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{
"count": 221415,
"next": "https://panelapp-aus.org/api/v1/activities/?format=api&page=1803",
"previous": "https://panelapp-aus.org/api/v1/activities/?format=api&page=1801",
"results": [
{
"created": "2020-05-11T08:17:27.462836+10:00",
"panel_name": "Stroke",
"panel_id": 3141,
"panel_version": "0.18",
"user_name": "Bryony Thompson",
"item_type": "entity",
"text": "Classified gene: CD59 as Green List (high evidence)",
"entity_name": "CD59",
"entity_type": "gene"
},
{
"created": "2020-05-11T08:17:27.453797+10:00",
"panel_name": "Stroke",
"panel_id": 3141,
"panel_version": "0.18",
"user_name": "Bryony Thompson",
"item_type": "entity",
"text": "Gene: cd59 has been classified as Green List (High Evidence).",
"entity_name": "CD59",
"entity_type": "gene"
},
{
"created": "2020-05-11T08:17:01.779169+10:00",
"panel_name": "Stroke",
"panel_id": 3141,
"panel_version": "0.17",
"user_name": "Bryony Thompson",
"item_type": "entity",
"text": "gene: CD59 was added\ngene: CD59 was added to Stroke. Sources: Literature\nMode of inheritance for gene: CD59 was set to BIALLELIC, autosomal or pseudoautosomal\nPublications for gene: CD59 were set to 30356112; 28622911; 1699124; 25716358\nPhenotypes for gene: CD59 were set to Hemolytic anemia, CD59-mediated, with or without immune-mediated polyneuropathy MIM#612300\nReview for gene: CD59 was set to GREEN\nAdded comment: Recurrent strokes have been reported in at least 6 cases, with an arterial thrombosis stroke subtype. Condition is paediatric onset. \nSources: Literature",
"entity_name": "CD59",
"entity_type": "gene"
},
{
"created": "2020-05-11T08:10:55.180228+10:00",
"panel_name": "Stroke",
"panel_id": 3141,
"panel_version": "0.16",
"user_name": "Bryony Thompson",
"item_type": "entity",
"text": "Marked gene: KRIT1 as ready",
"entity_name": "KRIT1",
"entity_type": "gene"
},
{
"created": "2020-05-11T08:10:55.167962+10:00",
"panel_name": "Stroke",
"panel_id": 3141,
"panel_version": "0.16",
"user_name": "Bryony Thompson",
"item_type": "entity",
"text": "Gene: krit1 has been classified as Green List (High Evidence).",
"entity_name": "KRIT1",
"entity_type": "gene"
},
{
"created": "2020-05-11T08:10:51.063853+10:00",
"panel_name": "Stroke",
"panel_id": 3141,
"panel_version": "0.16",
"user_name": "Bryony Thompson",
"item_type": "entity",
"text": "Classified gene: KRIT1 as Green List (high evidence)",
"entity_name": "KRIT1",
"entity_type": "gene"
},
{
"created": "2020-05-11T08:10:51.051393+10:00",
"panel_name": "Stroke",
"panel_id": 3141,
"panel_version": "0.16",
"user_name": "Bryony Thompson",
"item_type": "entity",
"text": "Gene: krit1 has been classified as Green List (High Evidence).",
"entity_name": "KRIT1",
"entity_type": "gene"
},
{
"created": "2020-05-11T08:10:33.002816+10:00",
"panel_name": "Stroke",
"panel_id": 3141,
"panel_version": "0.15",
"user_name": "Bryony Thompson",
"item_type": "entity",
"text": "gene: KRIT1 was added\ngene: KRIT1 was added to Stroke. Sources: Literature\nMode of inheritance for gene: KRIT1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted\nPublications for gene: KRIT1 were set to 30356112; 14755725; 11310633; 9811928\nPhenotypes for gene: KRIT1 were set to Cavernous malformations of CNS and retina\tMIM#116860; Cerebral cavernous malformations-1 MIM#116860; Hyperkeratotic cutaneous capillary-venous malformations associated with cerebral capillary malformations MIM#116860\nReview for gene: KRIT1 was set to GREEN\nAdded comment: Cases reported with intracerebral bleeding and cavernoma stroke subtypes. \nSources: Literature",
"entity_name": "KRIT1",
"entity_type": "gene"
},
{
"created": "2020-05-10T13:01:09.171971+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.2789",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Marked gene: NR4A2 as ready",
"entity_name": "NR4A2",
"entity_type": "gene"
},
{
"created": "2020-05-10T13:01:09.158460+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.2789",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: nr4a2 has been classified as Green List (High Evidence).",
"entity_name": "NR4A2",
"entity_type": "gene"
},
{
"created": "2020-05-10T13:00:59.240988+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.2789",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Classified gene: NR4A2 as Green List (high evidence)",
"entity_name": "NR4A2",
"entity_type": "gene"
},
{
"created": "2020-05-10T13:00:59.231795+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.2789",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: nr4a2 has been classified as Green List (High Evidence).",
"entity_name": "NR4A2",
"entity_type": "gene"
},
{
"created": "2020-05-10T13:00:39.380762+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.2788",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "gene: NR4A2 was added\ngene: NR4A2 was added to Mendeliome. Sources: Literature\nMode of inheritance for gene: NR4A2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted\nPublications for gene: NR4A2 were set to 31428396; 30504930; 29770430; 12756136; 9092472\nPhenotypes for gene: NR4A2 were set to Intellectual disability; epilepsy\nReview for gene: NR4A2 was set to GREEN\nAdded comment: Over ten individuals reported with mono-allelic variants in this gene and neurodevelopmental phenotypes. Link with dementia/Parkinson's disease disputed. \nSources: Literature",
"entity_name": "NR4A2",
"entity_type": "gene"
},
{
"created": "2020-05-10T12:56:16.529114+10:00",
"panel_name": "Incidentalome",
"panel_id": 126,
"panel_version": "0.20",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Marked gene: NR4A2 as ready",
"entity_name": "NR4A2",
"entity_type": "gene"
},
{
"created": "2020-05-10T12:56:16.517938+10:00",
"panel_name": "Incidentalome",
"panel_id": 126,
"panel_version": "0.20",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: nr4a2 has been classified as Red List (Low Evidence).",
"entity_name": "NR4A2",
"entity_type": "gene"
},
{
