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"count": 220751,
"next": "https://panelapp-aus.org/api/v1/activities/?format=api&page=1260",
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{
"created": "2021-07-27T10:08:27.885624+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.8522",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "gene: SYNCRIP was added\ngene: SYNCRIP was added to Mendeliome. Sources: Literature\nMode of inheritance for gene: SYNCRIP was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted\nPublications for gene: SYNCRIP were set to 34157790; 30504930; 27479843; 23020937\nPhenotypes for gene: SYNCRIP were set to Global developmental delay; Intellectual disability; Autism; Myoclonic atonic seizures; Abnormality of nervous system morphology\nReview for gene: SYNCRIP was set to GREEN\nAdded comment: Semino et al (2021 - PMID: 34157790) provide clinical details on 3 unrelated individuals with de novo SYNCRIP variants and provide a review of 5 additional subjects previously identified within large cohorts in the literature and databases.\r\n\r\nFeatures included DD, ID (7/7 for whom this information was available), ASD or autistic features (4/7). MRI abnormalities were observed in 3 (widening of CSF spaces, periventricular nodular heterotopia, prominent lat. ventricles). Epilepsy (myoclonic-astatic epilepsy / Doose syndrome) was reported for 2(/8) individuals.\r\n\r\nThe 3 patients here reported were identified following trio/singleton exome with Sanger confirmation of the variants and their de novo occurrence.\r\n\r\nVariants are in almost all cases de novo (7/7 for whom this was known) and in 5/8 cases were pLoF, in 2/8 missense SNVs while a case from DECIPHER had a 77.92 kb whole gene deletion not involving other genes with unknown inheritance.\r\n\r\nOverall the variants reported to date include [NM_006372.5]:\r\n1 - c.858_859del p.(Gly287Leufs*5)\r\n2 - c.854dupA p.(Asn285Lysfs*8)\r\n3 - c.734T>C p.(Leu245Pro)\r\n4 - chr6:85605276-85683190 deletion (GRCh38)\r\n5 - c.629T>C p.(Phe210Ser)\r\n6 - c.1573_1574delinsTT p.(Gln525Leu)\r\n7 - c.1247_1250del p.(Arg416Lysfs*145)\r\n8 - c.1518_1519insC p.(Ala507Argfs*14)\r\n\r\n[P1-3: this report, P4: DECIPHER 254774, P5-6: Guo et al 2019 - PMID: 30504930, P7: Lelieveld et al 2016 - PMID: 27479843, P8: Rauch et al 2012 - PMID: 23020937 / all other Refs not here reviewed, clinical details summarized by Semino et al in table 1]\r\n\r\nSYNCRIP (also known as HNRNPQ) encodes synaptotagmin‐binding cytoplasmic RNA‐interacting protein. As the authors note, this RNA-binding protein is involved in multiple pathways associated with neuronal/muscular developmental disorders. Several references are provided for its involvement in regulation of RNA metabolism, among others sequence recognition, pre-mRNA splicing, translation, transport and degradation.\r\n\r\nMutations in other RNA-interacting proteins and hnRNP members (e.g. HNRNPU, HNRNPD) are associated with NDD.\r\n\r\nThe missense variant (p.Leu245Pro) is within RRM2 one of the 3 RNA recognition motif (RRM) domains of the protein. These 3 domains, corresponding to the central part of the protein (aa 150-400), are relatively intolerant to variation (based on in silico predictions and/or variation in gnomAD). Leu245 localizes within an RNA binding pocket and in silico modeling suggests alteration of the tertiary structure and RNA-binding capacity of RRM2.\r\n\r\nThere are no additional studies performed.\r\n\r\nOverall haploinsufficiency appears to be the underlying disease mechanism based on the truncating variants and the gene deletion. [pLI in gnomAD : 1, %HI : 2.48%]\r\n\r\nAnimal models are not discussed.\r\n\r\nThere is no associated phenotype in OMIM. This gene is included in the DD panel of G2P (monoallelic LoF variants / SYNCRIP-related developmental disorder). SysID also lists SYNCRIP within the current primary ID genes. \nSources: Literature",
"entity_name": "SYNCRIP",
"entity_type": "gene"
},
{
"created": "2021-07-27T10:05:41.473519+10:00",
"panel_name": "Genetic Epilepsy",
"panel_id": 202,
"panel_version": "0.1149",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Marked gene: SYNCRIP as ready",
"entity_name": "SYNCRIP",
"entity_type": "gene"
},
{
"created": "2021-07-27T10:05:41.463883+10:00",
"panel_name": "Genetic Epilepsy",
"panel_id": 202,
"panel_version": "0.1149",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: syncrip has been classified as Amber List (Moderate Evidence).",
"entity_name": "SYNCRIP",
"entity_type": "gene"
},
{
"created": "2021-07-27T10:04:57.045033+10:00",
"panel_name": "Genetic Epilepsy",
"panel_id": 202,
"panel_version": "0.1149",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Classified gene: SYNCRIP as Amber List (moderate evidence)",
"entity_name": "SYNCRIP",
"entity_type": "gene"
},
{
"created": "2021-07-27T10:04:57.034942+10:00",
"panel_name": "Genetic Epilepsy",
"panel_id": 202,
"panel_version": "0.1149",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: syncrip has been classified as Amber List (Moderate Evidence).",
"entity_name": "SYNCRIP",
"entity_type": "gene"
},
{
"created": "2021-07-27T10:01:56.300188+10:00",
"panel_name": "Intellectual disability syndromic and non-syndromic",
"panel_id": 250,
"panel_version": "0.4003",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Marked gene: SYNCRIP as ready",
"entity_name": "SYNCRIP",
"entity_type": "gene"
},
{
"created": "2021-07-27T10:01:56.295030+10:00",
"panel_name": "Intellectual disability syndromic and non-syndromic",
"panel_id": 250,
"panel_version": "0.4003",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Added comment: Comment when marking as ready: Sufficient cases for Green rating on ID panel.",
"entity_name": "SYNCRIP",
"entity_type": "gene"
},
{
"created": "2021-07-27T10:01:56.260467+10:00",
"panel_name": "Intellectual disability syndromic and non-syndromic",
"panel_id": 250,
"panel_version": "0.4003",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: syncrip has been classified as Green List (High Evidence).",
"entity_name": "SYNCRIP",
"entity_type": "gene"
},
{
"created": "2021-07-27T10:01:50.306450+10:00",
"panel_name": "Intellectual disability syndromic and non-syndromic",
"panel_id": 250,
"panel_version": "0.4003",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Classified gene: SYNCRIP as Green List (high evidence)",
"entity_name": "SYNCRIP",
"entity_type": "gene"
},
{
"created": "2021-07-27T10:01:50.295642+10:00",
"panel_name": "Intellectual disability syndromic and non-syndromic",
"panel_id": 250,
"panel_version": "0.4003",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: syncrip has been classified as Green List (High Evidence).",
"entity_name": "SYNCRIP",
"entity_type": "gene"
},
{
"created": "2021-07-27T09:59:40.091696+10:00",
"panel_name": "Combined Immunodeficiency",
"panel_id": 223,
"panel_version": "0.232",
"user_name": "Danielle Ariti",
"item_type": "entity",
"text": "reviewed gene: DNMT3B: Rating: GREEN; Mode of pathogenicity: None; Publications: 20587527, 10555141, 17359920, 9718351, 10647011, 11102980, 12239717; Phenotypes: Immunodeficiency-centromeric instability-facial anomalies syndrome 1 MIM# 242860, facial dysmorphic features, flat nasal bridge, developmental delay, macroglossia, bacterial/opportunistic infections (recurrent), malabsorption, cytopaenia, malignancies, multiradial configurations of chromosomes 1, 9, 16, Hypogammaglobulinaemia, agammaglobulinaemia, variable antibody deficiency, decreased immunoglobulin production, low T/B/NK cells; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal",
"entity_name": "DNMT3B",
"entity_type": "gene"
},
{
"created": "2021-07-27T09:53:04.102824+10:00",
"panel_name": "Combined Immunodeficiency",
"panel_id": 223,
"panel_version": "0.232",
