{"count":220790,"next":"https://panelapp-aus.org/api/v1/activities/?format=json&page=1254","previous":"https://panelapp-aus.org/api/v1/activities/?format=json&page=1252","results":[{"created":"2021-08-02T21:04:22.816296+10:00","panel_name":"Pierre Robin Sequence","panel_id":160,"panel_version":"0.38","user_name":"Zornitza Stark","item_type":"entity","text":"Phenotypes for gene: PLCB4 were changed from  to Auriculocondylar syndrome 2, MIM# 614669","entity_name":"PLCB4","entity_type":"gene"},{"created":"2021-08-02T21:03:39.947478+10:00","panel_name":"Pierre Robin Sequence","panel_id":160,"panel_version":"0.37","user_name":"Zornitza Stark","item_type":"entity","text":"Publications for gene: PLCB4 were set to ","entity_name":"PLCB4","entity_type":"gene"},{"created":"2021-08-02T21:03:09.424691+10:00","panel_name":"Pierre Robin Sequence","panel_id":160,"panel_version":"0.36","user_name":"Zornitza Stark","item_type":"entity","text":"Mode of inheritance for gene: PLCB4 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal","entity_name":"PLCB4","entity_type":"gene"},{"created":"2021-08-02T21:02:44.087898+10:00","panel_name":"Pierre Robin Sequence","panel_id":160,"panel_version":"0.35","user_name":"Zornitza Stark","item_type":"entity","text":"reviewed gene: PLCB4: Rating: GREEN; Mode of pathogenicity: None; Publications: 22560091, 23315542, 33131036, 32201334, 28328130, 27007857, 23913798; Phenotypes: Auriculocondylar syndrome 2, MIM# 614669; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal","entity_name":"PLCB4","entity_type":"gene"},{"created":"2021-08-02T21:01:24.360050+10:00","panel_name":"Mendeliome","panel_id":137,"panel_version":"0.8614","user_name":"Zornitza Stark","item_type":"entity","text":"Marked gene: PLCB4 as ready","entity_name":"PLCB4","entity_type":"gene"},{"created":"2021-08-02T21:01:24.350921+10:00","panel_name":"Mendeliome","panel_id":137,"panel_version":"0.8614","user_name":"Zornitza Stark","item_type":"entity","text":"Gene: plcb4 has been classified as Green List (High Evidence).","entity_name":"PLCB4","entity_type":"gene"},{"created":"2021-08-02T21:01:12.302919+10:00","panel_name":"Mendeliome","panel_id":137,"panel_version":"0.8614","user_name":"Zornitza Stark","item_type":"entity","text":"Phenotypes for gene: PLCB4 were changed from  to Auriculocondylar syndrome 2, MIM# 614669","entity_name":"PLCB4","entity_type":"gene"},{"created":"2021-08-02T21:00:50.641917+10:00","panel_name":"Mendeliome","panel_id":137,"panel_version":"0.8613","user_name":"Zornitza Stark","item_type":"entity","text":"Publications for gene: PLCB4 were set to ","entity_name":"PLCB4","entity_type":"gene"},{"created":"2021-08-02T21:00:20.494476+10:00","panel_name":"Mendeliome","panel_id":137,"panel_version":"0.8612","user_name":"Zornitza Stark","item_type":"entity","text":"Mode of inheritance for gene: PLCB4 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal","entity_name":"PLCB4","entity_type":"gene"},{"created":"2021-08-02T21:00:02.228019+10:00","panel_name":"Mendeliome","panel_id":137,"panel_version":"0.8611","user_name":"Zornitza Stark","item_type":"entity","text":"reviewed gene: PLCB4: Rating: GREEN; Mode of pathogenicity: None; Publications: 22560091, 23315542, 33131036, 32201334, 28328130, 27007857, 23913798; Phenotypes: Auriculocondylar syndrome 2, MIM# 614669; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal","entity_name":"PLCB4","entity_type":"gene"},{"created":"2021-08-02T20:59:14.498228+10:00","panel_name":"Mandibulofacial Acrofacial dysostosis","panel_id":136,"panel_version":"0.57","user_name":"Zornitza Stark","item_type":"entity","text":"Marked gene: PLCB4 as ready","entity_name":"PLCB4","entity_type":"gene"},{"created":"2021-08-02T20:59:14.487528+10:00","panel_name":"Mandibulofacial Acrofacial dysostosis","panel_id":136,"panel_version":"0.57","user_name":"Zornitza Stark","item_type":"entity","text":"Gene: plcb4 has been classified as Green List (High Evidence).","entity_name":"PLCB4","entity_type":"gene"},{"created":"2021-08-02T20:58:58.635894+10:00","panel_name":"Mandibulofacial Acrofacial dysostosis","panel_id":136,"panel_version":"0.57","user_name":"Zornitza Stark","item_type":"entity","text":"Phenotypes for gene: PLCB4 were changed from  to Auriculocondylar syndrome 2, MIM# 614669","entity_name":"PLCB4","entity_type":"gene"},{"created":"2021-08-02T20:58:35.168413+10:00","panel_name":"Mandibulofacial Acrofacial dysostosis","panel_id":136,"panel_version":"0.56","user_name":"Zornitza Stark","item_type":"entity","text":"Publications for gene: PLCB4 were set to ","entity_name":"PLCB4","entity_type":"gene"},{"created":"2021-08-02T20:58:12.782669+10:00","panel_name":"Mandibulofacial Acrofacial dysostosis","panel_id":136,"panel_version":"0.55","user_name":"Zornitza Stark","item_type":"entity","text":"Mode of pathogenicity for gene: PLCB4 was changed from  to Other","entity_name":"PLCB4","entity_type":"gene"},{"created":"2021-08-02T20:57:46.586669+10:00","panel_name":"Mandibulofacial Acrofacial dysostosis","panel_id":136,"panel_version":"0.54","user_name":"Zornitza Stark","item_type":"entity","text":"Mode of inheritance for gene: PLCB4 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal","entity_name":"PLCB4","entity_type":"gene"},{"created":"2021-08-02T20:57:15.561264+10:00","panel_name":"Mandibulofacial Acrofacial dysostosis","panel_id":136,"panel_version":"0.53","user_name":"Zornitza Stark","item_type":"entity","text":"reviewed gene: PLCB4: Rating: GREEN; Mode of pathogenicity: None; Publications: 22560091, 23315542, 33131036, 32201334, 28328130, 27007857, 23913798; Phenotypes: Auriculocondylar syndrome 2, MIM# 614669; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal","entity_name":"PLCB4","entity_type":"gene"},{"created":"2021-08-02T20:51:04.601331+10:00","panel_name":"Mendeliome","panel_id":137,"panel_version":"0.8611","user_name":"Zornitza Stark","item_type":"entity","text":"Marked gene: PBX1 as