"created": "2020-05-10T12:56:11.779239+10:00",
"panel_name": "Incidentalome",
"panel_id": 126,
"panel_version": "0.20",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Classified gene: NR4A2 as Red List (low evidence)",
"entity_name": "NR4A2",
"entity_type": "gene"
},
{
"created": "2020-05-10T12:56:11.770502+10:00",
"panel_name": "Incidentalome",
"panel_id": 126,
"panel_version": "0.20",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: nr4a2 has been classified as Red List (Low Evidence).",
"entity_name": "NR4A2",
"entity_type": "gene"
},
{
"created": "2020-05-10T12:55:42.102735+10:00",
"panel_name": "Incidentalome",
"panel_id": 126,
"panel_version": "0.19",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "reviewed gene: NR4A2: Rating: RED; Mode of pathogenicity: None; Publications: 12756136, 9092472; Phenotypes: ; Mode of inheritance: None",
"entity_name": "NR4A2",
"entity_type": "gene"
},
{
"created": "2020-05-10T08:34:10.735861+10:00",
"panel_name": "Genetic Epilepsy",
"panel_id": 202,
"panel_version": "0.703",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Marked gene: NR4A2 as ready",
"entity_name": "NR4A2",
"entity_type": "gene"
},
{
"created": "2020-05-10T08:34:10.725124+10:00",
"panel_name": "Genetic Epilepsy",
"panel_id": 202,
"panel_version": "0.703",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: nr4a2 has been classified as Green List (High Evidence).",
"entity_name": "NR4A2",
"entity_type": "gene"
},
{
"created": "2020-05-10T08:34:05.335774+10:00",
"panel_name": "Genetic Epilepsy",
"panel_id": 202,
"panel_version": "0.703",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Publications for gene: NR4A2 were set to 31428396",
"entity_name": "NR4A2",
"entity_type": "gene"
},
{
"created": "2020-05-10T08:33:27.913398+10:00",
"panel_name": "Genetic Epilepsy",
"panel_id": 202,
"panel_version": "0.702",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "reviewed gene: NR4A2: Rating: GREEN; Mode of pathogenicity: None; Publications: 32366965; Phenotypes: Intellectual disability, epilepsy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted",
"entity_name": "NR4A2",
"entity_type": "gene"
},
{
"created": "2020-05-10T08:32:06.453783+10:00",
"panel_name": "Genetic Epilepsy",
"panel_id": 202,
"panel_version": "0.702",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Publications for gene: NR4A2 were set to https://doi.org/10.1038/s41436-020-0815-4; 31428396",
"entity_name": "NR4A2",
"entity_type": "gene"
},
{
"created": "2020-05-10T08:31:32.175381+10:00",
"panel_name": "Genetic Epilepsy",
"panel_id": 202,
"panel_version": "0.701",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Classified gene: NR4A2 as Green List (high evidence)",
"entity_name": "NR4A2",
"entity_type": "gene"
},
{
"created": "2020-05-10T08:31:32.163621+10:00",
"panel_name": "Genetic Epilepsy",
"panel_id": 202,
"panel_version": "0.701",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: nr4a2 has been classified as Green List (High Evidence).",
"entity_name": "NR4A2",
"entity_type": "gene"
},
{
"created": "2020-05-10T08:30:12.761080+10:00",
"panel_name": "Intellectual disability syndromic and non-syndromic",
"panel_id": 250,
"panel_version": "0.2632",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Marked gene: NR4A2 as ready",
"entity_name": "NR4A2",
"entity_type": "gene"
},
{
"created": "2020-05-10T08:30:12.753872+10:00",
"panel_name": "Intellectual disability syndromic and non-syndromic",
"panel_id": 250,
"panel_version": "0.2632",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Added comment: Comment when marking as ready: Upgrade to Green in view of new publication reporting 9 additional individuals.",
"entity_name": "NR4A2",
"entity_type": "gene"
},
{
"created": "2020-05-10T08:30:12.722203+10:00",
"panel_name": "Intellectual disability syndromic and non-syndromic",
"panel_id": 250,
"panel_version": "0.2632",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: nr4a2 has been classified as Green List (High Evidence).",
"entity_name": "NR4A2",
"entity_type": "gene"
},
{
"created": "2020-05-10T08:29:29.987751+10:00",
"panel_name": "Intellectual disability syndromic and non-syndromic",
"panel_id": 250,
"panel_version": "0.2632",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Classified gene: NR4A2 as Green List (high evidence)",
"entity_name": "NR4A2",
"entity_type": "gene"
},
{
"created": "2020-05-10T08:29:29.978875+10:00",
"panel_name": "Intellectual disability syndromic and non-syndromic",
"panel_id": 250,
"panel_version": "0.2632",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: nr4a2 has been classified as Green List (High Evidence).",
"entity_name": "NR4A2",
"entity_type": "gene"
},
{
"created": "2020-05-10T05:48:40.260511+10:00",
"panel_name": "Genetic Epilepsy",
"panel_id": 202,
"panel_version": "0.700",
"user_name": "Konstantinos Varvagiannis",
"item_type": "entity",
"text": "gene: NR4A2 was added\ngene: NR4A2 was added to Genetic Epilepsy. Sources: Literature\nMode of inheritance for gene: NR4A2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown\nPublications for gene: NR4A2 were set to https://doi.org/10.1038/s41436-020-0815-4; 31428396\nPhenotypes for gene: NR4A2 were set to Generalized hypotonia, Global developmental delay, Intellectual disability, Seizures, Behavioral abnormality, Abnormality of movement, Joint hypermobility\nPenetrance for gene: NR4A2 were set to unknown\nReview for gene: NR4A2 was set to GREEN\nAdded comment: Seizures have been reported in at least 6 unrelated individuals with NR4A2 variants (not including cases with contiguous gene deletions spanning also this gene). Please consider inclusion with amber or green rating. \r\n---\r\nSingh et al (2020 - https://doi.org/10.1038/s41436-020-0815-4) provide details on the phenotype of 9 unrelated individuals with NR4A2 pathogenic variants (in almost all cases de novo).