"user_name": "Danielle Ariti",
"item_type": "entity",
"text": "changed review comment from: 10 affected individuals from 5 unrelated families; homozygous and compound heterozygous variants (splicing, missense and small deletion variants) identified resulting in premature stop codons and truncated protein; multiple mouse models.\r\n\r\nAll individuals displayed immune deficiency and autoimmunity of variable severity. Some individuals presented at birth with failure to thrive due to lethal SCID features, whilst other CD3G-deficient individuals were in healthy condition decades into life. The most common immunologic profile includes partial T lymphocytopenia and low CD3, with normal B cells, NK cells, and immunoglobulins.; to: 10 affected individuals from 5 unrelated families; homozygous and compound heterozygous variants (splicing, missense and small deletion variants) identified resulting in premature stop codons and truncated protein; multiple mouse models.\r\n\r\nAll individuals displayed immune deficiency and autoimmunity of variable severity. Some individuals presented at birth with failure to thrive due to lethal SCID features, whilst other CD3G- deficient individuals only display immunological phenotype and no other features. The most common immunologic profile includes partial T lymphocytopenia and low CD3, with normal B cells, NK cells, and immunoglobulins.",
"entity_name": "CD3G",
"entity_type": "gene"
},
{
"created": "2021-07-27T09:50:55.322894+10:00",
"panel_name": "Combined Immunodeficiency",
"panel_id": 223,
"panel_version": "0.232",
"user_name": "Danielle Ariti",
"item_type": "entity",
"text": "changed review comment from: 17 affected individuals from 9 unrelated families; homozygous (missense) and compound heterozygous (missense/ nonsense) variants identified in CD27; one mouse model\r\n\r\nAffected individuals present with varied phenotypes (even within the same families); most commonly with lymphadenopathy, fever, hepatosplenomegaly, EBV-related infections, and immunodeficiency associated with hypogammaglobulinaemia. However, some CD27-deficient individuals are asymptomatic or display borderline-low hypogammaglobulinaemia.; to: 17 affected individuals from 9 unrelated families; homozygous (missense) and compound heterozygous (missense/ nonsense) variants identified in CD27; one mouse model\r\n\r\nAffected individuals present with varied phenotypes (even within the same families); most commonly with lymphadenopathy, fever, hepatosplenomegaly, EBV-related infections, and immunodeficiency associated with hypogammaglobulinaemia. However, some CD27-deficient individuals are asymptomatic-borderline low hypogammaglobulinaemia.",
"entity_name": "CD27",
"entity_type": "gene"
},
{
"created": "2021-07-27T09:24:02.449907+10:00",
"panel_name": "Intellectual disability syndromic and non-syndromic",
"panel_id": 250,
"panel_version": "0.4002",
"user_name": "Konstantinos Varvagiannis",
"item_type": "entity",
"text": "gene: SYNCRIP was added\ngene: SYNCRIP was added to Intellectual disability syndromic and non-syndromic. Sources: Literature\nMode of inheritance for gene: SYNCRIP was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown\nPublications for gene: SYNCRIP were set to 34157790; 30504930; 27479843; 23020937\nPhenotypes for gene: SYNCRIP were set to Global developmental delay; Intellectual disability; Autism; Myoclonic atonic seizures; Abnormality of nervous system morphology\nReview for gene: SYNCRIP was set to AMBER\nAdded comment: Semino et al (2021 - PMID: 34157790) provide clinical details on 3 unrelated individuals with de novo SYNCRIP variants and provide a review of 5 additional subjects previously identified within large cohorts in the literature and databases.\r\n\r\nFeatures included DD, ID (7/7 for whom this information was available), ASD or autistic features (4/7). MRI abnormalities were observed in 3 (widening of CSF spaces, periventricular nodular heterotopia, prominent lat. ventricles). Epilepsy (myoclonic-astatic epilepsy / Doose syndrome) was reported for 2(/8) individuals.\r\n\r\nThe 3 patients here reported were identified following trio/singleton exome with Sanger confirmation of the variants and their de novo occurrence.\r\n\r\nVariants are in almost all cases de novo (7/7 for whom this was known) and in 5/8 cases were pLoF, in 2/8 missense SNVs while a case from DECIPHER had a 77.92 kb whole gene deletion not involving other genes with unknown inheritance.\r\n\r\nOverall the variants reported to date include [NM_006372.5]:\r\n1 - c.858_859del p.(Gly287Leufs*5)\r\n2 - c.854dupA p.(Asn285Lysfs*8)\r\n3 - c.734T>C p.(Leu245Pro)\r\n4 - chr6:85605276-85683190 deletion (GRCh38)\r\n5 - c.629T>C p.(Phe210Ser)\r\n6 - c.1573_1574delinsTT p.(Gln525Leu)\r\n7 - c.1247_1250del p.(Arg416Lysfs*145)\r\n8 - c.1518_1519insC p.(Ala507Argfs*14)\r\n\r\n[P1-3: this report, P4: DECIPHER 254774, P5-6: Guo et al 2019 - PMID: 30504930, P7: Lelieveld et al 2016 - PMID: 27479843, P8: Rauch et al 2012 - PMID: 23020937 / all other Refs not here reviewed, clinical details summarized by Semino et al in table 1]\r\n\r\nSYNCRIP (also known as HNRNPQ) encodes synaptotagmin‐binding cytoplasmic RNA‐interacting protein. As the authors note, this RNA-binding protein is involved in multiple pathways associated with neuronal/muscular developmental disorders. Several references are provided for its involvement in regulation of RNA metabolism, among others sequence recognition, pre-mRNA splicing, translation, transport and degradation.\r\n\r\nMutations in other RNA-interacting proteins and hnRNP members (e.g. HNRNPU, HNRNPD) are associated with NDD.\r\n\r\nThe missense variant (p.Leu245Pro) is within RRM2 one of the 3 RNA recognition motif (RRM) domains of the protein. These 3 domains, corresponding to the central part of the protein (aa 150-400), are relatively intolerant to variation (based on in silico predictions and/or variation in gnomAD). Leu245 localizes within an RNA binding pocket and in silico modeling suggests alteration of the tertiary structure and RNA-binding capacity of RRM2.\r\n\r\nThere are no additional studies performed.\r\n\r\nOverall haploinsufficiency appears to be the underlying disease mechanism based on the truncating variants and the gene deletion. [pLI in gnomAD : 1, %HI : 2.48%]\r\n\r\nAnimal models are not discussed.\r\n\r\nThere is no associated phenotype in OMIM. This gene is included in the DD panel of G2P (monoallelic LoF variants / SYNCRIP-related developmental disorder). SysID also lists SYNCRIP within the current primary ID genes. \nSources: Literature",
"entity_name": "SYNCRIP",
"entity_type": "gene"
},
{
"created": "2021-07-27T09:23:07.072240+10:00",
"panel_name": "Genetic Epilepsy",
"panel_id": 202,
"panel_version": "0.1148",
"user_name": "Konstantinos Varvagiannis",
"item_type": "entity",