ready","entity_name":"PBX1","entity_type":"gene"},{"created":"2021-08-02T20:51:04.590640+10:00","panel_name":"Mendeliome","panel_id":137,"panel_version":"0.8611","user_name":"Zornitza Stark","item_type":"entity","text":"Gene: pbx1 has been classified as Green List (High Evidence).","entity_name":"PBX1","entity_type":"gene"},{"created":"2021-08-02T20:50:52.431434+10:00","panel_name":"Mendeliome","panel_id":137,"panel_version":"0.8611","user_name":"Zornitza Stark","item_type":"entity","text":"Phenotypes for gene: PBX1 were changed from  to Congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay, MIM# 617641","entity_name":"PBX1","entity_type":"gene"},{"created":"2021-08-02T20:50:26.747551+10:00","panel_name":"Mendeliome","panel_id":137,"panel_version":"0.8610","user_name":"Zornitza Stark","item_type":"entity","text":"Publications for gene: PBX1 were set to ","entity_name":"PBX1","entity_type":"gene"},{"created":"2021-08-02T20:50:06.362948+10:00","panel_name":"Mendeliome","panel_id":137,"panel_version":"0.8609","user_name":"Zornitza Stark","item_type":"entity","text":"Mode of inheritance for gene: PBX1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted","entity_name":"PBX1","entity_type":"gene"},{"created":"2021-08-02T20:49:47.285462+10:00","panel_name":"Mendeliome","panel_id":137,"panel_version":"0.8608","user_name":"Zornitza Stark","item_type":"entity","text":"reviewed gene: PBX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28566479, 29036646; Phenotypes: Congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay, MIM# 617641; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted","entity_name":"PBX1","entity_type":"gene"},{"created":"2021-08-02T20:49:00.731686+10:00","panel_name":"Mandibulofacial Acrofacial dysostosis","panel_id":136,"panel_version":"0.53","user_name":"Zornitza Stark","item_type":"entity","text":"Marked gene: PBX1 as ready","entity_name":"PBX1","entity_type":"gene"},{"created":"2021-08-02T20:49:00.720494+10:00","panel_name":"Mandibulofacial Acrofacial dysostosis","panel_id":136,"panel_version":"0.53","user_name":"Zornitza Stark","item_type":"entity","text":"Gene: pbx1 has been classified as Green List (High Evidence).","entity_name":"PBX1","entity_type":"gene"},{"created":"2021-08-02T20:48:56.854706+10:00","panel_name":"Mandibulofacial Acrofacial dysostosis","panel_id":136,"panel_version":"0.53","user_name":"Zornitza Stark","item_type":"entity","text":"Phenotypes for gene: PBX1 were changed from  to Congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay, MIM# 617641","entity_name":"PBX1","entity_type":"gene"},{"created":"2021-08-02T20:48:34.266623+10:00","panel_name":"Mandibulofacial Acrofacial dysostosis","panel_id":136,"panel_version":"0.52","user_name":"Zornitza Stark","item_type":"entity","text":"Publications for gene: PBX1 were set to ","entity_name":"PBX1","entity_type":"gene"},{"created":"2021-08-02T20:48:06.215331+10:00","panel_name":"Mandibulofacial Acrofacial dysostosis","panel_id":136,"panel_version":"0.51","user_name":"Zornitza Stark","item_type":"entity","text":"Mode of inheritance for gene: PBX1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted","entity_name":"PBX1","entity_type":"gene"},{"created":"2021-08-02T20:47:38.934431+10:00","panel_name":"Mandibulofacial Acrofacial dysostosis","panel_id":136,"panel_version":"0.50","user_name":"Zornitza Stark","item_type":"entity","text":"reviewed gene: PBX1: Rating: GREEN; Mode of pathogenicity: None; Publications: 28566479, 29036646; Phenotypes: Congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay, MIM# 617641; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted","entity_name":"PBX1","entity_type":"gene"},{"created":"2021-08-02T18:31:10.180796+10:00","panel_name":"Genetic Epilepsy","panel_id":202,"panel_version":"0.1154","user_name":"Zornitza Stark","item_type":"entity","text":"Marked gene: SPTBN1 as ready","entity_name":"SPTBN1","entity_type":"gene"},{"created":"2021-08-02T18:31:10.170273+10:00","panel_name":"Genetic Epilepsy","panel_id":202,"panel_version":"0.1154","user_name":"Zornitza Stark","item_type":"entity","text":"Gene: sptbn1 has been classified as Green List (High Evidence).","entity_name":"SPTBN1","entity_type":"gene"},{"created":"2021-08-02T18:30:00.123068+10:00","panel_name":"Genetic Epilepsy","panel_id":202,"panel_version":"0.1154","user_name":"Zornitza Stark","item_type":"entity","text":"Classified gene: SPTBN1 as Green List (high evidence)","entity_name":"SPTBN1","entity_type":"gene"},{"created":"2021-08-02T18:30:00.032647+10:00","panel_name":"Genetic Epilepsy","panel_id":202,"panel_version":"0.1154","user_name":"Zornitza Stark","item_type":"entity","text":"Gene: sptbn1 has been classified as Green List (High Evidence).","entity_name":"SPTBN1","entity_type":"gene"},{"created":"2021-08-02T18:29:23.124636+10:00","panel_name":"Intellectual disability syndromic and non-syndromic","panel_id":250,"panel_version":"0.4022","user_name":"Zornitza Stark","item_type":"entity","text":"Marked gene: SPTBN1 as ready","entity_name":"SPTBN1","entity_type":"gene"},{"created":"2021-08-02T18:29:23.113071+10:00","panel_name":"Intellectual disability syndromic and non-syndromic","panel_id":250,"panel_version":"0.4022","user_name":"Zornitza Stark","item_type":"entity","text":"Gene: sptbn1 has been classified as Green List (High Evidence).","entity_name":"SPTBN1","entity_type":"gene"},{"created":"2021-08-02T18:29:17.024157+10:00","panel_name":"Intellectual disability syndromic and non-syndromic","panel_id":250,"panel_version":"0.4022","user_name":"Zornitza Stark","item_type":"entity","text":"Classified gene: SPTBN1 as Green List (high evidence)","entity_name":"SPTBN1","entity_type":"gene"},{"created":"2021-08-02T18:29:17.000852+10:00","panel_name":"Intellectual disability syndromic and non-syndromic","panel_id":250,"panel_version":"0.4022","user_name":"Zornitza Stark","item_type":"entity","text":"Gene: sptbn1 has been classified as Green List (High