheritance for gene: LGI1 was changed from BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v9.116 | LGI1 | Arina Puzriakova Phenotypes for gene: LGI1 were changed from Epilepsy, familial temporal lobe, 1 600512; AUTOSOMAL DOMINANT PARTIAL EPILEPSY WITH AUDITORY FEATURES to Epilepsy, familial temporal lobe, 1, OMIM:600512; developmental and epileptic encephalopathy, MONDO:0100620 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v9.115 | LGI1 | Arina Puzriakova Publications for gene: LGI1 were set to 0 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v9.114 | LGI1 | Arina Puzriakova Mode of inheritance for gene: LGI1 was 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 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v9.113 | LGI1 |
Ida Ertmanska changed review comment from: 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'.; 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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| Intellectual disability v9.113 | LGI1 |
Ida Ertmanska commented on gene: LGI1: 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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| Intellectual disability v9.113 | LGI1 |
Ida Ertmanska changed review comment from: Monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF) - not associated with intellectual disability / developmental delay. 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) and 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. LGI1 is associated with AD Epilepsy, familial temporal lobe, 1 (600512) in OMIM - accessed 7th Oct 2025. LGI1 association with autosomal dominant epilepsy with auditory features is Definitive in ClinGen (July 2020). Since epilepsy is the first presenting symptom, and possibly the leading cause of intellectual disability and developmental delay in the above patients, LGI1 should be rated RED for Intellectual disability.; to: Monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF) - later-onset epilepsy, not associated with intellectual disability / developmental delay (PMID: 26773249). 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) and 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. LGI1 is associated with AD Epilepsy, familial temporal lobe, 1 (600512) in OMIM - accessed 7th Oct 2025. LGI1 association with autosomal dominant epilepsy with auditory features is Definitive in ClinGen (July 2020). Since epilepsy is the first presenting symptom, and possibly the leading cause of intellectual disability and developmental delay in the above patients, LGI1 should be rated RED for Intellectual disability. |
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| Intellectual disability v9.113 | LGI1 |
Ida Ertmanska changed review comment from: Monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF) - not associated with intellectual disability / developmental delay. 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) and 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. LGI1 is associated with AD Epilepsy, familial temporal lobe, 1 (600512) in OMIM - accessed 7th Oct 2025. LGI1 association with autosomal dominant epilepsy with auditory features is Definitive in ClinGen (July 2020). Since epilepsy is the first presenting symptom, and possibly the leading cause of intellectual disability and developmental delay in those patients, LGI1 should be rated RED for Intellectual disability.; to: Monoallelic variants in LGI1 are associated with Autosomal Dominant Epilepsy with Auditory Features (ADEAF) - not associated with intellectual disability / developmental delay. 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) and 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. LGI1 is associated with AD Epilepsy, familial temporal lobe, 1 (600512) in OMIM - accessed 7th Oct 2025. LGI1 association with autosomal dominant epilepsy with auditory features is Definitive in ClinGen (July 2020). Since epilepsy is the first presenting symptom, and possibly the leading cause of intellectual disability and developmental delay in the above patients, LGI1 should be rated RED for Intellectual disability. |
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| Intellectual disability v9.113 | LGI1 | Ida Ertmanska reviewed gene: LGI1: Rating: RED; Mode of pathogenicity: None; Publications: 26773249, 40455867, 41000458; Phenotypes: 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 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability v3.34 | ADAM22 | Rebecca Foulger commented on gene: ADAM22: PMID:27066583. Muona et al., 2016 report a Finnish proband-parent-trio with intractable seizures and ID. Compound het variants c.1202G>A, p.Cys401Tyr and c.2396delG, p.Ser799IlefsTer96 were found in ADAM22. Functional assays showed that mutant proteins failed to form the LGI1-ADAM22 ligand-receptor complex. The variants are unlikely to be full LOF. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability | LGI1 | BRIDGE consortium edited their review of LGI1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability | LGI1 | BRIDGE consortium edited their review of LGI1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Intellectual disability | LGI1 | BRIDGE consortium reviewed LGI1 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||