"text": "gene: SYNCRIP was added\ngene: SYNCRIP was added to Genetic Epilepsy. Sources: Literature\nMode of inheritance for gene: SYNCRIP was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown\nPublications for gene: SYNCRIP were set to 34157790; 30504930; 27479843; 23020937\nPhenotypes for gene: SYNCRIP were set to Global developmental delay; Intellectual disability; Autism; Myoclonic atonic seizures; Abnormality of nervous system morphology\nReview for gene: SYNCRIP was set to AMBER\nAdded comment: Semino et al (2021 - PMID: 34157790) provide clinical details on 3 unrelated individuals with de novo SYNCRIP variants and provide a review of 5 additional subjects previously identified within large cohorts in the literature and databases.\r\n\r\nFeatures included DD, ID (7/7 for whom this information was available), ASD or autistic features (4/7). MRI abnormalities were observed in 3 (widening of CSF spaces, periventricular nodular heterotopia, prominent lat. ventricles). Epilepsy (myoclonic-astatic epilepsy / Doose syndrome) was reported for 2(/8) individuals.\r\n\r\nThe 3 patients here reported were identified following trio/singleton exome with Sanger confirmation of the variants and their de novo occurrence.\r\n\r\nVariants are in almost all cases de novo (7/7 for whom this was known) and in 5/8 cases were pLoF, in 2/8 missense SNVs while a case from DECIPHER had a 77.92 kb whole gene deletion not involving other genes with unknown inheritance.\r\n\r\nOverall the variants reported to date include [NM_006372.5]:\r\n1 - c.858_859del p.(Gly287Leufs*5)\r\n2 - c.854dupA p.(Asn285Lysfs*8)\r\n3 - c.734T>C p.(Leu245Pro)\r\n4 - chr6:85605276-85683190 deletion (GRCh38)\r\n5 - c.629T>C p.(Phe210Ser)\r\n6 - c.1573_1574delinsTT p.(Gln525Leu)\r\n7 - c.1247_1250del p.(Arg416Lysfs*145)\r\n8 - c.1518_1519insC p.(Ala507Argfs*14)\r\n\r\n[P1-3: this report, P4: DECIPHER 254774, P5-6: Guo et al 2019 - PMID: 30504930, P7: Lelieveld et al 2016 - PMID: 27479843, P8: Rauch et al 2012 - PMID: 23020937 / all other Refs not here reviewed, clinical details summarized by Semino et al in table 1]\r\n\r\nSYNCRIP (also known as HNRNPQ) encodes synaptotagmin‐binding cytoplasmic RNA‐interacting protein. As the authors note, this RNA-binding protein is involved in multiple pathways associated with neuronal/muscular developmental disorders. Several references are provided for its involvement in regulation of RNA metabolism, among others sequence recognition, pre-mRNA splicing, translation, transport and degradation.\r\n\r\nMutations in other RNA-interacting proteins and hnRNP members (e.g. HNRNPU, HNRNPD) are associated with NDD.\r\n\r\nThe missense variant (p.Leu245Pro) is within RRM2 one of the 3 RNA recognition motif (RRM) domains of the protein. These 3 domains, corresponding to the central part of the protein (aa 150-400), are relatively intolerant to variation (based on in silico predictions and/or variation in gnomAD). Leu245 localizes within an RNA binding pocket and in silico modeling suggests alteration of the tertiary structure and RNA-binding capacity of RRM2.\r\n\r\nThere are no additional studies performed.\r\n\r\nOverall haploinsufficiency appears to be the underlying disease mechanism based on the truncating variants and the gene deletion. [pLI in gnomAD : 1, %HI : 2.48%]\r\n\r\nAnimal models are not discussed.\r\n\r\nThere is no associated phenotype in OMIM. This gene is included in the DD panel of G2P (monoallelic LoF variants / SYNCRIP-related developmental disorder). SysID also lists SYNCRIP within the current primary ID genes. \nSources: Literature",
"entity_name": "SYNCRIP",
"entity_type": "gene"
},
{
"created": "2021-07-26T13:16:32.567666+10:00",
"panel_name": "Phagocyte Defects",
"panel_id": 233,
"panel_version": "0.102",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Marked gene: NCF1 as ready",
"entity_name": "NCF1",
"entity_type": "gene"
},
{
"created": "2021-07-26T13:16:32.557932+10:00",
"panel_name": "Phagocyte Defects",
"panel_id": 233,
"panel_version": "0.102",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: ncf1 has been classified as Green List (High Evidence).",
"entity_name": "NCF1",
"entity_type": "gene"
},
{
"created": "2021-07-26T13:15:54.866920+10:00",
"panel_name": "Phagocyte Defects",
"panel_id": 233,
"panel_version": "0.102",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Phenotypes for gene: NCF1 were changed from to Chronic granulomatous disease 1, autosomal recessive, MIM# 233700",
"entity_name": "NCF1",
"entity_type": "gene"
},
{
"created": "2021-07-26T13:15:28.594096+10:00",
"panel_name": "Phagocyte Defects",
"panel_id": 233,
"panel_version": "0.101",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Publications for gene: NCF1 were set to ",
"entity_name": "NCF1",
"entity_type": "gene"
},
{
"created": "2021-07-26T13:15:03.169478+10:00",
"panel_name": "Phagocyte Defects",
"panel_id": 233,
"panel_version": "0.100",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Mode of inheritance for gene: NCF1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal",
"entity_name": "NCF1",
"entity_type": "gene"
},
{
"created": "2021-07-26T13:14:11.702161+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.8521",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Marked gene: MSN as ready",
"entity_name": "MSN",
"entity_type": "gene"
},
{
"created": "2021-07-26T13:14:11.692708+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.8521",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: msn has been classified as Green List (High Evidence).",
"entity_name": "MSN",
"entity_type": "gene"
},
{
"created": "2021-07-26T13:14:03.539497+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.8521",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Phenotypes for gene: MSN were changed from to Immunodeficiency 50, MIM# 300988",
"entity_name": "MSN",
"entity_type": "gene"
},
{
"created": "2021-07-26T13:13:44.871692+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.8520",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Publications for gene: MSN were set to ",
"entity_name": "MSN",
"entity_type": "gene"
},
{
"created": "2021-07-26T13:13:28.375422+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.8519",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Mode of inheritance for gene: MSN was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females",
"entity_name": "MSN",
"entity_type": "gene"
},
{
"created": "2021-07-26T13:13:09.452622+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.8518",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "reviewed gene: MSN: Rating: GREEN; Mode of pathogenicity: None; Publications: 27405666; Phenotypes: Immunodeficiency 50, MIM# 300988; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females",
"entity_name": "MSN",
"entity_type": "gene"
},
{
"created": "2021-07-26T13:11:44.796608+10:00",
"panel_name": "Phagocyte Defects",
"panel_id": 233,
"panel_version": "0.99",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Marked gene: MSN as ready",
"entity_name": "MSN",
"entity_type": "gene"
},
{
"created": "2021-07-26T13:11:44.784479+10:00",
"panel_name": "Phagocyte Defects",
"panel_id": 233,
"panel_version": "0.99",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: msn has been classified as Green List (High Evidence).",
"entity_name": "MSN",
"entity_type": "gene"
},
{
"created": "2021-07-26T13:11:36.943361+10:00",
"panel_name": "Phagocyte Defects",
"panel_id": 233,
"panel_version": "0.99",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "changed review comment from: Seven males from five unrelated families reported. \nSources: Expert list; to: Seven males from five unrelated families reported. Profound lymphopaenia, fluctuating neutropaenia.\r\nSources: Expert list",
"entity_name": "MSN",
"entity_type": "gene"
},
{
"created": "2021-07-26T13:10:24.591828+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.8518",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Marked gene: JAGN1 as ready",
"entity_name": "JAGN1",
"entity_type": "gene"
},
{
"created": "2021-07-26T13:10:24.581939+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.8518",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: jagn1 has been classified as Green List (High Evidence).",
"entity_name": "JAGN1",
"entity_type": "gene"
},
{
"created": "2021-07-26T13:10:17.309370+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.8518",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Phenotypes for gene: JAGN1 were changed from to Neutropaenia, severe congenital, 6, autosomal recessive, MIM# 616022",
"entity_name": "JAGN1",
"entity_type": "gene"
},
{
"created": "2021-07-26T13:09:55.469248+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.8517",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Publications for gene: JAGN1 were set to ",