Evidence).","entity_name":"SPTBN1","entity_type":"gene"},{"created":"2021-08-02T18:28:39.013322+10:00","panel_name":"Polydactyly","panel_id":159,"panel_version":"0.236","user_name":"Zornitza Stark","item_type":"entity","text":"Marked gene: HMGB1 as ready","entity_name":"HMGB1","entity_type":"gene"},{"created":"2021-08-02T18:28:39.002405+10:00","panel_name":"Polydactyly","panel_id":159,"panel_version":"0.236","user_name":"Zornitza Stark","item_type":"entity","text":"Gene: hmgb1 has been classified as Red List (Low Evidence).","entity_name":"HMGB1","entity_type":"gene"},{"created":"2021-08-02T18:28:35.108898+10:00","panel_name":"Polydactyly","panel_id":159,"panel_version":"0.236","user_name":"Zornitza Stark","item_type":"entity","text":"Classified gene: HMGB1 as Red List (low evidence)","entity_name":"HMGB1","entity_type":"gene"},{"created":"2021-08-02T18:28:35.095133+10:00","panel_name":"Polydactyly","panel_id":159,"panel_version":"0.236","user_name":"Zornitza Stark","item_type":"entity","text":"Gene: hmgb1 has been classified as Red List (Low Evidence).","entity_name":"HMGB1","entity_type":"gene"},{"created":"2021-08-02T18:27:46.288367+10:00","panel_name":"Skeletal dysplasia","panel_id":258,"panel_version":"0.110","user_name":"Zornitza Stark","item_type":"entity","text":"Classified gene: UBA2 as Green List (high evidence)","entity_name":"UBA2","entity_type":"gene"},{"created":"2021-08-02T18:27:46.275816+10:00","panel_name":"Skeletal dysplasia","panel_id":258,"panel_version":"0.110","user_name":"Zornitza Stark","item_type":"entity","text":"Gene: uba2 has been classified as Green List (High Evidence).","entity_name":"UBA2","entity_type":"gene"},{"created":"2021-08-02T18:22:32.989633+10:00","panel_name":"Mendeliome","panel_id":137,"panel_version":"0.8608","user_name":"Zornitza Stark","item_type":"entity","text":"Phenotypes for gene: VRK1 were changed from Pontocerebellar hypoplasia type 1A, MIM# 607596; SMA to Pontocerebellar hypoplasia type 1A, MIM# 607596; Adult-onset spinal muscular atrophy without pontocerebellar hypoplasia","entity_name":"VRK1","entity_type":"gene"},{"created":"2021-08-02T18:22:11.036359+10:00","panel_name":"Mendeliome","panel_id":137,"panel_version":"0.8607","user_name":"Zornitza Stark","item_type":"entity","text":"Publications for gene: VRK1 were set to 19646678; 21937992; 25609612; 24126608; 27281532","entity_name":"VRK1","entity_type":"gene"},{"created":"2021-08-02T18:21:41.753468+10:00","panel_name":"Mendeliome","panel_id":137,"panel_version":"0.8606","user_name":"Zornitza Stark","item_type":"entity","text":"changed review comment from: Complex phenotype with mixed peripheral and central neurological features. Two families reported where PCH was prominent and accompanied by ataxia. At least three families also reported where peripheral neuropathy dominated the clinical picture without PCH/ataxia.; to: Complex phenotype with mixed peripheral and central neurological features. Two families reported where PCH was prominent and accompanied by ataxia. At least three families also reported where peripheral neuropathy dominated the clinical picture without PCH/ataxia.\r\n\r\nFurther delineation of phenotype 2021:\r\nPMID 34169149: expanding spectrum of neurologic disorders associated with VRK1. Two Hispanic individuals, one homozygous (R321C: VUS and LP/P in ClinVar) and one cHet (R321C+V236M, latter P and more recently VUS in ClinVar), with slowly progressive weakness and a clinical syndrome consistent with adult-onset spinal muscular atrophy WITHOUT pontocerebellar atrophy. No hom in gnomAD and both have been reported in cHet individuals with other features: R321C in association with adult-onset amyotrophic lateral sclerosis and V236M with rapidly progressive sensorimotor polyneuropathy and microcephaly. Authors suggest PMID 26583493 and 31837156 have similar reports. PMID 26583493 reports a 32yo Hispanic individual, cHet H119R+R321C, with early-onset amyotrophic lateral sclerosis, 5 years progressive weakness. PMID 31837156 reports two patients with adult-onset length-dependent motor neuropathy from unrelated consanguineous families of Moroccan Jewish descent, both hom for R387H.","entity_name":"VRK1","entity_type":"gene"},{"created":"2021-08-02T18:20:54.642035+10:00","panel_name":"Mendeliome","panel_id":137,"panel_version":"0.8606","user_name":"Zornitza Stark","item_type":"entity","text":"edited their review of gene: VRK1: Changed publications: 19646678, 21937992, 25609612, 24126608, 27281532, 34169149, 26583493; Changed phenotypes: Pontocerebellar hypoplasia type 1A, MIM# 607596, Adult-onset spinal muscular atrophy without pontocerebellar hypoplasia","entity_name":"VRK1","entity_type":"gene"},{"created":"2021-08-02T18:17:05.046481+10:00","panel_name":"Motor Neurone Disease","panel_id":25,"panel_version":"0.126","user_name":"Zornitza Stark","item_type":"entity","text":"Phenotypes for gene: VRK1 were changed from Distal hereditary motor neuropathy; dHMN/dSMA to Adult-onset spinal muscular atrophy without pontocerebellar hypoplasia; Distal hereditary motor neuropathy; dHMN/dSMA","entity_name":"VRK1","entity_type":"gene"},{"created":"2021-08-02T18:16:43.139095+10:00","panel_name":"Motor Neurone Disease","panel_id":25,"panel_version":"0.125","user_name":"Zornitza Stark","item_type":"entity","text":"Publications for gene: VRK1 were set to 31560180; 32242460; 31178479; 31837156; 30847374","entity_name":"VRK1","entity_type":"gene"},{"created":"2021-08-02T18:15:58.299283+10:00","panel_name":"Motor Neurone Disease","panel_id":25,"panel_version":"0.124","user_name":"Zornitza Stark","item_type":"entity","text":"Classified gene: VRK1 as Amber List (moderate evidence)","entity_name":"VRK1","entity_type":"gene"},{"created":"2021-08-02T18:15:58.288476+10:00","panel_name":"Motor Neurone Disease","panel_id":25,"panel_version":"0.124","user_name":"Zornitza Stark","item_type":"entity","text":"Gene: vrk1 has been classified as Amber List (Moderate Evidence).","entity_name":"VRK1","entity_type":"gene"},{"created":"2021-08-02T18:14:53.240132+10:00","panel_name":"Genetic