\r\n\r\nFeatures included hypotonia (in 6/9), DD (9/9), varying levels of ID (mild to severe in 8/8 for whom this information was available), seizures (6/9 - variable epilepsy phenotypes), behavioral problems (5/9 - with autism reported for one). Less frequent features incl. hypermobility (in 3), ataxia/movement disorder (in 3). \r\n\r\n8 total pLoF and missense variants were identified as de novo events following trio exome sequencing with Sanger validation (7/8 variants). For 1(/8) individual with a stopgain variant, a single parental sample was available. A 9th individual was found to harbor a ~3.7 Mb 2q deletion spanning also other genes (which might also contribute to his phenotype of epilepsy).\r\n\r\nOnly the effect of a variant affecting the splice-acceptor site was studied (c.865-1_865delGCinsAAAAAGGAGT - NM_006186.3) with RT-PCR demonstrating an out-of-frame skipping of exon 4. Another variant (NM_006186.3:c.325dup) found in a subject with DD, ID and epilepsy had also previously been reported in another individual with similar phenotype of epilepsy and ID (Ramos et al - PMID: 31428396 - the variant was de novo with other causes for his phenotype excluded).\r\n\r\nAs discussed by Singh et al, NR4A2 encodes a steroid-thyroid-retinoid receptor which acts as a nuclear receptor transcription factor. The authors summarize previous reports on NR4A2 haploinsufficiency (NR4A2 has a pLI of 1 and HI score of 1.28% - Z-score is 2.24).\r\n\r\nThe authors comment on mouse models suggesting a role of NR4A2 for dopaminergic neurons, and provide plausible explanations for the phenotype of ID/seizures. \nSources: Literature",
"entity_name": "NR4A2",
"entity_type": "gene"
},
{
"created": "2020-05-10T05:42:53.149748+10:00",
"panel_name": "Intellectual disability syndromic and non-syndromic",
"panel_id": 250,
"panel_version": "0.2631",
"user_name": "Konstantinos Varvagiannis",
"item_type": "entity",
"text": "reviewed gene: NR4A2: Rating: GREEN; Mode of pathogenicity: None; Publications: https://doi.org/10.1038/s41436-020-0815-4, 31428396, 29770430, 30504930, 28544326, 27569545, 23554088, 28135719, 27479843, 25363768; Phenotypes: Generalized hypotonia, Global developmental delay, Intellectual disability, Seizures, Behavioral abnormality, Abnormality of movement, Joint hypermobility; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown",
"entity_name": "NR4A2",
"entity_type": "gene"
},
{
"created": "2020-05-09T17:32:35.748149+10:00",
"panel_name": "Leukodystrophy - paediatric",
"panel_id": 298,
"panel_version": "0.122",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Marked gene: MLC1 as ready",
"entity_name": "MLC1",
"entity_type": "gene"
},
{
"created": "2020-05-09T17:32:35.737438+10:00",
"panel_name": "Leukodystrophy - paediatric",
"panel_id": 298,
"panel_version": "0.122",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: mlc1 has been classified as Green List (High Evidence).",
"entity_name": "MLC1",
"entity_type": "gene"
},
{
"created": "2020-05-09T17:32:21.073421+10:00",
"panel_name": "Leukodystrophy - paediatric",
"panel_id": 298,
"panel_version": "0.122",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Classified gene: MLC1 as Green List (high evidence)",
"entity_name": "MLC1",
"entity_type": "gene"
},
{
"created": "2020-05-09T17:32:21.060304+10:00",
"panel_name": "Leukodystrophy - paediatric",
"panel_id": 298,
"panel_version": "0.122",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: mlc1 has been classified as Green List (High Evidence).",
"entity_name": "MLC1",
"entity_type": "gene"
},
{
"created": "2020-05-09T17:32:11.053042+10:00",
"panel_name": "Leukodystrophy - paediatric",
"panel_id": 298,
"panel_version": "0.121",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "gene: MLC1 was added\ngene: MLC1 was added to Leukodystrophy - paediatric. Sources: Expert list\nMode of inheritance for gene: MLC1 was set to BIALLELIC, autosomal or pseudoautosomal\nPublications for gene: MLC1 were set to 11254442; 21419380; 21624973\nPhenotypes for gene: MLC1 were set to Megalencephalic leukoencephalopathy with subcortical cysts, MIM#\t604004\nReview for gene: MLC1 was set to GREEN\nAdded comment: Childhood onset, progressive MRI changes. \nSources: Expert list",
"entity_name": "MLC1",
"entity_type": "gene"
},
{
"created": "2020-05-09T17:26:50.429401+10:00",
"panel_name": "Leukodystrophy - paediatric",
"panel_id": 298,
"panel_version": "0.120",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Marked gene: MCOLN1 as ready",
"entity_name": "MCOLN1",
"entity_type": "gene"
},
{
"created": "2020-05-09T17:26:50.420396+10:00",
"panel_name": "Leukodystrophy - paediatric",
"panel_id": 298,
"panel_version": "0.120",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: mcoln1 has been classified as Green List (High Evidence).",
"entity_name": "MCOLN1",
"entity_type": "gene"
},
{
"created": "2020-05-09T17:26:45.388943+10:00",
"panel_name": "Leukodystrophy - paediatric",
"panel_id": 298,
"panel_version": "0.120",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Classified gene: MCOLN1 as Green List (high evidence)",
"entity_name": "MCOLN1",
"entity_type": "gene"
},
{
"created": "2020-05-09T17:26:45.376682+10:00",
"panel_name": "Leukodystrophy - paediatric",
"panel_id": 298,
"panel_version": "0.120",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: mcoln1 has been classified as Green List (High Evidence).",
"entity_name": "MCOLN1",
"entity_type": "gene"
},
{
"created": "2020-05-09T17:26:34.749220+10:00",
"panel_name": "Leukodystrophy - paediatric",
"panel_id": 298,
"panel_version": "0.119",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "gene: MCOLN1 was added\ngene: MCOLN1 was added to Leukodystrophy - paediatric. Sources: Expert list\nMode of inheritance for gene: MCOLN1 was set to BIALLELIC, autosomal or pseudoautosomal\nPublications for gene: MCOLN1 were set to 10973263; 11030752\nPhenotypes for gene: MCOLN1 were set to Mucolipidosis IV, MIM#\t252650\nReview for gene: MCOLN1 was set to GREEN\nAdded comment: Sources: Expert list",
"entity_name": "MCOLN1",
"entity_type": "gene"