"entity_name": "JAGN1",
"entity_type": "gene"
},
{
"created": "2021-07-26T13:09:31.517094+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.8516",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Mode of inheritance for gene: JAGN1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal",
"entity_name": "JAGN1",
"entity_type": "gene"
},
{
"created": "2021-07-26T13:09:11.740247+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.8515",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "reviewed gene: JAGN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25129144; Phenotypes: Neutropaenia, severe congenital, 6, autosomal recessive, MIM# 616022; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal",
"entity_name": "JAGN1",
"entity_type": "gene"
},
{
"created": "2021-07-26T13:08:25.646583+10:00",
"panel_name": "Phagocyte Defects",
"panel_id": 233,
"panel_version": "0.99",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Marked gene: JAGN1 as ready",
"entity_name": "JAGN1",
"entity_type": "gene"
},
{
"created": "2021-07-26T13:08:25.636911+10:00",
"panel_name": "Phagocyte Defects",
"panel_id": 233,
"panel_version": "0.99",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: jagn1 has been classified as Green List (High Evidence).",
"entity_name": "JAGN1",
"entity_type": "gene"
},
{
"created": "2021-07-26T13:08:21.913192+10:00",
"panel_name": "Phagocyte Defects",
"panel_id": 233,
"panel_version": "0.99",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Phenotypes for gene: JAGN1 were changed from to Neutropaenia, severe congenital, 6, autosomal recessive, MIM# 616022",
"entity_name": "JAGN1",
"entity_type": "gene"
},
{
"created": "2021-07-26T13:07:35.577792+10:00",
"panel_name": "Phagocyte Defects",
"panel_id": 233,
"panel_version": "0.98",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Publications for gene: JAGN1 were set to ",
"entity_name": "JAGN1",
"entity_type": "gene"
},
{
"created": "2021-07-26T13:07:06.864487+10:00",
"panel_name": "Phagocyte Defects",
"panel_id": 233,
"panel_version": "0.97",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Mode of inheritance for gene: JAGN1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal",
"entity_name": "JAGN1",
"entity_type": "gene"
},
{
"created": "2021-07-26T13:06:39.430193+10:00",
"panel_name": "Phagocyte Defects",
"panel_id": 233,
"panel_version": "0.96",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "reviewed gene: JAGN1: Rating: GREEN; Mode of pathogenicity: None; Publications: 25129144; Phenotypes: Neutropaenia, severe congenital, 6, autosomal recessive, MIM# 616022; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal",
"entity_name": "JAGN1",
"entity_type": "gene"
},
{
"created": "2021-07-26T13:01:19.519866+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.8515",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Marked gene: ITGB2 as ready",
"entity_name": "ITGB2",
"entity_type": "gene"
},
{
"created": "2021-07-26T13:01:19.508491+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.8515",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: itgb2 has been classified as Green List (High Evidence).",
"entity_name": "ITGB2",
"entity_type": "gene"
},
{
"created": "2021-07-26T13:01:10.997388+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.8515",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Phenotypes for gene: ITGB2 were changed from to Leukocyte adhesion deficiency, MIM# 116920",
"entity_name": "ITGB2",
"entity_type": "gene"
},
{
"created": "2021-07-26T13:00:51.731799+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.8514",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Publications for gene: ITGB2 were set to ",
"entity_name": "ITGB2",
"entity_type": "gene"
},
{
"created": "2021-07-26T13:00:28.402440+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.8513",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Mode of inheritance for gene: ITGB2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal",
"entity_name": "ITGB2",
"entity_type": "gene"
},
{
"created": "2021-07-26T12:59:59.870031+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.8512",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "reviewed gene: ITGB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 1968911, 1694220, 33957747, 32279896, 31374327; Phenotypes: Leukocyte adhesion deficiency, MIM# 116920; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal",
"entity_name": "ITGB2",
"entity_type": "gene"
},
{
"created": "2021-07-26T12:59:28.244993+10:00",
"panel_name": "Phagocyte Defects",
"panel_id": 233,
"panel_version": "0.96",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Marked gene: ITGB2 as ready",
"entity_name": "ITGB2",
"entity_type": "gene"
},
{
"created": "2021-07-26T12:59:28.233633+10:00",
"panel_name": "Phagocyte Defects",
"panel_id": 233,
"panel_version": "0.96",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: itgb2 has been classified as Green List (High Evidence).",
"entity_name": "ITGB2",
"entity_type": "gene"
},
{
"created": "2021-07-26T12:59:07.329668+10:00",
"panel_name": "Phagocyte Defects",
"panel_id": 233,
"panel_version": "0.96",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Phenotypes for gene: ITGB2 were changed from to Leukocyte adhesion deficiency, MIM# 116920",
"entity_name": "ITGB2",
"entity_type": "gene"
},
{
"created": "2021-07-26T12:58:34.542673+10:00",
"panel_name": "Phagocyte Defects",
"panel_id": 233,
"panel_version": "0.95",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Publications for gene: ITGB2 were set to ",
"entity_name": "ITGB2",
"entity_type": "gene"
},
{
"created": "2021-07-26T12:58:09.878291+10:00",
"panel_name": "Phagocyte Defects",
"panel_id": 233,
"panel_version": "0.94",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Mode of inheritance for gene: ITGB2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal",
"entity_name": "ITGB2",
"entity_type": "gene"
},
{
"created": "2021-07-26T12:57:37.861790+10:00",
"panel_name": "Phagocyte Defects",
"panel_id": 233,
"panel_version": "0.93",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "reviewed gene: ITGB2: Rating: GREEN; Mode of pathogenicity: None; Publications: 1968911, 1694220, 33957747, 32279896, 31374327; Phenotypes: Leukocyte adhesion deficiency, MIM# 116920; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal",
"entity_name": "ITGB2",
"entity_type": "gene"
},
{
"created": "2021-07-26T10:56:29.653181+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.8512",
"user_name": "Melanie Marty",
"item_type": "entity",
"text": "commented on gene: NLRP2",
"entity_name": "NLRP2",
"entity_type": "gene"
},
{
"created": "2021-07-26T10:27:32.990273+10:00",
"panel_name": "Phagocyte Defects",
"panel_id": 233,
"panel_version": "0.93",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Marked gene: GATA2 as ready",
"entity_name": "GATA2",
"entity_type": "gene"
},
{
"created": "2021-07-26T10:27:32.979835+10:00",
"panel_name": "Phagocyte Defects",
"panel_id": 233,
"panel_version": "0.93",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: gata2 has been classified as Green List (High Evidence).",
"entity_name": "GATA2",
"entity_type": "gene"
},
{
"created": "2021-07-26T10:27:27.586186+10:00",
"panel_name": "Phagocyte Defects",
"panel_id": 233,
"panel_version": "0.93",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Phenotypes for gene: GATA2 were changed from to Emberger syndrome, MIM# 614038",
"entity_name": "GATA2",
"entity_type": "gene"
},
{
"created": "2021-07-26T10:27:01.697304+10:00",
"panel_name": "Phagocyte Defects",
"panel_id": 233,
"panel_version": "0.92",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Publications for gene: GATA2 were set to ",
"entity_name": "GATA2",
"entity_type": "gene"
},
{