Epilepsy","panel_id":202,"panel_version":"0.1153","user_name":"Zornitza Stark","item_type":"entity","text":"Marked gene: CLCN3 as ready","entity_name":"CLCN3","entity_type":"gene"},{"created":"2021-08-02T18:14:53.230187+10:00","panel_name":"Genetic Epilepsy","panel_id":202,"panel_version":"0.1153","user_name":"Zornitza Stark","item_type":"entity","text":"Gene: clcn3 has been classified as Green List (High Evidence).","entity_name":"CLCN3","entity_type":"gene"},{"created":"2021-08-02T18:14:49.675122+10:00","panel_name":"Genetic Epilepsy","panel_id":202,"panel_version":"0.1153","user_name":"Zornitza Stark","item_type":"entity","text":"Classified gene: CLCN3 as Green List (high evidence)","entity_name":"CLCN3","entity_type":"gene"},{"created":"2021-08-02T18:14:49.664677+10:00","panel_name":"Genetic Epilepsy","panel_id":202,"panel_version":"0.1153","user_name":"Zornitza Stark","item_type":"entity","text":"Gene: clcn3 has been classified as Green List (High Evidence).","entity_name":"CLCN3","entity_type":"gene"},{"created":"2021-08-02T18:14:24.737304+10:00","panel_name":"Callosome","panel_id":205,"panel_version":"0.309","user_name":"Zornitza Stark","item_type":"entity","text":"Marked gene: CLCN3 as ready","entity_name":"CLCN3","entity_type":"gene"},{"created":"2021-08-02T18:14:24.724509+10:00","panel_name":"Callosome","panel_id":205,"panel_version":"0.309","user_name":"Zornitza Stark","item_type":"entity","text":"Gene: clcn3 has been classified as Green List (High Evidence).","entity_name":"CLCN3","entity_type":"gene"},{"created":"2021-08-02T18:14:20.477036+10:00","panel_name":"Callosome","panel_id":205,"panel_version":"0.309","user_name":"Zornitza Stark","item_type":"entity","text":"Classified gene: CLCN3 as Green List (high evidence)","entity_name":"CLCN3","entity_type":"gene"},{"created":"2021-08-02T18:14:20.467076+10:00","panel_name":"Callosome","panel_id":205,"panel_version":"0.309","user_name":"Zornitza Stark","item_type":"entity","text":"Gene: clcn3 has been classified as Green List (High Evidence).","entity_name":"CLCN3","entity_type":"gene"},{"created":"2021-08-02T18:14:05.459614+10:00","panel_name":"Genetic Epilepsy","panel_id":202,"panel_version":"0.1152","user_name":"Zornitza Stark","item_type":"entity","text":"gene: CLCN3 was added\ngene: CLCN3 was added to Genetic Epilepsy. Sources: Literature\nMode of inheritance for gene: CLCN3 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal\nPublications for gene: CLCN3 were set to 34186028\nPhenotypes for gene: CLCN3 were set to Neurodevelopmental disorder\nMode of pathogenicity for gene: CLCN3 was set to Other\nReview for gene: CLCN3 was set to GREEN\nAdded comment: 11 individuals reported, 9 that carried 8 different rare heterozygous missense variants in CLCN3, and 2 siblings that were homozygous for an NMD-predicted frameshift variant likely abolishing ClC-3 function. All missense variants were confirmed to be de novo in eight individuals for whom parental data was available.\r\n\r\nThe 11 individuals in the cohort share clinical features of variable severity. All 11 have GDD or ID and dysmorphic features, and a majority has mood or behavioural disorders and structural brain abnormalities:\r\n- Structural brain abnormalities on MRI (9/11) included partial or full agenesis of the corpus callosum (6/9), disorganized cerebellar folia (4/9), delayed myelination (3/9), decreased white matter volume (3/9), pons hypoplasia (3/9), and dysmorphic dentate nuclei (3/9). Six of those with brain abnormalities also presented with seizures.\r\n- Nine have abnormal vision, including strabismus in four and inability to fix or follow in the two with homozygous loss-of-function variants.\r\n- Hypotonia ranging from mild to severe was reported in 7 of the 11 individuals.\r\n- Six have mood or behavioural disorders, particularly anxiety (3/6).\r\n- Consistent dysmorphic facial features included microcephaly, prominent forehead, hypertelorism, down-slanting palpebral fissures, full cheeks, and micrognathia.\r\n\r\nThe severity of disease in the two siblings with homozygous disruption of ClC-3 is consistent with the drastic phenotype seen in Clcn3 KO mice. The disease was more severe in two siblings carrying homozygous loss-of-function variants with the presence of GDD, absent speech, seizures, and salt and pepper fundal pigmentation in both individuals, with one deceased at 14 months of age. The siblings also had significant neuroanatomical findings including diffusely decreased white matter volume, thin corpora callosa, small hippocampi, and disorganized cerebellar folia. Supporting biallelic inheritance for LoF variants, disruption of mouse Clcn3 results in drastic neurodegeneration with loss of the hippocampus a few months after birth and early retinal degeneration. Clcn3−/− mice display severe neurodegeneration, whereas heterozygous Clcn3+/− mice appear normal.\r\n\r\nPatch-clamp studies were used to investigate four of the missense variants. These suggested a gain of function in two variants with increased current in HEK cells, however they also showed reduced rectification of voltage and a loss of transient current, plus decreased current amplitude, glycosylation and surface expression when expressed in oocytes, and were suspected to interfere with channel gating and a negative feedback mechanism. These effects were also shown to vary depending on pH levels. The current of the remaining two variants did not differ from WT. For heterozygous missense variants, the disruption induced may be at least partially conferred to mutant/WT homodimers and mutant/ClC-4 heterodimers.