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Early-onset Dementia v1.25 TREM2 Zornitza Stark Phenotypes for gene: TREM2 were changed from Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2, MIM# 618193 to Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2, MIM# 618193; {Alzhieimer disease 17, susceptibility to}, MIM# 615080
Early-onset Dementia v1.24 TREM2 Zornitza Stark edited their review of gene: TREM2: Changed phenotypes: Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2, MIM# 618193, {Alzhieimer disease 17, susceptibility to}, MIM# 615080
Early-onset Dementia v1.23 TUBA4A Bryony Thompson edited their review of gene: TUBA4A: Changed phenotypes: Inherited neurodegenerative disorder MONDO:0024237, TUBA4A-related
Early-onset Dementia v1.15 GLA Lynn Tan gene: GLA was added
gene: GLA was added to Early-onset Dementia. Sources: Literature
Mode of inheritance for gene: GLA was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: GLA were set to 36927868; 38254927; 9213072; 23949010; 32510623
Phenotypes for gene: GLA were set to Fabry disease MONDO:0010526
Review for gene: GLA was set to GREEN
gene: GLA was marked as current diagnostic
Added comment: PMID 36927868 (2023)
Index patient with GLA T410A (α-Gal A activity 32%) developed dementia and died of stroke in her 70s

PMID: 9213072 (1997)
47M biochemically confirmed Fabry’s with predominant manifestation being a dementing illness

PMID: 23949010 (2014)
Systematic review on cognitive dysfunction in Fabry's disease: patients with Fabry disease may be impaired in: executive functioning assessed by two standardised tests, the Stroop test and the Trail Making test part B, information processing speed and attention. Five case studies documenting neuropsychological impairment also described.

PMID: 32510623
Prospective cohort study to describe cognitive function changes in Fabry's over a year. Eighty‐one patients were included of which 76 patients (94%) completed both assessments (age: 44 years, 34% men, 75% classical phenotype). Four patients (5.3%) showed reliable decrease in cognitive functioning, two women and one man with classical disease and one woman with non‐classical disease (age range: 19‐41 years). Changes were from excellent to good/average and from good to average. None had a history of stroke or extensive WMLs. Follow‐up CESD scores were similar in two patients (+0 and +1) and increased in two others (+6, +11).

PMID: 38254927 (2023)
"This vasculopathy, along with elevating the risk of cerebral ischemia and stroke, is likely the pathophysiological basis for cognitive impairments in FD patients. Nevertheless, there is currently insufficient evidence indicating a direct association between neuropsychological findings and alterations in morphology in the CNS of FD patients as determined by brain imaging techniques such as magnetic resonance imaging."
Sources: Literature
Early-onset Dementia v1.15 NOTCH3 Ain Roesley Mode of inheritance for gene: NOTCH3 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Early-onset Dementia v1.14 COL4A2 Lynn Tan edited their review of gene: COL4A2: Added comment: PMID: 35699195
The frequency of cognitive features in COL4A2 was 27% [11/41 individuals from 22 pedigrees]. These 11 patients all had developmental delay.

PMID: 37272523
Ontario Neurodegenerative Disease Research Initiative (ONDRI) sample size 510: 8 patients with COL4A1/2 variants had Alzheimer's disease/mild cognitive impairment, 3 patients with COL4A1/2 variants had frontotemporal dementia

PMID: 36300346
UK Biobank cohort study (n = 454 756): 2 patients with COL4A1/2 variants had vascular dementia, 8 patients with COL4A1/2 variants had all-cause dementia

Dev delay vs early-onset dementia
PMID: 37272523 and PMID: 36300346 -combined cohort with both COL4A1 and COL4A2

Sources: Literature; Changed rating: AMBER
Early-onset Dementia v1.14 POLG Lynn Tan gene: POLG was added
gene: POLG was added to Early-onset Dementia. Sources: Literature
Mode of inheritance for gene: POLG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLG were set to 15477547; 14694057; 16638794
Phenotypes for gene: POLG were set to Mitochondrial DNA depletion syndrome 4a MONDO:0008758
Review for gene: POLG was set to AMBER
gene: POLG was marked as current diagnostic
Added comment: PMID: 15477547
5 patients with "cognitive impairment" in their 30s-50s, one male "had mild cognitive decline in the fifth decade".

PMID: 14694057
Biallelic POLG A467T variants: The 18-year-old patient is the elder son of nonconsanguineous parents, aged 45 and 41 years. The clinical features of myoclonus, seizure, axonal sensory ataxic neuropathy, and hepatotoxicity induced by valproate and mild cognitive decline and cardiomyopathy were indicative of a multisystem disorder and suggestive of mitochondrial disease.