"created": "2021-07-26T10:26:30.428908+10:00",
"panel_name": "Phagocyte Defects",
"panel_id": 233,
"panel_version": "0.91",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Mode of inheritance for gene: GATA2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted",
"entity_name": "GATA2",
"entity_type": "gene"
},
{
"created": "2021-07-26T10:25:56.035856+10:00",
"panel_name": "Phagocyte Defects",
"panel_id": 233,
"panel_version": "0.90",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "edited their review of gene: GATA2: Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted",
"entity_name": "GATA2",
"entity_type": "gene"
},
{
"created": "2021-07-26T10:25:50.264177+10:00",
"panel_name": "Phagocyte Defects",
"panel_id": 233,
"panel_version": "0.90",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "reviewed gene: GATA2: Rating: GREEN; Mode of pathogenicity: None; Publications: 26710799; Phenotypes: Emberger syndrome, MIM# 614038; Mode of inheritance: None",
"entity_name": "GATA2",
"entity_type": "gene"
},
{
"created": "2021-07-26T10:03:50.481582+10:00",
"panel_name": "Dystonia - complex",
"panel_id": 290,
"panel_version": "0.188",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "edited their review of gene: CAMK4: Changed phenotypes: Intellectual disability, Autism, Behavioral abnormality, Abnormality of movement, Dystonia, Ataxia, Chorea, Myoclonus",
"entity_name": "CAMK4",
"entity_type": "gene"
},
{
"created": "2021-07-26T10:03:31.903304+10:00",
"panel_name": "Dystonia - complex",
"panel_id": 290,
"panel_version": "0.188",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Marked gene: CAMK4 as ready",
"entity_name": "CAMK4",
"entity_type": "gene"
},
{
"created": "2021-07-26T10:03:31.892497+10:00",
"panel_name": "Dystonia - complex",
"panel_id": 290,
"panel_version": "0.188",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: camk4 has been classified as Green List (High Evidence).",
"entity_name": "CAMK4",
"entity_type": "gene"
},
{
"created": "2021-07-26T10:03:28.696446+10:00",
"panel_name": "Dystonia - complex",
"panel_id": 290,
"panel_version": "0.188",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Phenotypes for gene: CAMK4 were changed from 30262571; 33098801; 33211350 to Intellectual disability; Autism; Behavioral abnormality; Abnormality of movement; Dystonia; Ataxia; Chorea; Myoclonus",
"entity_name": "CAMK4",
"entity_type": "gene"
},
{
"created": "2021-07-26T10:03:03.008535+10:00",
"panel_name": "Dystonia - complex",
"panel_id": 290,
"panel_version": "0.187",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Classified gene: CAMK4 as Green List (high evidence)",
"entity_name": "CAMK4",
"entity_type": "gene"
},
{
"created": "2021-07-26T10:03:02.994492+10:00",
"panel_name": "Dystonia - complex",
"panel_id": 290,
"panel_version": "0.187",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: camk4 has been classified as Green List (High Evidence).",
"entity_name": "CAMK4",
"entity_type": "gene"
},
{
"created": "2021-07-26T10:02:49.457105+10:00",
"panel_name": "Dystonia - complex",
"panel_id": 290,
"panel_version": "0.186",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "gene: CAMK4 was added\ngene: CAMK4 was added to Dystonia - complex. Sources: Expert Review\nMode of inheritance for gene: CAMK4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted\nPublications for gene: CAMK4 were set to 30262571; 33098801; 33211350\nPhenotypes for gene: CAMK4 were set to 30262571; 33098801; 33211350\nReview for gene: CAMK4 was set to GREEN\nAdded comment: 3 publications by Zech et al (2018, 2020 - PMIDs : 30262571, 33098801, 33211350) provide clinical details on 3 individuals, each harboring a private de novo CAMK4 variant. \r\n\r\nOverlapping features included DD, ID, behavoral issues, autism and abnormal hyperkinetic movements. Dystonia and chorea in all 3 appeared 3-20 years after initial symptoms. \r\n\r\nCAMK4 encodes Calcium/Calmodulin-dependent protein kinase IV, an important mediator of calcium-mediated activity and dynamics, particularly in the brain. It is involved in neuronal transmission, synaptic plasticity, and neuronal gene expression required for brain development and neuronal homeostasis (summary by OMIM based on Zech et al, 2018).\r\n\r\nThe 473 aa enzyme has a protein kinase domain (aa 46-300) and a C-terminal autoregulatory domain (aa 305-341) the latter comprising an autoinhibitory domain (AID / aa 305-321) and a calmodulin-binding domain (CBD / aa 322-341) [NP_001735.1 / NM_001744.4 - also used below].\r\n\r\nVariants in all 3 subjects were identified following trio-WES and were in all cases protein-truncating, mapping to exon 10 or exon 10-intron 10 junction, expected to escape NMD and cause selective abrogation of the autoinhibitory domain (aa 305-321) leading overall to gain-of-function.\r\n\r\nVariation databases include pLoF CAMK4 variants albeit in all cases usptream or downstream of this region (pLI of this gene in gnomAD: 0.51). Variants leading to selective abrogation of the autoregulatory domain have not been reported.\r\n\r\nExtensive evidence for the GoF effect of the variant has been provided in the first publication. Several previous studies have demonstrated that abrogation of the AID domain leads to consitutive activation (details below).\r\n\r\nMouse models - though corresponding to homozygous loss of function - support a role for CAMKIV in cognitive and motor symptoms. Null mice display tremulous and ataxic movements, deficiencies in balance and sensorimotor performance associated with reduced number of Purkinje neurons (Ribar et al 2000, PMID: 11069976 - not reviewed). Wei et al (2002, PMID: 12006982 - not reviewed) provided evidence for alteration in hippocampal physiology and memory function. \r\n\r\nHeterozygous mutations in other genes for calcium/calmodulin-dependent protein kinases (CAMKs) e.g. CAMK2A/CAMK2B (encoding subunits of CAMKII) have been reported in individuals with ID.\r\n\r\n---\r\n\r\nThe proband in the first publication (PMID: 30262571) was a male with DD, ID, behavioral difficulties (ASD, autoaggression, stereotypies) and hyperkinetic movement disorder (myoclonus, chorea, ataxia) with severe generalized dystonia (onset at the age of 13y). Brain MRI demonstrated cerebellar atrophy. \r\n\r\nExtensive work-up incl. karyotyping, CMA, DYT-TOR1A, THAP1, GCH1, SCA1/2/3/6/7/8/12/17, Friedreich's ataxia and FMR1 analysis was negative.F\r\n\r\nTrio WES identified a dn splice site variant (c.981+1G>A) in the last exon-intron junction. RT-PCR followed by gel electrophoresis and Sanger in fibroblasts from an affected and control subject revealed that the proband had - as predicted by the type/location of the variant - in equal amount 2 cDNA products, a normal as well as a truncated one. \r\n\r\nSequencing of the shortest revealed utilization of a cryptic donor splice site upstream of the mutated donor leading to a 77bp out-of-frame deletion and introduction of a premature stop codon in the last codon (p.Lys303Serfs*28). Western blot in fibroblast cell lines revealed 2 bands corresponding to the normal protein product as well as to the p.Lys303Serfs*28 although expression of the latter was lower than that of the full length protein.\r\n\r\nSeveral previous studies have shown that mutant CAMKIV species that lack the autoinhibitory domain are consitutively active (several Refs provided). Among others Chatila et al (1996, PMID: 8702940) studied an in vitro-engineered truncation mutant (Δ1-317 - truncation at position 317 of the protein) with functionally validated gain-of-function effect.\r\n\r\nTo prove enhanced activity of the splicing variant, Zech et al assessed phosphorylation of CREB (cyclic AMP-responsive element binding protein), a downstream substrate of CAMKIV. Immunobloting revealed significant increase of CREB phosphorylation in patient fibroblasts compared to controls. Overactivation of CAMKIV signaling was reversed when cells were treated with STO-609 an inhibitor of CAMKK, the ustream activator of CAMKIV.\r\n\r\nOverall the authors demonstrated that loss of CAMKIV autoregulatory domain due to this splice variant had a gain-of-function effect.\r\n\r\n----\r\n\r\nFollowing trio-WES, Zech et al (2020 - PMID: 33098801) identified another relevant subject within cohort of 764 individuals with dystonia. This 12-y.o. male, harboring a different variant affecting the same donor site (c.981+1G>T), presented DD, ID, dystonia (onset at 3y) and additional movement disorders (myoclonus, ataxia) as well as similar behavior (ASD, autoaggression, stereotypies). [Details in suppl. p20].\r\n\r\n----\r\n\r\nFinally Zech et al (2020 - PMID: 33211350) reported on a 24-y.o. woman with adolescence onset choreodystonia. Other features included DD, moderate ID, absence seizures in infancy, OCD with anxiety and later diagnosis of ASD. Trio WES revealed a dn stopgain variant (c.940C>T; p.Gln314*). \nSources: Expert Review",