\r\n\r\nBoth loss and gain of function in this gene resulted in the same phenotype. \nSources: Literature","entity_name":"CLCN3","entity_type":"gene"},{"created":"2021-08-02T18:13:46.947550+10:00","panel_name":"Callosome","panel_id":205,"panel_version":"0.308","user_name":"Zornitza Stark","item_type":"entity","text":"gene: CLCN3 was added\ngene: CLCN3 was added to Callosome. Sources: Literature\nMode of inheritance for gene: CLCN3 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal\nPublications for gene: CLCN3 were set to 34186028\nPhenotypes for gene: CLCN3 were set to Neurodevelopmental disorder\nMode of pathogenicity for gene: CLCN3 was set to Other\nReview for gene: CLCN3 was set to GREEN\nAdded comment: 11 individuals reported, 9 that carried 8 different rare heterozygous missense variants in CLCN3, and 2 siblings that were homozygous for an NMD-predicted frameshift variant likely abolishing ClC-3 function. All missense variants were confirmed to be de novo in eight individuals for whom parental data was available.\r\n\r\nThe 11 individuals in the cohort share clinical features of variable severity. All 11 have GDD or ID and dysmorphic features, and a majority has mood or behavioural disorders and structural brain abnormalities:\r\n- Structural brain abnormalities on MRI (9/11) included partial or full agenesis of the corpus callosum (6/9), disorganized cerebellar folia (4/9), delayed myelination (3/9), decreased white matter volume (3/9), pons hypoplasia (3/9), and dysmorphic dentate nuclei (3/9). Six of those with brain abnormalities also presented with seizures.\r\n- Nine have abnormal vision, including strabismus in four and inability to fix or follow in the two with homozygous loss-of-function variants.\r\n- Hypotonia ranging from mild to severe was reported in 7 of the 11 individuals.\r\n- Six have mood or behavioural disorders, particularly anxiety (3/6).\r\n- Consistent dysmorphic facial features included microcephaly, prominent forehead, hypertelorism, down-slanting palpebral fissures, full cheeks, and micrognathia.\r\n\r\nThe severity of disease in the two siblings with homozygous disruption of ClC-3 is consistent with the drastic phenotype seen in Clcn3 KO mice. The disease was more severe in two siblings carrying homozygous loss-of-function variants with the presence of GDD, absent speech, seizures, and salt and pepper fundal pigmentation in both individuals, with one deceased at 14 months of age. The siblings also had significant neuroanatomical findings including diffusely decreased white matter volume, thin corpora callosa, small hippocampi, and disorganized cerebellar folia. Supporting biallelic inheritance for LoF variants, disruption of mouse Clcn3 results in drastic neurodegeneration with loss of the hippocampus a few months after birth and early retinal degeneration. Clcn3−/− mice display severe neurodegeneration, whereas heterozygous Clcn3+/− mice appear normal.\r\n\r\nPatch-clamp studies were used to investigate four of the missense variants. These suggested a gain of function in two variants with increased current in HEK cells, however they also showed reduced rectification of voltage and a loss of transient current, plus decreased current amplitude, glycosylation and surface expression when expressed in oocytes, and were suspected to interfere with channel gating and a negative feedback mechanism. These effects were also shown to vary depending on pH levels. The current of the remaining two variants did not differ from WT. For heterozygous missense variants, the disruption induced may be at least partially conferred to mutant/WT homodimers and mutant/ClC-4 heterodimers.\r\n\r\nBoth loss and gain of function in this gene resulted in the same phenotype. \nSources: Literature","entity_name":"CLCN3","entity_type":"gene"},{"created":"2021-08-02T18:11:29.766765+10:00","panel_name":"Intellectual disability syndromic and non-syndromic","panel_id":250,"panel_version":"0.4021","user_name":"Zornitza Stark","item_type":"entity","text":"Marked gene: CLCN3 as ready","entity_name":"CLCN3","entity_type":"gene"},{"created":"2021-08-02T18:11:29.750480+10:00","panel_name":"Intellectual disability syndromic and non-syndromic","panel_id":250,"panel_version":"0.4021","user_name":"Zornitza Stark","item_type":"entity","text":"Gene: clcn3 has been classified as Green List (High Evidence).","entity_name":"CLCN3","entity_type":"gene"},{"created":"2021-08-02T18:11:24.155801+10:00","panel_name":"Intellectual disability syndromic and non-syndromic","panel_id":250,"panel_version":"0.4021","user_name":"Zornitza Stark","item_type":"entity","text":"Classified gene: CLCN3 as Green List (high evidence)","entity_name":"CLCN3","entity_type":"gene"},{"created":"2021-08-02T18:11:24.145471+10:00","panel_name":"Intellectual disability syndromic and non-syndromic","panel_id":250,"panel_version":"0.4021","user_name":"Zornitza Stark","item_type":"entity","text":"Gene: clcn3 has been classified as Green List (High Evidence).","entity_name":"CLCN3","entity_type":"gene"},{"created":"2021-08-02T18:10:18.677118+10:00","panel_name":"Intellectual disability syndromic and non-syndromic","panel_id":250,"panel_version":"0.4020","user_name":"Zornitza Stark","item_type":"entity","text":"gene: CLCN3 was added\ngene: CLCN3 was added to Intellectual disability syndromic and non-syndromic. Sources: Literature\nMode of inheritance for gene: CLCN3 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal\nPublications for gene: CLCN3 were set to 34186028\nPhenotypes for gene: CLCN3 were set to Neurodevelopmental disorder\nMode of pathogenicity for gene: CLCN3 was set to Other\nReview for gene: CLCN3 was set to GREEN\nAdded comment: 11 individuals reported, 9 that carried 8 different rare heterozygous missense variants in CLCN3, and 2 siblings that were homozygous for an NMD-predicted frameshift variant likely abolishing ClC-3 function. All missense variants were confirmed to be de novo in eight individuals for whom parental data was available.\r\n\r\nThe 11 individuals in the cohort share clinical features of variable severity. All 11 have GDD or ID and dysmorphic features, and a majority has mood or behavioural disorders and structural brain abnormalities:\r\n- Structural brain abnormalities on MRI (9/11) included partial or full agenesis of the corpus callosum (6/9), disorganized cerebellar folia (4/9), delayed myelination (3/9), decreased white matter volume (3/9), pons hypoplasia (3/9), and dysmorphic dentate nuclei (3/9). Six of those with brain abnormalities also presented with seizures.