},
{
"created": "2020-05-09T12:04:15.761299+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.2787",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "edited their review of gene: TET2: Added comment: Association study (PMID 32330418) found enrichment of non-coding and LoF TET2 variants in cohort of individuals with early onset dementia, unclear if this is monogenic or polygenic contribution.; Changed publications: 30890702, 31827242, 32330418",
"entity_name": "TET2",
"entity_type": "gene"
},
{
"created": "2020-05-09T11:43:44.143294+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.2787",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Marked gene: TOMM70 as ready",
"entity_name": "TOMM70",
"entity_type": "gene"
},
{
"created": "2020-05-09T11:43:44.129023+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.2787",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: tomm70 has been classified as Amber List (Moderate Evidence).",
"entity_name": "TOMM70",
"entity_type": "gene"
},
{
"created": "2020-05-09T11:43:35.766160+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.2787",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Classified gene: TOMM70 as Amber List (moderate evidence)",
"entity_name": "TOMM70",
"entity_type": "gene"
},
{
"created": "2020-05-09T11:43:35.754043+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.2787",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: tomm70 has been classified as Amber List (Moderate Evidence).",
"entity_name": "TOMM70",
"entity_type": "gene"
},
{
"created": "2020-05-09T11:43:17.368402+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.2786",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "gene: TOMM70 was added\ngene: TOMM70 was added to Mendeliome. Sources: Expert list\nMode of inheritance for gene: TOMM70 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal\nPublications for gene: TOMM70 were set to 31907385; 32356556\nPhenotypes for gene: TOMM70 were set to Severe anaemia, lactic acidosis, developmental delay; White matter abnormalities, developmental delay, regression, movement disorder\nReview for gene: TOMM70 was set to AMBER\nAdded comment: TOM70 is a member of the TOM complex that transports cytosolic proteins into mitochondria.\r\nBi-allelic disease: one individual reported with compound heterozygous variants in TOMM70 [c.794C>T (p.T265M) and c.1745C>T (p.A582V)]. Clinical features included severe anaemia, lactic acidosis, and developmental delay. Some functional data: in vitro cell model compensatory experiments.\r\nMonoallelic disease: de novo mono allelic variants in the C-terminal region of TOMM70 reported in two individuals. While both individuals exhibited shared symptoms including hypotonia, hyperreflexia, ataxia, dystonia, and significant white matter abnormalities, there were differences between the two individuals, most prominently the age of symptom onset, with one experiencing episodes of regression. Some functional data. \nSources: Expert list",
"entity_name": "TOMM70",
"entity_type": "gene"
},
{
"created": "2020-05-09T11:39:06.311864+10:00",
"panel_name": "Mitochondrial disease",
"panel_id": 203,
"panel_version": "0.448",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Publications for gene: TOMM70 were set to ",
"entity_name": "TOMM70",
"entity_type": "gene"
},
{
"created": "2020-05-09T11:38:35.469923+10:00",
"panel_name": "Mitochondrial disease",
"panel_id": 203,
"panel_version": "0.447",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "edited their review of gene: TOMM70: Changed publications: 31907385",
"entity_name": "TOMM70",
"entity_type": "gene"
},
{
"created": "2020-05-09T11:38:17.808720+10:00",
"panel_name": "Leukodystrophy - paediatric",
"panel_id": 298,
"panel_version": "0.118",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Marked gene: TOMM70 as ready",
"entity_name": "TOMM70",
"entity_type": "gene"
},
{
"created": "2020-05-09T11:38:17.797553+10:00",
"panel_name": "Leukodystrophy - paediatric",
"panel_id": 298,
"panel_version": "0.118",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: tomm70 has been classified as Amber List (Moderate Evidence).",
"entity_name": "TOMM70",
"entity_type": "gene"
},
{
"created": "2020-05-09T11:38:13.996815+10:00",
"panel_name": "Leukodystrophy - paediatric",
"panel_id": 298,
"panel_version": "0.118",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Classified gene: TOMM70 as Amber List (moderate evidence)",
"entity_name": "TOMM70",
"entity_type": "gene"
},
{
"created": "2020-05-09T11:38:13.984646+10:00",
"panel_name": "Leukodystrophy - paediatric",
"panel_id": 298,
"panel_version": "0.118",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: tomm70 has been classified as Amber List (Moderate Evidence).",
"entity_name": "TOMM70",
"entity_type": "gene"
},
{
"created": "2020-05-09T11:38:04.832147+10:00",
"panel_name": "Leukodystrophy - paediatric",
"panel_id": 298,
"panel_version": "0.117",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "gene: TOMM70 was added\ngene: TOMM70 was added to Leukodystrophy - paediatric. Sources: Literature\nMode of inheritance for gene: TOMM70 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted\nPublications for gene: TOMM70 were set to 32356556\nPhenotypes for gene: TOMM70 were set to White matter abnormalities; Developmental delay; Regression; Movement disorder\nReview for gene: TOMM70 was set to AMBER\nAdded comment: De novo mono allelic variants in the C-terminal region of TOMM70 reported in two individuals. While both individuals exhibited shared symptoms including hypotonia, hyperreflexia, ataxia, dystonia, and significant white matter abnormalities, there were differences between the two individuals, most prominently the age of symptom onset, with one experiencing episodes of regression. Some functional data. Note bi-allelic disease also reported in one individual, with features of a mitochondrial disorder. \nSources: Literature",
"entity_name": "TOMM70",