PMID: 16638794
We studied 26 patients belonging to 20 families with a disorder caused by biallelic mutations in the POLG gene. Mild cognitive abnormalities were clinically suspected in eight patients. In four a mild cognitive impairment was confirmed by neuropsychological examination.

Cognitive impairment -developmental delay/regression/ID in childhood vs dementia (and decline from a baseline) later in life
Sources: Literature
Early-onset Dementia v1.14 COL4A1 Lynn Tan gene: COL4A1 was added
gene: COL4A1 was added to Early-onset Dementia. Sources: Literature
Mode of inheritance for gene: COL4A1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: COL4A1 were set to 35699195; 37272523; 36300346; 30413629
Phenotypes for gene: COL4A1 were set to Brain small vessel disease 1 with or without ocular anomalies MONDO:0008289; Microangiopathy and leukoencephalopathy, pontine, autosomal dominant MONDO:0032814
Review for gene: COL4A1 was set to GREEN
gene: COL4A1 was marked as current diagnostic
Added comment: PMID: 35699195
Systematic review: frequency of cognitive features in COL4A1 was 33% [128/390 individuals from 233 pedigrees]. Developmental delay was present in over 80% of individuals with COL4A1/2 with cognitive features.

PMID: 37272523
Ontario Neurodegenerative Disease Research Initiative (ONDRI) sample size 510: 8 patients with COL4A1/2 variants had Alzheimer's disease/mild cognitive impairment, 3 patients with COL4A1/2 variants had frontotemporal dementia

PMID: 36300346
UK Biobank cohort study (n = 454 756): 2 patients with COL4A1/2 variants had vascular dementia, 8 patients with COL4A1/2 variants had all-cause dementia

PMID: 30413629
Child with COL4A1 p. G601S variant: developmental delay, moderate cognitive impairment, autism, and normal neurologic examination. Focal-onset drug-resistant seizures started at 11 years of age.
3-year-old girl with de novo COL4A1 p.G1239R: Surgical delivery was performed because prenatal hydrocephalus was suspected. The child developed microcephaly, severe cognitive impairment, and drug-resistant epileptic spasms.
Sources: Literature
Early-onset Dementia v1.14 TREX1 Lynn Tan gene: TREX1 was added
gene: TREX1 was added to Early-onset Dementia. Sources: Literature
Mode of inheritance for gene: TREX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TREX1 were set to 29380913; 35699195; 36586737; 35307828
Phenotypes for gene: TREX1 were set to Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations MONDO:0008641
Review for gene: TREX1 was set to GREEN
gene: TREX1 was marked as current diagnostic
Added comment: PMID: 35699195
Systematic review: frequency of cognitive features in TREX1 was 29% [36/123 individuals from 34 pedigrees]

PMID: 29380913
Symptoms for this disorder start in adulthood and frequently include rapid loss of vision, multifocal strokes and dementia.

PMID: 36586737
1. Female patient displayed the first symptoms at a very early-age, 57 years old, and originated from Serbia. She presented with mild cognitive impairment.
2. 53-year old Dutch patient who displayed presenile dementia
3. 39-year old Finnish patient presenting migrane without aura, severe and pervasive cognitive impairment