"entity_name": "CAMK4",
"entity_type": "gene"
},
{
"created": "2021-07-26T10:02:17.230542+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.8512",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Marked gene: CAMK4 as ready",
"entity_name": "CAMK4",
"entity_type": "gene"
},
{
"created": "2021-07-26T10:02:17.215413+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.8512",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: camk4 has been classified as Green List (High Evidence).",
"entity_name": "CAMK4",
"entity_type": "gene"
},
{
"created": "2021-07-26T10:02:01.879119+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.8512",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Classified gene: CAMK4 as Green List (high evidence)",
"entity_name": "CAMK4",
"entity_type": "gene"
},
{
"created": "2021-07-26T10:02:01.855245+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.8512",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: camk4 has been classified as Green List (High Evidence).",
"entity_name": "CAMK4",
"entity_type": "gene"
},
{
"created": "2021-07-26T10:01:16.495140+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.8511",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "gene: CAMK4 was added\ngene: CAMK4 was added to Mendeliome. Sources: Expert Review\nMode of inheritance for gene: CAMK4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted\nPublications for gene: CAMK4 were set to 30262571; 33098801; 33211350\nPhenotypes for gene: CAMK4 were set to Intellectual disability; Autism; Behavioral abnormality; Abnormality of movement; Dystonia; Ataxia; Chorea; Myoclonus\nReview for gene: CAMK4 was set to GREEN\nAdded comment: 3 publications by Zech et al (2018, 2020 - PMIDs : 30262571, 33098801, 33211350) provide clinical details on 3 individuals, each harboring a private de novo CAMK4 variant. \r\n\r\nOverlapping features included DD, ID, behavoral issues, autism and abnormal hyperkinetic movements. Dystonia and chorea in all 3 appeared 3-20 years after initial symptoms. \r\n\r\nCAMK4 encodes Calcium/Calmodulin-dependent protein kinase IV, an important mediator of calcium-mediated activity and dynamics, particularly in the brain. It is involved in neuronal transmission, synaptic plasticity, and neuronal gene expression required for brain development and neuronal homeostasis (summary by OMIM based on Zech et al, 2018).\r\n\r\nThe 473 aa enzyme has a protein kinase domain (aa 46-300) and a C-terminal autoregulatory domain (aa 305-341) the latter comprising an autoinhibitory domain (AID / aa 305-321) and a calmodulin-binding domain (CBD / aa 322-341) [NP_001735.1 / NM_001744.4 - also used below].\r\n\r\nVariants in all 3 subjects were identified following trio-WES and were in all cases protein-truncating, mapping to exon 10 or exon 10-intron 10 junction, expected to escape NMD and cause selective abrogation of the autoinhibitory domain (aa 305-321) leading overall to gain-of-function.\r\n\r\nVariation databases include pLoF CAMK4 variants albeit in all cases usptream or downstream of this region (pLI of this gene in gnomAD: 0.51). Variants leading to selective abrogation of the autoregulatory domain have not been reported.\r\n\r\nExtensive evidence for the GoF effect of the variant has been provided in the first publication. Several previous studies have demonstrated that abrogation of the AID domain leads to consitutive activation (details below).\r\n\r\nMouse models - though corresponding to homozygous loss of function - support a role for CAMKIV in cognitive and motor symptoms. Null mice display tremulous and ataxic movements, deficiencies in balance and sensorimotor performance associated with reduced number of Purkinje neurons (Ribar et al 2000, PMID: 11069976 - not reviewed). Wei et al (2002, PMID: 12006982 - not reviewed) provided evidence for alteration in hippocampal physiology and memory function. \r\n\r\nHeterozygous mutations in other genes for calcium/calmodulin-dependent protein kinases (CAMKs) e.g. CAMK2A/CAMK2B (encoding subunits of CAMKII) have been reported in individuals with ID.\r\n\r\n---\r\n\r\nThe proband in the first publication (PMID: 30262571) was a male with DD, ID, behavioral difficulties (ASD, autoaggression, stereotypies) and hyperkinetic movement disorder (myoclonus, chorea, ataxia) with severe generalized dystonia (onset at the age of 13y). Brain MRI demonstrated cerebellar atrophy. \r\n\r\nExtensive work-up incl. karyotyping, CMA, DYT-TOR1A, THAP1, GCH1, SCA1/2/3/6/7/8/12/17, Friedreich's ataxia and FMR1 analysis was negative.F\r\n\r\nTrio WES identified a dn splice site variant (c.981+1G>A) in the last exon-intron junction. RT-PCR followed by gel electrophoresis and Sanger in fibroblasts from an affected and control subject revealed that the proband had - as predicted by the type/location of the variant - in equal amount 2 cDNA products, a normal as well as a truncated one. \r\n\r\nSequencing of the shortest revealed utilization of a cryptic donor splice site upstream of the mutated donor leading to a 77bp out-of-frame deletion and introduction of a premature stop codon in the last codon (p.Lys303Serfs*28). Western blot in fibroblast cell lines revealed 2 bands corresponding to the normal protein product as well as to the p.Lys303Serfs*28 although expression of the latter was lower than that of the full length protein.\r\n\r\nSeveral previous studies have shown that mutant CAMKIV species that lack the autoinhibitory domain are consitutively active (several Refs provided). Among others Chatila et al (1996, PMID: 8702940) studied an in vitro-engineered truncation mutant (Δ1-317 - truncation at position 317 of the protein) with functionally validated gain-of-function effect.\r\n\r\nTo prove enhanced activity of the splicing variant, Zech et al assessed phosphorylation of CREB (cyclic AMP-responsive element binding protein), a downstream substrate of CAMKIV. Immunobloting revealed significant increase of CREB phosphorylation in patient fibroblasts compared to controls. Overactivation of CAMKIV signaling was reversed when cells were treated with STO-609 an inhibitor of CAMKK, the ustream activator of CAMKIV.\r\n\r\nOverall the authors demonstrated that loss of CAMKIV autoregulatory domain due to this splice variant had a gain-of-function effect.\r\n\r\n----\r\n\r\nFollowing trio-WES, Zech et al (2020 - PMID: 33098801) identified another relevant subject within cohort of 764 individuals with dystonia. This 12-y.o. male, harboring a different variant affecting the same donor site (c.981+1G>T), presented DD, ID, dystonia (onset at 3y) and additional movement disorders (myoclonus, ataxia) as well as similar behavior (ASD, autoaggression, stereotypies). [Details in suppl. p20].\r\n\r\n----\r\n\r\nFinally Zech et al (2020 - PMID: 33211350) reported on a 24-y.o. woman with adolescence onset choreodystonia. Other features included DD, moderate ID, absence seizures in infancy, OCD with anxiety and later diagnosis of ASD. Trio WES revealed a dn stopgain variant (c.940C>T; p.Gln314*). \nSources: Expert Review",