"entity_type": "gene"
},
{
"created": "2020-05-09T11:28:05.704977+10:00",
"panel_name": "Mitochondrial disease",
"panel_id": 203,
"panel_version": "0.447",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Marked gene: TOMM70 as ready",
"entity_name": "TOMM70",
"entity_type": "gene"
},
{
"created": "2020-05-09T11:28:05.694190+10:00",
"panel_name": "Mitochondrial disease",
"panel_id": 203,
"panel_version": "0.447",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: tomm70 has been classified as Amber List (Moderate Evidence).",
"entity_name": "TOMM70",
"entity_type": "gene"
},
{
"created": "2020-05-09T11:28:00.185195+10:00",
"panel_name": "Mitochondrial disease",
"panel_id": 203,
"panel_version": "0.447",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Classified gene: TOMM70 as Amber List (moderate evidence)",
"entity_name": "TOMM70",
"entity_type": "gene"
},
{
"created": "2020-05-09T11:28:00.176037+10:00",
"panel_name": "Mitochondrial disease",
"panel_id": 203,
"panel_version": "0.447",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: tomm70 has been classified as Amber List (Moderate Evidence).",
"entity_name": "TOMM70",
"entity_type": "gene"
},
{
"created": "2020-05-09T11:27:16.073458+10:00",
"panel_name": "Mitochondrial disease",
"panel_id": 203,
"panel_version": "0.446",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "gene: TOMM70 was added\ngene: TOMM70 was added to Mitochondrial disease. Sources: Literature\nMode of inheritance for gene: TOMM70 was set to BIALLELIC, autosomal or pseudoautosomal\nPhenotypes for gene: TOMM70 were set to Severe anaemia; Lactic acidosis; Developmental delay\nReview for gene: TOMM70 was set to AMBER\nAdded comment: TOM70 is a member of the TOM complex that transports cytosolic proteins into mitochondria. One individual reported with compound heterozygous variants in TOMM70 [c.794C>T (p.T265M) and c.1745C>T (p.A582V)]. Clinical features included severe anaemia, lactic acidosis, and developmental delay. Some functional data: in vitro cell model compensatory experiments. \nSources: Literature",
"entity_name": "TOMM70",
"entity_type": "gene"
},
{
"created": "2020-05-09T08:34:18.679830+10:00",
"panel_name": "Renal Hypertension and Disorders of Aldosterone Metabolism",
"panel_id": 190,
"panel_version": "0.15",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Marked gene: CUL3 as ready",
"entity_name": "CUL3",
"entity_type": "gene"
},
{
"created": "2020-05-09T08:34:18.668964+10:00",
"panel_name": "Renal Hypertension and Disorders of Aldosterone Metabolism",
"panel_id": 190,
"panel_version": "0.15",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: cul3 has been classified as Green List (High Evidence).",
"entity_name": "CUL3",
"entity_type": "gene"
},
{
"created": "2020-05-09T08:34:16.557705+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.2785",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Publications for gene: CUL3 were set to 22495309; 22914163; 25363760; 27824329; 32341456",
"entity_name": "CUL3",
"entity_type": "gene"
},
{
"created": "2020-05-09T08:34:05.171867+10:00",
"panel_name": "Renal Hypertension and Disorders of Aldosterone Metabolism",
"panel_id": 190,
"panel_version": "0.15",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Phenotypes for gene: CUL3 were changed from Pseudohypoaldosteronism, type IIE, MIM# 614496 to Pseudohypoaldosteronism, type IIE, MIM# 614496",
"entity_name": "CUL3",
"entity_type": "gene"
},
{
"created": "2020-05-09T08:33:46.291174+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.2784",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "edited their review of gene: CUL3: Changed publications: 22495309, 22914163, 25363760, 27824329, 32341456, 22266938",
"entity_name": "CUL3",
"entity_type": "gene"
},
{
"created": "2020-05-09T08:33:37.975012+10:00",
"panel_name": "Renal Hypertension and Disorders of Aldosterone Metabolism",
"panel_id": 190,
"panel_version": "0.15",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Phenotypes for gene: CUL3 were changed from to Pseudohypoaldosteronism, type IIE, MIM# 614496",
"entity_name": "CUL3",
"entity_type": "gene"
},
{
"created": "2020-05-09T08:33:08.274597+10:00",
"panel_name": "Renal Hypertension and Disorders of Aldosterone Metabolism",
"panel_id": 190,
"panel_version": "0.14",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Publications for gene: CUL3 were set to ",
"entity_name": "CUL3",
"entity_type": "gene"
},
{
"created": "2020-05-09T08:32:35.722887+10:00",
"panel_name": "Renal Hypertension and Disorders of Aldosterone Metabolism",
"panel_id": 190,
"panel_version": "0.13",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Mode of inheritance for gene: CUL3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted",
"entity_name": "CUL3",
"entity_type": "gene"
},
{
"created": "2020-05-09T08:32:04.052576+10:00",
"panel_name": "Renal Hypertension and Disorders of Aldosterone Metabolism",
"panel_id": 190,
"panel_version": "0.12",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "reviewed gene: CUL3: Rating: GREEN; Mode of pathogenicity: None; Publications: 22266938; Phenotypes: Pseudohypoaldosteronism, type IIE, MIM# 614496; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted",
"entity_name": "CUL3",
"entity_type": "gene"
},
{
"created": "2020-05-09T08:30:22.047151+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.2784",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Marked gene: CUL3 as ready",
"entity_name": "CUL3",
"entity_type": "gene"
},
{
"created": "2020-05-09T08:30:22.038172+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.2784",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: cul3 has been classified as Green List (High Evidence).",
"entity_name": "CUL3",
"entity_type": "gene"
},
{
"created": "2020-05-09T08:30:15.366723+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.2784",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Phenotypes for gene: CUL3 were changed from to Pseudohypoaldosteronism, type IIE 614496; Intellectual disability; Autism; Seizures",