\r\n- Nine have abnormal vision, including strabismus in four and inability to fix or follow in the two with homozygous loss-of-function variants.\r\n- Hypotonia ranging from mild to severe was reported in 7 of the 11 individuals.\r\n- Six have mood or behavioural disorders, particularly anxiety (3/6).\r\n- Consistent dysmorphic facial features included microcephaly, prominent forehead, hypertelorism, down-slanting palpebral fissures, full cheeks, and micrognathia.\r\n\r\nThe severity of disease in the two siblings with homozygous disruption of ClC-3 is consistent with the drastic phenotype seen in Clcn3 KO mice. The disease was more severe in two siblings carrying homozygous loss-of-function variants with the presence of GDD, absent speech, seizures, and salt and pepper fundal pigmentation in both individuals, with one deceased at 14 months of age. The siblings also had significant neuroanatomical findings including diffusely decreased white matter volume, thin corpora callosa, small hippocampi, and disorganized cerebellar folia. Supporting biallelic inheritance for LoF variants, disruption of mouse Clcn3 results in drastic neurodegeneration with loss of the hippocampus a few months after birth and early retinal degeneration. Clcn3−/− mice display severe neurodegeneration, whereas heterozygous Clcn3+/− mice appear normal.\r\n\r\nPatch-clamp studies were used to investigate four of the missense variants. These suggested a gain of function in two variants with increased current in HEK cells, however they also showed reduced rectification of voltage and a loss of transient current, plus decreased current amplitude, glycosylation and surface expression when expressed in oocytes, and were suspected to interfere with channel gating and a negative feedback mechanism. These effects were also shown to vary depending on pH levels. The current of the remaining two variants did not differ from WT. For heterozygous missense variants, the disruption induced may be at least partially conferred to mutant/WT homodimers and mutant/ClC-4 heterodimers.\r\n\r\nBoth loss and gain of function in this gene resulted in the same phenotype. \nSources: Literature","entity_name":"CLCN3","entity_type":"gene"},{"created":"2021-08-02T18:08:01.524221+10:00","panel_name":"Mendeliome","panel_id":137,"panel_version":"0.8606","user_name":"Zornitza Stark","item_type":"entity","text":"Marked gene: CLCN3 as ready","entity_name":"CLCN3","entity_type":"gene"},{"created":"2021-08-02T18:08:01.514452+10:00","panel_name":"Mendeliome","panel_id":137,"panel_version":"0.8606","user_name":"Zornitza Stark","item_type":"entity","text":"Gene: clcn3 has been classified as Green List (High Evidence).","entity_name":"CLCN3","entity_type":"gene"},{"created":"2021-08-02T18:07:50.253789+10:00","panel_name":"Mendeliome","panel_id":137,"panel_version":"0.8606","user_name":"Zornitza Stark","item_type":"entity","text":"Mode of inheritance for gene: CLCN3 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal","entity_name":"CLCN3","entity_type":"gene"},{"created":"2021-08-02T18:07:37.914087+10:00","panel_name":"Mendeliome","panel_id":137,"panel_version":"0.8605","user_name":"Zornitza Stark","item_type":"entity","text":"Classified gene: CLCN3 as Green List (high evidence)","entity_name":"CLCN3","entity_type":"gene"},{"created":"2021-08-02T18:07:37.904292+10:00","panel_name":"Mendeliome","panel_id":137,"panel_version":"0.8605","user_name":"Zornitza Stark","item_type":"entity","text":"Gene: clcn3 has been classified as Green List (High Evidence).","entity_name":"CLCN3","entity_type":"gene"},{"created":"2021-08-02T18:05:33.882962+10:00","panel_name":"Microcephaly","panel_id":138,"panel_version":"1.37","user_name":"Zornitza Stark","item_type":"entity","text":"Marked gene: TNPO2 as ready","entity_name":"TNPO2","entity_type":"gene"},{"created":"2021-08-02T18:05:33.873501+10:00","panel_name":"Microcephaly","panel_id":138,"panel_version":"1.37","user_name":"Zornitza Stark","item_type":"entity","text":"Gene: tnpo2 has been classified as Green List (High Evidence).","entity_name":"TNPO2","entity_type":"gene"},{"created":"2021-08-02T18:05:30.159044+10:00","panel_name":"Microcephaly","panel_id":138,"panel_version":"1.37","user_name":"Zornitza Stark","item_type":"entity","text":"Classified gene: TNPO2 as Green List (high evidence)","entity_name":"TNPO2","entity_type":"gene"},{"created":"2021-08-02T18:05:30.149847+10:00","panel_name":"Microcephaly","panel_id":138,"panel_version":"1.37","user_name":"Zornitza Stark","item_type":"entity","text":"Gene: tnpo2 has been classified as Green List (High Evidence).","entity_name":"TNPO2","entity_type":"gene"},{"created":"2021-08-02T18:05:00.536625+10:00","panel_name":"Microcephaly","panel_id":138,"panel_version":"1.36","user_name":"Zornitza Stark","item_type":"entity","text":"gene: TNPO2 was added\ngene: TNPO2 was added to Microcephaly. Sources: Literature\nMode of inheritance for gene: TNPO2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted\nPublications for gene: TNPO2 were set to 34314705\nPhenotypes for gene: TNPO2 were set to Intellectual disability, neurologic deficits and dysmorphic features\nMode of pathogenicity for gene: TNPO2 was set to Other\nReview for gene: TNPO2 was set to GREEN\nAdded comment: PMID: 34314705 - all de novo missense variants with intellectual disability (9/9), speech impairment (15/15), motor impairment (15/15), ophthalmologic abnormalities (10/15), muscle tone abnormalities (11/15, primarily hypotonia), seizures (6/15, febrile to non-febrile), microcephaly (5/15) and MRI anomalies (7/13, 3/13 had cerebellar hypoplasia/dysplasia). Null fly model was homozygous lethal, no obvious phenotypes in heterozygotes. Upregulated gene expression also resulted in lethality. Overexpression of