"entity_name": "CAMK4",
"entity_type": "gene"
},
{
"created": "2021-07-26T10:00:14.244679+10:00",
"panel_name": "Intellectual disability syndromic and non-syndromic",
"panel_id": 250,
"panel_version": "0.4002",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Marked gene: CAMK4 as ready",
"entity_name": "CAMK4",
"entity_type": "gene"
},
{
"created": "2021-07-26T10:00:14.232558+10:00",
"panel_name": "Intellectual disability syndromic and non-syndromic",
"panel_id": 250,
"panel_version": "0.4002",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: camk4 has been classified as Green List (High Evidence).",
"entity_name": "CAMK4",
"entity_type": "gene"
},
{
"created": "2021-07-26T09:51:42.667794+10:00",
"panel_name": "Intellectual disability syndromic and non-syndromic",
"panel_id": 250,
"panel_version": "0.4002",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Classified gene: CAMK4 as Green List (high evidence)",
"entity_name": "CAMK4",
"entity_type": "gene"
},
{
"created": "2021-07-26T09:51:42.658898+10:00",
"panel_name": "Intellectual disability syndromic and non-syndromic",
"panel_id": 250,
"panel_version": "0.4002",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: camk4 has been classified as Green List (High Evidence).",
"entity_name": "CAMK4",
"entity_type": "gene"
},
{
"created": "2021-07-25T21:59:49.890967+10:00",
"panel_name": "Intellectual disability syndromic and non-syndromic",
"panel_id": 250,
"panel_version": "0.4001",
"user_name": "Konstantinos Varvagiannis",
"item_type": "entity",
"text": "gene: CAMK4 was added\ngene: CAMK4 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature,Other\nMode of inheritance for gene: CAMK4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown\nPublications for gene: CAMK4 were set to 30262571; 33098801; 33211350\nPhenotypes for gene: CAMK4 were set to Global developmental delay; Intellectual disability; Autism; Behavioral abnormality; Abnormality of movement; Dystonia; Ataxia; Chorea; Myoclonus\nPenetrance for gene: CAMK4 were set to Complete\nReview for gene: CAMK4 was set to GREEN\nAdded comment: 3 publications by Zech et al (2018, 2020 - PMIDs : 30262571, 33098801, 33211350) provide clinical details on 3 individuals, each harboring a private de novo CAMK4 variant. \r\n\r\nOverlapping features included DD, ID, behavoral issues, autism and abnormal hyperkinetic movements. Dystonia and chorea in all 3 appeared 3-20 years after initial symptoms. \r\n\r\nCAMK4 encodes Calcium/Calmodulin-dependent protein kinase IV, an important mediator of calcium-mediated activity and dynamics, particularly in the brain. It is involved in neuronal transmission, synaptic plasticity, and neuronal gene expression required for brain development and neuronal homeostasis (summary by OMIM based on Zech et al, 2018).\r\n\r\nThe 473 aa enzyme has a protein kinase domain (aa 46-300) and a C-terminal autoregulatory domain (aa 305-341) the latter comprising an autoinhibitory domain (AID / aa 305-321) and a calmodulin-binding domain (CBD / aa 322-341) [NP_001735.1 / NM_001744.4 - also used below].\r\n\r\nVariants in all 3 subjects were identified following trio-WES and were in all cases protein-truncating, mapping to exon 10 or exon 10-intron 10 junction, expected to escape NMD and cause selective abrogation of the autoinhibitory domain (aa 305-321) leading overall to gain-of-function.\r\n\r\nVariation databases include pLoF CAMK4 variants albeit in all cases usptream or downstream of this region (pLI of this gene in gnomAD: 0.51). Variants leading to selective abrogation of the autoregulatory domain have not been reported.\r\n\r\nExtensive evidence for the GoF effect of the variant has been provided in the first publication. Several previous studies have demonstrated that abrogation of the AID domain leads to consitutive activation (details below).\r\n\r\nMouse models - though corresponding to homozygous loss of function - support a role for CAMKIV in cognitive and motor symptoms. Null mice display tremulous and ataxic movements, deficiencies in balance and sensorimotor performance associated with reduced number of Purkinje neurons (Ribar et al 2000, PMID: 11069976 - not reviewed). Wei et al (2002, PMID: 12006982 - not reviewed) provided evidence for alteration in hippocampal physiology and memory function. \r\n\r\nHeterozygous mutations in other genes for calcium/calmodulin-dependent protein kinases (CAMKs) e.g. CAMK2A/CAMK2B (encoding subunits of CAMKII) have been reported in individuals with ID.\r\n\r\n---\r\n\r\nThe proband in the first publication (PMID: 30262571) was a male with DD, ID, behavioral difficulties (ASD, autoaggression, stereotypies) and hyperkinetic movement disorder (myoclonus, chorea, ataxia) with severe generalized dystonia (onset at the age of 13y). Brain MRI demonstrated cerebellar atrophy. \r\n\r\nExtensive work-up incl. karyotyping, CMA, DYT-TOR1A, THAP1, GCH1, SCA1/2/3/6/7/8/12/17, Friedreich's ataxia and FMR1 analysis was negative.F\r\n\r\nTrio WES identified a dn splice site variant (c.981+1G>A) in the last exon-intron junction. RT-PCR followed by gel electrophoresis and Sanger in fibroblasts from an affected and control subject revealed that the proband had - as predicted by the type/location of the variant - in equal amount 2 cDNA products, a normal as well as a truncated one. \r\n\r\nSequencing of the shortest revealed utilization of a cryptic donor splice site upstream of the mutated donor leading to a 77bp out-of-frame deletion and introduction of a premature stop codon in the last codon (p.Lys303Serfs*28). Western blot in fibroblast cell lines revealed 2 bands corresponding to the normal protein product as well as to the p.Lys303Serfs*28 although expression of the latter was lower than that of the full length protein.\r\n\r\nSeveral previous studies have shown that mutant CAMKIV species that lack the autoinhibitory domain are consitutively active (several Refs provided). Among others Chatila et al (1996, PMID: 8702940) studied an in vitro-engineered truncation mutant (Δ1-317 - truncation at position 317 of the protein) with functionally validated gain-of-function effect.\r\n\r\nTo prove enhanced activity of the splicing variant, Zech et al assessed phosphorylation of CREB (cyclic AMP-responsive element binding protein), a downstream substrate of CAMKIV. Immunobloting revealed significant increase of CREB phosphorylation in patient fibroblasts compared to controls. Overactivation of CAMKIV signaling was reversed when cells were treated with STO-609 an inhibitor of CAMKK, the ustream activator of CAMKIV.\r\n\r\nOverall the authors demonstrated that loss of CAMKIV autoregulatory domain due to this splice variant had a gain-of-function effect.\r\n\r\n----\r\n\r\nFollowing trio-WES, Zech et al (2020 - PMID: 33098801) identified another relevant subject within cohort of 764 individuals with dystonia. This 12-y.o. male, harboring a different variant affecting the same donor site (c.981+1G>T), presented DD, ID, dystonia (onset at 3y) and additional movement disorders (myoclonus, ataxia) as well as similar behavior (ASD, autoaggression, stereotypies). [Details in suppl. p20].\r\n\r\n----\r\n\r\nFinally Zech et al (2020 - PMID: 33211350) reported on a 24-y.o. woman with adolescence onset choreodystonia. Other features included DD, moderate ID, absence seizures in infancy, OCD with anxiety and later diagnosis of ASD. Trio WES revealed a dn stopgain variant (c.940C>T; p.Gln314*).\r\n\r\n----\r\n\r\nThere is no associated phenotype in OMIM, G2P.\r\n\r\nIn SysID CAMK4 is listed among the current primary ID genes.\r\n\r\n----\r\n\r\nPlease consider inclusion in other relevant panels. \nSources: Literature, Other",