"entity_name": "CUL3",
"entity_type": "gene"
},
{
"created": "2020-05-09T08:29:57.053565+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.2783",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Publications for gene: CUL3 were set to ",
"entity_name": "CUL3",
"entity_type": "gene"
},
{
"created": "2020-05-09T08:29:33.954019+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.2782",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Mode of inheritance for gene: CUL3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted",
"entity_name": "CUL3",
"entity_type": "gene"
},
{
"created": "2020-05-09T08:29:13.283258+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.2781",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "reviewed gene: CUL3: Rating: GREEN; Mode of pathogenicity: None; Publications: 22495309, 22914163, 25363760, 27824329, 32341456; Phenotypes: Pseudohypoaldosteronism, type IIE 614496, Intellectual disability, Autism, Seizures; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted",
"entity_name": "CUL3",
"entity_type": "gene"
},
{
"created": "2020-05-09T08:25:35.119753+10:00",
"panel_name": "Autism",
"panel_id": 51,
"panel_version": "0.91",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Phenotypes for gene: CUL3 were changed from Autism to Autism; Intellectual disability; Epilepsy",
"entity_name": "CUL3",
"entity_type": "gene"
},
{
"created": "2020-05-09T08:25:02.146698+10:00",
"panel_name": "Autism",
"panel_id": 51,
"panel_version": "0.90",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "edited their review of gene: CUL3: Added comment: Further publication (PMID 32341456) reporting three unrelated individuals with neurodevelopmental phenotype.; Changed publications: 22495309, 22914163, 25363760, 27824329, 32341456; Changed phenotypes: Autism, Intellectual disability, Epilepsy",
"entity_name": "CUL3",
"entity_type": "gene"
},
{
"created": "2020-05-09T08:23:04.205346+10:00",
"panel_name": "Genetic Epilepsy",
"panel_id": 202,
"panel_version": "0.700",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Marked gene: CUL3 as ready",
"entity_name": "CUL3",
"entity_type": "gene"
},
{
"created": "2020-05-09T08:23:04.196254+10:00",
"panel_name": "Genetic Epilepsy",
"panel_id": 202,
"panel_version": "0.700",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: cul3 has been classified as Amber List (Moderate Evidence).",
"entity_name": "CUL3",
"entity_type": "gene"
},
{
"created": "2020-05-09T08:22:58.438684+10:00",
"panel_name": "Genetic Epilepsy",
"panel_id": 202,
"panel_version": "0.700",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Phenotypes for gene: CUL3 were changed from Global developmental delay; Intellectual disability; Seizures; Abnormality of cardiovascular system morphology; Abnormality of the palate; Pseudohypoaldosteronism, type IIE - MIM #614496 to Global developmental delay; Intellectual disability; Seizures; Abnormality of cardiovascular system morphology; Abnormality of the palate",
"entity_name": "CUL3",
"entity_type": "gene"
},
{
"created": "2020-05-09T08:21:57.021440+10:00",
"panel_name": "Genetic Epilepsy",
"panel_id": 202,
"panel_version": "0.699",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Classified gene: CUL3 as Amber List (moderate evidence)",
"entity_name": "CUL3",
"entity_type": "gene"
},
{
"created": "2020-05-09T08:21:57.009200+10:00",
"panel_name": "Genetic Epilepsy",
"panel_id": 202,
"panel_version": "0.699",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: cul3 has been classified as Amber List (Moderate Evidence).",
"entity_name": "CUL3",
"entity_type": "gene"
},
{
"created": "2020-05-09T08:20:52.864541+10:00",
"panel_name": "Intellectual disability syndromic and non-syndromic",
"panel_id": 250,
"panel_version": "0.2631",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Marked gene: CUL3 as ready",
"entity_name": "CUL3",
"entity_type": "gene"
},
{
"created": "2020-05-09T08:20:52.852974+10:00",
"panel_name": "Intellectual disability syndromic and non-syndromic",
"panel_id": 250,
"panel_version": "0.2631",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: cul3 has been classified as Green List (High Evidence).",
"entity_name": "CUL3",
"entity_type": "gene"
},
{
"created": "2020-05-09T08:20:38.814904+10:00",
"panel_name": "Intellectual disability syndromic and non-syndromic",
"panel_id": 250,
"panel_version": "0.2631",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Phenotypes for gene: CUL3 were changed from Global developmental delay; Intellectual disability; Seizures; Abnormality of cardiovascular system morphology; Abnormality of the palate; Pseudohypoaldosteronism, type IIE - MIM #614496 to Global developmental delay; Intellectual disability; Seizures; Abnormality of cardiovascular system morphology; Abnormality of the palate",
"entity_name": "CUL3",
"entity_type": "gene"
},
{
"created": "2020-05-09T08:20:04.273243+10:00",
"panel_name": "Intellectual disability syndromic and non-syndromic",
"panel_id": 250,
"panel_version": "0.2630",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Classified gene: CUL3 as Green List (high evidence)",
"entity_name": "CUL3",
"entity_type": "gene"
},
{
"created": "2020-05-09T08:20:04.263787+10:00",
"panel_name": "Intellectual disability syndromic and non-syndromic",
"panel_id": 250,
"panel_version": "0.2630",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: cul3 has been classified as Green List (High Evidence).",
"entity_name": "CUL3",
"entity_type": "gene"
},
{
"created": "2020-05-08T19:00:40.069965+10:00",
"panel_name": "Genetic Epilepsy",
"panel_id": 202,
"panel_version": "0.698",
"user_name": "Konstantinos Varvagiannis",
"item_type": "entity",