PMID: 35307828
First stroke at age 39, diagnosed with severe amyloid angiopathy, and he also started suffering from migraines without aura and was later diagnosed with cognitive impairment
Sources: Literature
Early-onset Dementia v1.12 CST3 Bryony Thompson Phenotypes for gene: CST3 were changed from Cerebral amyloid angiopathy MIM#105150 to Cerebral amyloid angiopathy MIM#105150; leukodystrophy MONDO:0019046
Early-onset Dementia v1.9 CST3 Bryony Thompson edited their review of gene: CST3: Added comment: New gene-disease association: 16 patients from 8 leukodystrophy families carrying one of four different stop-gain or frameshift dominant variants in the C-terminal (in the NMD-exclusion zone) of the CST3 gene. Suggested mechanism of disease by rendering the protein more prone to aggregation. The clinical phenotype consists of recurrent episodes of hemiplegic migraine associated with transient unilateral focal deficits and slowly progressing motor symptoms and cognitive decline in mid-old adult ages. Clinical & radiological features differ from Cerebral Amyloid Angiopathy.; Changed publications: 22435454, 8866434, 2602413, 8108423, 38489591; Changed phenotypes: Cerebral amyloid angiopathy MIM#105150, leukodystrophy MONDO:0019046
Early-onset Dementia v1.9 APP Bryony Thompson Mode of pathogenicity for gene: APP was changed from to Other
Early-onset Dementia v1.7 APP Bryony Thompson Phenotypes for gene: APP were changed from to Alzheimer disease MONDO:0007088
Early-onset Dementia v1.6 APP Bryony Thompson Mode of inheritance for gene: APP was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Dementia v1.5 CCNF Zornitza Stark edited their review of gene: CCNF: Changed rating: AMBER
Early-onset Dementia v1.5 CHMP2B Bryony Thompson Phenotypes for gene: CHMP2B were changed from to Frontotemporal dementia and/or amyotrophic lateral sclerosis 7 (MIM#600795; MONDO:0010936)
Early-onset Dementia v1.3 CHMP2B Bryony Thompson Mode of pathogenicity for gene: CHMP2B was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Early-onset Dementia v1.2 CHMP2B Bryony Thompson Mode of pathogenicity for gene: CHMP2B was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Early-onset Dementia v1.1 CHMP2B Bryony Thompson Mode of inheritance for gene: CHMP2B was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Dementia v1.1 CHMP2B Bryony Thompson Mode of inheritance for gene: CHMP2B was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Dementia v0.218 ANG Bryony Thompson Marked gene: ANG as ready
Early-onset Dementia v0.218 ANG Bryony Thompson Gene: ang has been classified as Red List (Low Evidence).
Early-onset Dementia v0.216 XK Sangavi Sivagnanasundram edited their review of gene: XK: Added comment: McLeod Syndrome (MLS) is multisystem disorder with central nervous system (CNS), neuromuscular, cardiovascular, and hematologic manifestations in males.

Dementia is not a typical feature of MLS but cognitive impairment has been identified in multiple individuals with MLS.

PMID: 12899725
Reported in one individual with McLeod Syndrome (MLS) who developed mild dementia during disease progression (age of onset was later in life). Testing confirmed he has a complete deletion of exon 2.

PMID: 11761473
Approx 15 individuals identified with neurological impact to the central nervous system resulting in cognitive impairment.; Changed rating: GREEN; Changed publications: 12899725, 11761473
Early-onset Dementia v0.216 CCNF Bryony Thompson edited their review of gene: CCNF: Changed rating: AMBER
Early-onset Dementia v0.216 NHLRC1 Zornitza Stark Phenotypes for gene: NHLRC1 were changed from to Epilepsy, progressive myoclonic 2B (Lafora Disease) MIM#254780
Early-onset Dementia v0.214 NHLRC1 Zornitza Stark Mode of inheritance for gene: NHLRC1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Early-onset Dementia v0.213 NPC2 Zornitza Stark Phenotypes for gene: NPC2 were changed from to Niemann-pick disease, type C2 MIM#607625
Early-onset Dementia v0.211 NPC2 Zornitza Stark Mode of inheritance for gene: NPC2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Early-onset Dementia v0.210 OPTN Zornitza Stark Phenotypes for gene: OPTN were changed from to Amyotrophic lateral sclerosis 12 with or without frontotemporal dementia (MIM#613435)
Early-onset Dementia v0.208 OPTN Zornitza Stark Mode of inheritance for gene: OPTN was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early-onset Dementia v0.207 PANK2 Zornitza Stark Phenotypes for gene: PANK2 were changed from to Neurodegeneration with brain iron accumulation 1 (MIM#234200)
Early-onset Dementia v0.205 PANK2 Zornitza Stark Mode of inheritance for gene: PANK2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Early-onset Dementia v0.204 PRNP Zornitza Stark Phenotypes for gene: PRNP were changed from to Prion Disease (MIM#176640); Creutzfeldt-Jakob disease (MIM#123400)
Early-onset Dementia v0.202 PRNP Zornitza Stark Mode of inheritance for gene: PRNP was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Dementia v0.201 PSEN1 Zornitza Stark Phenotypes for gene: PSEN1 were changed from to Alzheimer disease, type 3 (MIM#607822; MONDO:0011913)
Early-onset Dementia v0.199 PSEN1 Zornitza Stark Mode of inheritance for gene: PSEN1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Dementia v0.198 PSEN2 Zornitza Stark Phenotypes for gene: PSEN2 were changed from to Alzheimer disease-4 (MIM#606889)
Early-onset Dementia v0.196 PSEN2 Zornitza Stark Mode of inheritance for gene: PSEN2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Dementia v0.195 SQSTM1 Zornitza Stark Phenotypes for gene: SQSTM1 were changed from to Frontotemporal dementia and/or amyotrophic lateral sclerosis 3 (MIM#616437)
Early-onset Dementia v0.193 SQSTM1 Zornitza Stark Mode of inheritance for gene: SQSTM1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Dementia v0.191 TARDBP Zornitza Stark Phenotypes for gene: TARDBP were changed from to Amyotrophic lateral sclerosis 10, with or without FTD (MIM#612069)
Early-onset Dementia v0.189 TARDBP Zornitza Stark Mode of inheritance for gene: TARDBP was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early-onset Dementia v0.188 TBK1 Zornitza Stark Phenotypes for gene: TBK1 were changed from to Frontotemporal dementia and/or amyotrophic lateral sclerosis 4, MIM# 616439
Early-onset Dementia v0.186 TBK1 Zornitza Stark Mode of inheritance for gene: TBK1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Dementia v0.185 TYROBP Zornitza Stark Phenotypes for gene: TYROBP were changed from to Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 1 (MIM#221770)
Early-onset Dementia v0.183 TYROBP Zornitza Stark Mode of inheritance for gene: TYROBP was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Early-onset Dementia v0.182 PLA2G6 Zornitza Stark Phenotypes for gene: PLA2G6 were changed from to Parkinson disease 14, autosomal recessive, MIM# 612953
Early-onset Dementia v0.180 PLA2G6 Zornitza Stark Mode of inheritance for gene: PLA2G6 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Early-onset Dementia v0.179 NPC1 Sangavi Sivagnanasundram edited their review of gene: NPC1: Changed rating: AMBER
Early-onset Dementia v0.179 NPC1 Sangavi Sivagnanasundram changed review comment from: NPC is a slowly progressive lysosomal disorder with subtle cognitive impairment in affected individuals at first which progresses to dementia during the disease course. LoF is the mechanism of disease.