"entity_name": "CAMK4",
"entity_type": "gene"
},
{
"created": "2021-07-25T18:38:30.188021+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.8510",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Marked gene: FERMT3 as ready",
"entity_name": "FERMT3",
"entity_type": "gene"
},
{
"created": "2021-07-25T18:38:30.174912+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.8510",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: fermt3 has been classified as Green List (High Evidence).",
"entity_name": "FERMT3",
"entity_type": "gene"
},
{
"created": "2021-07-25T18:38:21.656638+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.8510",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Phenotypes for gene: FERMT3 were changed from to Leukocyte adhesion deficiency, type III, MIM# 612840",
"entity_name": "FERMT3",
"entity_type": "gene"
},
{
"created": "2021-07-25T18:38:02.560763+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.8509",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Publications for gene: FERMT3 were set to ",
"entity_name": "FERMT3",
"entity_type": "gene"
},
{
"created": "2021-07-25T18:37:43.383937+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.8508",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Mode of inheritance for gene: FERMT3 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal",
"entity_name": "FERMT3",
"entity_type": "gene"
},
{
"created": "2021-07-25T18:37:25.580467+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.8507",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "reviewed gene: FERMT3: Rating: GREEN; Mode of pathogenicity: None; Publications: 19234460, 19064721; Phenotypes: Leukocyte adhesion deficiency, type III, MIM# 612840; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal",
"entity_name": "FERMT3",
"entity_type": "gene"
},
{
"created": "2021-07-25T18:36:39.024065+10:00",
"panel_name": "Phagocyte Defects",
"panel_id": 233,
"panel_version": "0.90",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Marked gene: FERMT3 as ready",
"entity_name": "FERMT3",
"entity_type": "gene"
},
{
"created": "2021-07-25T18:36:39.012088+10:00",
"panel_name": "Phagocyte Defects",
"panel_id": 233,
"panel_version": "0.90",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: fermt3 has been classified as Green List (High Evidence).",
"entity_name": "FERMT3",
"entity_type": "gene"
},
{
"created": "2021-07-25T18:36:35.911378+10:00",
"panel_name": "Phagocyte Defects",
"panel_id": 233,
"panel_version": "0.90",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Phenotypes for gene: FERMT3 were changed from to Leukocyte adhesion deficiency, type III, MIM# 612840",
"entity_name": "FERMT3",
"entity_type": "gene"
},
{
"created": "2021-07-25T18:36:17.699754+10:00",
"panel_name": "Phagocyte Defects",
"panel_id": 233,
"panel_version": "0.89",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Publications for gene: FERMT3 were set to ",
"entity_name": "FERMT3",
"entity_type": "gene"
},
{
"created": "2021-07-25T18:35:47.293716+10:00",
"panel_name": "Phagocyte Defects",
"panel_id": 233,
"panel_version": "0.88",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Mode of inheritance for gene: FERMT3 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal",
"entity_name": "FERMT3",
"entity_type": "gene"
},
{
"created": "2021-07-25T18:35:18.963738+10:00",
"panel_name": "Phagocyte Defects",
"panel_id": 233,
"panel_version": "0.87",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "reviewed gene: FERMT3: Rating: GREEN; Mode of pathogenicity: None; Publications: 19234460, 19064721; Phenotypes: Leukocyte adhesion deficiency, type III, MIM# 612840; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal",
"entity_name": "FERMT3",
"entity_type": "gene"
},
{
"created": "2021-07-25T18:14:26.412594+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.8507",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Phenotypes for gene: ELANE were changed from Neutropaenia, severe congenital 1, autosomal dominant, MIM# 202700 to Neutropaenia, severe congenital 1, autosomal dominant, MIM# 202700; Neutropaenia, cyclic, MIM# 162800",
"entity_name": "ELANE",
"entity_type": "gene"
},
{
"created": "2021-07-25T18:14:06.683449+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.8506",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "edited their review of gene: ELANE: Changed phenotypes: Neutropaenia, severe congenital 1, autosomal dominant, MIM# 202700, Neutropaenia, cyclic, MIM# 162800",
"entity_name": "ELANE",
"entity_type": "gene"
},
{
"created": "2021-07-25T18:13:52.472138+10:00",
"panel_name": "Phagocyte Defects",
"panel_id": 233,
"panel_version": "0.87",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "changed review comment from: Well established gene-disease association.; to: Well established gene-disease association.\r\n\r\nSevere congenital neutropaenia is a heterogeneous disorder of haematopoiesis characterized by a maturation arrest of granulopoiesis at the level of promyelocytes with peripheral blood absolute neutrophil counts below 0.5 x 10(9)/l and early onset of severe bacterial infections. About 60% of affected individuals of European and Middle Eastern ancestry have dominant ELANE mutations.",
"entity_name": "ELANE",
"entity_type": "gene"
},
{
"created": "2021-07-25T18:13:42.476506+10:00",
"panel_name": "Phagocyte Defects",
"panel_id": 233,
"panel_version": "0.87",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Marked gene: ELANE as ready",
"entity_name": "ELANE",
"entity_type": "gene"
},
{
"created": "2021-07-25T18:13:42.466668+10:00",
"panel_name": "Phagocyte Defects",
"panel_id": 233,
"panel_version": "0.87",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Gene: elane has been classified as Green List (High Evidence).",
"entity_name": "ELANE",
"entity_type": "gene"
},
{
"created": "2021-07-25T18:13:11.051597+10:00",
"panel_name": "Phagocyte Defects",
"panel_id": 233,
"panel_version": "0.87",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Phenotypes for gene: ELANE were changed from to Neutropaenia, severe congenital 1, autosomal dominant, MIM# 202700; Neutropaenia, cyclic, MIM# 162800",
"entity_name": "ELANE",
"entity_type": "gene"
},
{
"created": "2021-07-25T18:12:38.806458+10:00",
"panel_name": "Phagocyte Defects",
"panel_id": 233,
"panel_version": "0.86",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Publications for gene: ELANE were set to ",
"entity_name": "ELANE",
"entity_type": "gene"
},
{
"created": "2021-07-25T18:12:14.950545+10:00",
"panel_name": "Phagocyte Defects",
"panel_id": 233,
"panel_version": "0.85",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Mode of inheritance for gene: ELANE was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted",
"entity_name": "ELANE",
"entity_type": "gene"
},
{
"created": "2021-07-25T18:11:49.685072+10:00",
"panel_name": "Phagocyte Defects",
"panel_id": 233,
"panel_version": "0.84",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "reviewed gene: ELANE: Rating: GREEN; Mode of pathogenicity: None; Publications: 10581030, 11001877; Phenotypes: Neutropaenia, severe congenital 1, autosomal dominant, MIM# 202700, Neutropaenia, cyclic, MIM# 162800; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted",
"entity_name": "ELANE",
"entity_type": "gene"
},
{
"created": "2021-07-25T17:58:02.209746+10:00",
"panel_name": "Mendeliome",
"panel_id": 137,
"panel_version": "0.8506",
"user_name": "Zornitza Stark",
"item_type": "entity",
"text": "Marked gene: CYBB as ready",
"entity_name": "CYBB",
"entity_type": "gene"
}
]
}