"text": "gene: CUL3 was added\ngene: CUL3 was added to Genetic Epilepsy. Sources: Literature\nMode of inheritance for gene: CUL3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown\nPublications for gene: CUL3 were set to 32341456\nPhenotypes for gene: CUL3 were set to Global developmental delay; Intellectual disability; Seizures; Abnormality of cardiovascular system morphology; Abnormality of the palate; Pseudohypoaldosteronism, type IIE - MIM #614496\nPenetrance for gene: CUL3 were set to unknown\nReview for gene: CUL3 was set to AMBER\nAdded comment: Nakashima et al (2020 - PMID:32341456) provide clinical details on 3 unrelated individuals with de novo CUL3 variants. \r\n\r\nFeatures included DD, variable degrees of ID (P1: severe, P3: mild, P2: NA although he displayed motor and severe speech and language delay and had severe learning difficulties). Two out of three had intractable seizures (onset 2 - 6 months). One presented with congenital heart defects (ASD, PV stenosis) and another submucosal palatoschisis/bifid uvula. There were no facial dysmorphisms reported.\r\n\r\nCUL3 encodes Cullin-3, a core piece of the E3 ubiquitin ligase complex, thus playing a role in the ubiquitin-proteasome system. [ https://ghr.nlm.nih.gov/gene/CUL3 ]. Germline variants in some other Cullin family genes (eg. CUL4B, CUL7) cause disorders with ID as a feature.\r\n\r\nThe 3 individuals reported by Nakashima had variable previous investigations (karyotype, CMA, metabolic testing) which were non-diagnostic. Singleton or trio exome sequencing identified 2 frameshift and 1 missense variant (NM_003590.4:c.854T>C / p.Val285Ala), further confirmed with Sanger sequencing. De novo occurrence was confirmed by analysis of microsatellite markers in an individual with singleton ES.\r\n\r\nWhile the frameshift variants were presumed to lead to NMD (not studied), studies in HEK293T cells suggested that the Val285Ala reduced binding ability with KEAP1, possibly leading to instability of the Cullin-RING ligase (CRL) complex and impairment of the ubiquitin-proteasome system.\r\n\r\nIn OMIM, the phenotype associated with heterozygous CUL3 mutations is Pseudohypoaldosteronism type IIE (PHA2E - # 614496). As OMIM and Nakashima et al comment, PHA2E-associated variants are clustered around exon 9, most lead to skipping of exon 9 and produce an in-frame deletion of 57 aa in the cullin homology domain. Few (probably 3) missense variants in exon 9 have also been reported. Individuals with PHA2E do not display DD/ID and conversely individuals with NDD did not display features of PHA2E.\r\n\r\nNakashima et al summarize the phenotypes associated with 12 further de novo CUL3 variants in the literature with most pLOF ones detected in individuals with autism and/or developmental disorders and in few cases with congenital heart disease. Few additional missense variants and a stoploss one have been reported in individuals with NDD and one in SCZ.\r\n\r\nHeterozygous Cul3 (/tissue-specific) deletion in mice resulted in autism-like behavior. Cul3 deficient mice also demonstrated NMDAR hypofunction and decreased spine density. [PMIDs cited : 31455858, 31780330]\r\n\r\nOverall haploinsufficiency is favored as the underlying mechanism of variants associated with NDD. Nakashima et al comment that the pathogenesis of missense variants remains unknown and/or that a dominant-negative effect on CRL may be possible. \r\n\r\nStudies on larger cohorts reporting on individuals with relevant phenotypes due to de novo CUL3 variants (eg. DDD study - PMID: 28135719, Lelieveld et al - PMID: 27479843), are better summarized in denovo-db (after filtering for coding variants):\r\n\r\nhttp://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=cul3\r\n\r\nOverall, this gene can be considered for inclusion in the ID (amber/green), epilepsy (amber) and/or ASD panels. \nSources: Literature",
"entity_name": "CUL3",
"entity_type": "gene"
},
{
"created": "2020-05-08T18:57:16.270251+10:00",
"panel_name": "Intellectual disability syndromic and non-syndromic",
"panel_id": 250,
"panel_version": "0.2629",
"user_name": "Konstantinos Varvagiannis",
"item_type": "entity",
"text": "gene: CUL3 was added\ngene: CUL3 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature\nMode of inheritance for gene: CUL3 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown\nPublications for gene: CUL3 were set to 32341456\nPhenotypes for gene: CUL3 were set to Global developmental delay; Intellectual disability; Seizures; Abnormality of cardiovascular system morphology; Abnormality of the palate; Pseudohypoaldosteronism, type IIE - MIM #614496\nPenetrance for gene: CUL3 were set to unknown\nReview for gene: CUL3 was set to GREEN\nAdded comment: Please consider inclusion with amber / green rating.\r\n--\r\nNakashima et al (2020 - PMID:32341456) provide clinical details on 3 unrelated individuals with de novo CUL3 variants. \r\n\r\nFeatures included DD, variable degrees of ID (P1: severe, P3: mild, P2: NA although he displayed motor and severe speech and language delay and had severe learning difficulties). Two out of three had intractable seizures (onset 2 - 6 months). One presented with congenital heart defects (ASD, PV stenosis) and another submucosal palatoschisis/bifid uvula. There were no facial dysmorphisms reported.\r\n\r\nCUL3 encodes Cullin-3, a core piece of the E3 ubiquitin ligase complex, thus playing a role in the ubiquitin-proteasome system. [ https://ghr.nlm.nih.gov/gene/CUL3 ]. Germline variants in some other Cullin family genes (eg. CUL4B, CUL7) cause disorders with ID as a feature.\r\n\r\nThe 3 individuals reported by Nakashima had variable previous investigations (karyotype, CMA, metabolic testing) which were non-diagnostic. Singleton or trio exome sequencing identified 2 frameshift and 1 missense variant (NM_003590.4:c.854T>C / p.Val285Ala), further confirmed with Sanger sequencing. De novo occurrence was confirmed by analysis of microsatellite markers in an individual with singleton ES.\r\n\r\nWhile the frameshift variants were presumed to lead to NMD (not studied), studies in HEK293T cells suggested that the Val285Ala reduced binding ability with KEAP1, possibly leading to instability of the Cullin-RING ligase (CRL) complex and impairment of the ubiquitin-proteasome system.