some human variants in fly models resulted in \"toxicity\" and phenotypic defects, authors speculate two variants are GOF, 1 variant is LOF. gnomAD: minimal PTCs present \nSources: Literature","entity_name":"TNPO2","entity_type":"gene"},{"created":"2021-08-02T18:00:18.393047+10:00","panel_name":"Genetic Epilepsy","panel_id":202,"panel_version":"0.1151","user_name":"Zornitza Stark","item_type":"entity","text":"Marked gene: TNPO2 as ready","entity_name":"TNPO2","entity_type":"gene"},{"created":"2021-08-02T18:00:18.382698+10:00","panel_name":"Genetic Epilepsy","panel_id":202,"panel_version":"0.1151","user_name":"Zornitza Stark","item_type":"entity","text":"Gene: tnpo2 has been classified as Green List (High Evidence).","entity_name":"TNPO2","entity_type":"gene"},{"created":"2021-08-02T18:00:13.682005+10:00","panel_name":"Genetic Epilepsy","panel_id":202,"panel_version":"0.1151","user_name":"Zornitza Stark","item_type":"entity","text":"Classified gene: TNPO2 as Green List (high evidence)","entity_name":"TNPO2","entity_type":"gene"},{"created":"2021-08-02T18:00:13.670801+10:00","panel_name":"Genetic Epilepsy","panel_id":202,"panel_version":"0.1151","user_name":"Zornitza Stark","item_type":"entity","text":"Gene: tnpo2 has been classified as Green List (High Evidence).","entity_name":"TNPO2","entity_type":"gene"},{"created":"2021-08-02T17:59:49.849952+10:00","panel_name":"Genetic Epilepsy","panel_id":202,"panel_version":"0.1150","user_name":"Zornitza Stark","item_type":"entity","text":"gene: TNPO2 was added\ngene: TNPO2 was added to Genetic Epilepsy. Sources: Literature\nMode of inheritance for gene: TNPO2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted\nPublications for gene: TNPO2 were set to 34314705\nPhenotypes for gene: TNPO2 were set to Intellectual disability, neurologic deficits and dysmorphic features\nMode of pathogenicity for gene: TNPO2 was set to Other\nReview for gene: TNPO2 was set to GREEN\nAdded comment: PMID: 34314705 - all de novo missense variants with intellectual disability (9/9), speech impairment (15/15), motor impairment (15/15), ophthalmologic abnormalities (10/15), muscle tone abnormalities (11/15, primarily hypotonia), seizures (6/15, febrile to non-febrile), microcephaly (5/15) and MRI anomalies (7/13, 3/13 had cerebellar hypoplasia/dysplasia). Null fly model was homozygous lethal, no obvious phenotypes in heterozygotes. Upregulated gene expression also resulted in lethality. Overexpression of some human variants in fly models resulted in \"toxicity\" and phenotypic defects, authors speculate two variants are GOF, 1 variant is LOF. gnomAD: minimal PTCs present. \nSources: Literature","entity_name":"TNPO2","entity_type":"gene"},{"created":"2021-08-02T17:57:28.701520+10:00","panel_name":"Intellectual disability syndromic and non-syndromic","panel_id":250,"panel_version":"0.4019","user_name":"Zornitza Stark","item_type":"entity","text":"Marked gene: TNPO2 as ready","entity_name":"TNPO2","entity_type":"gene"},{"created":"2021-08-02T17:57:28.690595+10:00","panel_name":"Intellectual disability syndromic and non-syndromic","panel_id":250,"panel_version":"0.4019","user_name":"Zornitza Stark","item_type":"entity","text":"Gene: tnpo2 has been classified as Green List (High Evidence).","entity_name":"TNPO2","entity_type":"gene"},{"created":"2021-08-02T17:57:24.199241+10:00","panel_name":"Intellectual disability syndromic and non-syndromic","panel_id":250,"panel_version":"0.4019","user_name":"Zornitza Stark","item_type":"entity","text":"Phenotypes for gene: TNPO2 were changed from Developmental delays, neurologic deficits and dysmorphic features to Intellectual disability, neurologic deficits and dysmorphic features","entity_name":"TNPO2","entity_type":"gene"},{"created":"2021-08-02T17:56:46.440130+10:00","panel_name":"Intellectual disability syndromic and non-syndromic","panel_id":250,"panel_version":"0.4018","user_name":"Zornitza Stark","item_type":"entity","text":"Classified gene: TNPO2 as Green List (high evidence)","entity_name":"TNPO2","entity_type":"gene"},{"created":"2021-08-02T17:56:46.429338+10:00","panel_name":"Intellectual disability syndromic and non-syndromic","panel_id":250,"panel_version":"0.4018","user_name":"Zornitza Stark","item_type":"entity","text":"Gene: tnpo2 has been classified as Green List (High Evidence).","entity_name":"TNPO2","entity_type":"gene"},{"created":"2021-08-02T17:56:10.894693+10:00","panel_name":"Mendeliome","panel_id":137,"panel_version":"0.8604","user_name":"Zornitza Stark","item_type":"entity","text":"Marked gene: TNPO2 as ready","entity_name":"TNPO2","entity_type":"gene"},{"created":"2021-08-02T17:56:10.885034+10:00","panel_name":"Mendeliome","panel_id":137,"panel_version":"0.8604","user_name":"Zornitza Stark","item_type":"entity","text":"Gene: tnpo2 has been classified as Green List (High Evidence).","entity_name":"TNPO2","entity_type":"gene"},{"created":"2021-08-02T17:55:57.011035+10:00","panel_name":"Mendeliome","panel_id":137,"panel_version":"0.8604","user_name":"Zornitza Stark","item_type":"entity","text":"Phenotypes for gene: TNPO2 were changed from Developmental delays, neurologic deficits and dysmorphic features to Intellectual disability, neurologic deficits and dysmorphic features","entity_name":"TNPO2","entity_type":"gene"},{"created":"2021-08-02T17:55:00.432330+10:00","panel_name":"Mendeliome","panel_id":137,"panel_version":"0.8603","user_name":"Zornitza Stark","item_type":"entity","text":"Classified gene: TNPO2 as Green List (high evidence)","entity_name":"TNPO2","entity_type":"gene"},{"created":"2021-08-02T17:55:00.419169+10:00","panel_name":"Mendeliome","panel_id":137,"panel_version":"0.8603","user_name":"Zornitza Stark","item_type":"entity","text":"Gene: tnpo2 has been classified as Green List (High Evidence).","entity_name":"TNPO2","entity_type":"gene"},{"created":"2021-08-02T17:11:59.695866+10:00","panel_name":"Mendeliome","panel_id":137,"panel_version":"0.8602","user_name":"Daniel