\r\n\r\nIn OMIM, the phenotype associated with heterozygous CUL3 mutations is Pseudohypoaldosteronism type IIE (PHA2E - # 614496). As OMIM and Nakashima et al comment, PHA2E-associated variants are clustered around exon 9, most lead to skipping of exon 9 and produce an in-frame deletion of 57 aa in the cullin homology domain. Few (probably 3) missense variants in exon 9 have also been reported. Individuals with PHA2E do not display DD/ID and conversely individuals with NDD did not display features of PHA2E.\r\n\r\nNakashima et al summarize the phenotypes associated with 12 further de novo CUL3 variants in the literature with most pLOF ones detected in individuals with autism and/or developmental disorders and in few cases with congenital heart disease. Few additional missense variants and a stoploss one have been reported in individuals with NDD and one in SCZ.\r\n\r\nHeterozygous Cul3 (/tissue-specific) deletion in mice resulted in autism-like behavior. Cul3 deficient mice also demonstrated NMDAR hypofunction and decreased spine density. [PMIDs cited : 31455858, 31780330]\r\n\r\nOverall haploinsufficiency is favored as the underlying mechanism of variants associated with NDD. Nakashima et al comment that the pathogenesis of missense variants remains unknown and/or that a dominant-negative effect on CRL may be possible. \r\n\r\nStudies on larger cohorts reporting on individuals with relevant phenotypes due to de novo CUL3 variants (eg. DDD study - PMID: 28135719, Lelieveld et al - PMID: 27479843), are summarized in denovo-db (after filtering for coding variants):\r\n\r\nhttp://denovo-db.gs.washington.edu/denovo-db/QueryVariantServlet?searchBy=Gene&target=cul3\r\n\r\nOverall, this gene can be considered for inclusion in the ID (amber/green), epilepsy (amber) and/or ASD panels. \nSources: Literature",
"entity_name": "CUL3",
"entity_type": "gene"
},
{
"created": "2020-05-08T18:11:22.024702+10:00",
"panel_name": "Stroke",
"panel_id": 3141,
"panel_version": "0.14",
"user_name": "Bryony Thompson",
"item_type": "entity",
"text": "Marked gene: CBS as ready",
"entity_name": "CBS",
"entity_type": "gene"
},
{
"created": "2020-05-08T18:11:22.012831+10:00",
"panel_name": "Stroke",
"panel_id": 3141,
"panel_version": "0.14",
"user_name": "Bryony Thompson",
"item_type": "entity",
"text": "Gene: cbs has been classified as Green List (High Evidence).",
"entity_name": "CBS",
"entity_type": "gene"
},
{
"created": "2020-05-08T18:11:11.843543+10:00",
"panel_name": "Stroke",
"panel_id": 3141,
"panel_version": "0.14",
"user_name": "Bryony Thompson",
"item_type": "entity",
"text": "Classified gene: CBS as Green List (high evidence)",
"entity_name": "CBS",
"entity_type": "gene"
},
{
"created": "2020-05-08T18:11:11.831562+10:00",
"panel_name": "Stroke",
"panel_id": 3141,
"panel_version": "0.14",
"user_name": "Bryony Thompson",
"item_type": "entity",
"text": "Gene: cbs has been classified as Green List (High Evidence).",
"entity_name": "CBS",
"entity_type": "gene"
},
{
"created": "2020-05-08T18:11:02.873886+10:00",
"panel_name": "Stroke",
"panel_id": 3141,
"panel_version": "0.13",
"user_name": "Bryony Thompson",
"item_type": "entity",
"text": "gene: CBS was added\ngene: CBS was added to Stroke. Sources: Literature\nMode of inheritance for gene: CBS was set to BIALLELIC, autosomal or pseudoautosomal\nPublications for gene: CBS were set to 30356112; 20142522; 12552044\nPhenotypes for gene: CBS were set to Homocystinuria, B6-responsive and nonresponsive types MIM#236200; Thrombosis, hyperhomocysteinemic MIM#236200\nReview for gene: CBS was set to GREEN\nAdded comment: Large artery atherosclerosis/non-atherosclerosis, small-vessel disease, venous thrombosis, and arterial thrombosis stroke subtypes have been reported in the condition. \nSources: Literature",
"entity_name": "CBS",
"entity_type": "gene"
},
{
"created": "2020-05-08T17:59:36.149911+10:00",
"panel_name": "Genetic Epilepsy",
"panel_id": 202,
"panel_version": "0.698",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Marked gene: KCNT1 as ready",
"entity_name": "KCNT1",
"entity_type": "gene"
},
{
"created": "2020-05-08T17:59:36.141123+10:00",
"panel_name": "Genetic Epilepsy",
"panel_id": 202,
"panel_version": "0.698",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: kcnt1 has been classified as Green List (High Evidence).",
"entity_name": "KCNT1",
"entity_type": "gene"
},
{
"created": "2020-05-08T17:59:33.068823+10:00",
"panel_name": "Genetic Epilepsy",
"panel_id": 202,
"panel_version": "0.698",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Phenotypes for gene: KCNT1 were changed from to Epilepsy, nocturnal frontal lobe, 5, MIM# 615005; Epileptic encephalopathy, early infantile, 14, MIM# 614959",
"entity_name": "KCNT1",
"entity_type": "gene"
},
{
"created": "2020-05-08T17:59:02.509571+10:00",
"panel_name": "Genetic Epilepsy",
"panel_id": 202,
"panel_version": "0.697",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Publications for gene: KCNT1 were set to ",
"entity_name": "KCNT1",
"entity_type": "gene"
},
{
"created": "2020-05-08T17:58:30.367415+10:00",
"panel_name": "Genetic Epilepsy",
"panel_id": 202,
"panel_version": "0.696",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Mode of inheritance for gene: KCNT1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted",
"entity_name": "KCNT1",
"entity_type": "gene"
},
{
"created": "2020-05-08T17:57:58.147620+10:00",
"panel_name": "Genetic Epilepsy",
"panel_id": 202,
"panel_version": "0.695",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "reviewed gene: KCNT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23086397, 23086396, 31872048, 31532509; Phenotypes: Epilepsy, nocturnal frontal lobe, 5, MIM# 615005, Epileptic encephalopathy, early infantile, 14, MIM# 614959; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted",
"entity_name": "KCNT1",
"entity_type": "gene"
}
]
}