Flanagan","item_type":"entity","text":"reviewed gene: ZDHHC15: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: cerebral palsy, intellectual disability, autism spectrum disorder, epilepsy; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females","entity_name":"ZDHHC15","entity_type":"gene"},{"created":"2021-08-02T17:04:39.551629+10:00","panel_name":"Mendeliome","panel_id":137,"panel_version":"0.8602","user_name":"Zornitza Stark","item_type":"entity","text":"Marked gene: DNAH10 as ready","entity_name":"DNAH10","entity_type":"gene"},{"created":"2021-08-02T17:04:39.542280+10:00","panel_name":"Mendeliome","panel_id":137,"panel_version":"0.8602","user_name":"Zornitza Stark","item_type":"entity","text":"Gene: dnah10 has been classified as Green List (High Evidence).","entity_name":"DNAH10","entity_type":"gene"},{"created":"2021-08-02T17:03:00.371277+10:00","panel_name":"Mendeliome","panel_id":137,"panel_version":"0.8602","user_name":"Zornitza Stark","item_type":"entity","text":"Classified gene: DNAH10 as Green List (high evidence)","entity_name":"DNAH10","entity_type":"gene"},{"created":"2021-08-02T17:03:00.360273+10:00","panel_name":"Mendeliome","panel_id":137,"panel_version":"0.8602","user_name":"Zornitza Stark","item_type":"entity","text":"Gene: dnah10 has been classified as Green List (High Evidence).","entity_name":"DNAH10","entity_type":"gene"},{"created":"2021-08-02T16:58:14.961993+10:00","panel_name":"Motor Neurone Disease","panel_id":25,"panel_version":"0.123","user_name":"Michelle Torres","item_type":"entity","text":"reviewed gene: VRK1: Rating: AMBER; Mode of pathogenicity: None; Publications: 34169149, 26583493, 31837156; Phenotypes: Adult-onset spinal muscular atrophy without pontocerebellar hypoplasia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal","entity_name":"VRK1","entity_type":"gene"},{"created":"2021-08-02T16:55:37.711800+10:00","panel_name":"Mendeliome","panel_id":137,"panel_version":"0.8601","user_name":"Kristin Rigbye","item_type":"entity","text":"gene: CLCN3 was added\ngene: CLCN3 was added to Mendeliome. Sources: Literature\nMode of inheritance for gene: CLCN3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal\nPublications for gene: CLCN3 were set to PMID: 34186028\nPhenotypes for gene: CLCN3 were set to Neurodevelopmental disorder\nMode of pathogenicity for gene: CLCN3 was set to Other\nReview for gene: CLCN3 was set to GREEN\nAdded comment: 11 individuals reported, 9 that carried 8 different rare heterozygous missense variants in CLCN3, and 2 siblings that were homozygous for an NMD-predicted frameshift variant likely abolishing ClC-3 function. All missense variants were confirmed to be de novo in eight individuals for whom parental data was available.\r\n\r\nThe 11 individuals in the cohort share clinical features of variable severity. All 11 have GDD or ID and dysmorphic features, and a majority has mood or behavioural disorders and structural brain abnormalities:\r\n- Structural brain abnormalities on MRI (9/11) included partial or full agenesis of the corpus callosum (6/9), disorganized cerebellar folia (4/9), delayed myelination (3/9), decreased white matter volume (3/9), pons hypoplasia (3/9), and dysmorphic dentate nuclei (3/9). Six of those with brain abnormalities also presented with seizures.\r\n- Nine have abnormal vision, including strabismus in four and inability to fix or follow in the two with homozygous loss-of-function variants.\r\n- Hypotonia ranging from mild to severe was reported in 7 of the 11 individuals.\r\n- Six have mood or behavioural disorders, particularly anxiety (3/6).\r\n- Consistent dysmorphic facial features included microcephaly, prominent forehead, hypertelorism, down-slanting palpebral fissures, full cheeks, and micrognathia.\r\n\r\nThe severity of disease in the two siblings with homozygous disruption of ClC-3 is consistent with the drastic phenotype seen in Clcn3 KO mice. The disease was more severe in two siblings carrying homozygous loss-of-function variants with the presence of GDD, absent speech, seizures, and salt and pepper fundal pigmentation in both individuals, with one deceased at 14 months of age. The siblings also had significant neuroanatomical findings including diffusely decreased white matter volume, thin corpora callosa, small hippocampi, and disorganized cerebellar folia. Supporting biallelic inheritance for LoF variants, disruption of mouse Clcn3 results in drastic neurodegeneration with loss of the hippocampus a few months after birth and early retinal degeneration. Clcn3−/− mice display severe neurodegeneration, whereas heterozygous Clcn3+/− mice appear normal.\r\n\r\nPatch-clamp studies were used to investigate four of the missense variants. These suggested a gain of function in two variants with increased current in HEK cells, however they also showed reduced rectification of voltage and a loss of transient current, plus decreased current amplitude, glycosylation and surface expression when expressed in oocytes, and were suspected to interfere with channel gating and a negative feedback mechanism. These effects were also shown to vary depending on pH levels. The current of the remaining two variants did not differ from WT. For heterozygous missense variants, the disruption induced may be at least partially conferred to mutant/WT homodimers and mutant/ClC-4 heterodimers.\r\n\r\nBoth loss and gain of function in this gene resulted in the same phenotype. \nSources: Literature","entity_name":"CLCN3","entity_type":"gene"},{"created":"2021-08-02T16:46:07.070700+10:00","panel_name":"Motor Neurone Disease","panel_id":25,"panel_version":"0.123","user_name":"Michelle Torres","item_type":"entity","text":"Deleted their review","entity_name":"VRK1","entity_type":"gene"},{"created":"2021-08-02T16:46:03.839000+10:00","panel_name":"Motor Neurone Disease","panel_id":25,"panel_version":"0.123","user_name":"Michelle Torres","item_type":"entity","text":"commented on gene: VRK1","entity_name":"VRK1","entity_type":"gene"}]}