PMID: 11182931
reported in one individual with NPC and dementia as a phenotype.; to: NPC is a slowly progressive lysosomal disorder with subtle cognitive impairment in affected individuals at first which progresses to dementia during the disease course. NPC type 1 is also known as "juvenile alzheimers disease". LoF is the mechanism of disease.

PMID: 11182931
reported in one individual with NPC and dementia as a phenotype.
Early-onset Dementia v0.179 NPC1 Sangavi Sivagnanasundram edited their review of gene: NPC1: Changed rating: GREEN; Changed publications: 20301473, 11182931, 22495346
Early-onset Dementia v0.179 NPC1 Zornitza Stark Phenotypes for gene: NPC1 were changed from to Niemann-Pick disease, type C1 (MIM#257220; MONDO:0009757)
Early-onset Dementia v0.177 NPC1 Zornitza Stark Mode of inheritance for gene: NPC1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Early-onset Dementia v0.176 UBQLN2 Zornitza Stark Phenotypes for gene: UBQLN2 were changed from Amyotrophic lateral sclerosis 15, with or without frontotemporal dementia (MIM#300857) to Amyotrophic lateral sclerosis 15, with or without frontotemporal dementia (MIM#300857)
Early-onset Dementia v0.175 UBQLN2 Zornitza Stark Phenotypes for gene: UBQLN2 were changed from to Amyotrophic lateral sclerosis 15, with or without frontotemporal dementia (MIM#300857)
Early-onset Dementia v0.173 UBQLN2 Zornitza Stark Mode of inheritance for gene: UBQLN2 was changed from Unknown to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Early-onset Dementia v0.172 VCP Zornitza Stark Phenotypes for gene: VCP were changed from to Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia 1 (MIM#167320); Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 (MIM#613954)
Early-onset Dementia v0.170 VCP Zornitza Stark Mode of inheritance for gene: VCP was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Dementia v0.169 XK Zornitza Stark Phenotypes for gene: XK were changed from to McLeod syndrome with or without chronic granulomatous disease (MIM#300842)
Early-onset Dementia v0.167 XK Zornitza Stark Mode of inheritance for gene: XK was changed from Unknown to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Early-onset Dementia v0.166 GRN Zornitza Stark Phenotypes for gene: GRN were changed from to frontotemporal dementia and/or amyotrophic lateral sclerosis MONDO:0030923
Early-onset Dementia v0.164 GRN Zornitza Stark Mode of inheritance for gene: GRN was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Dementia v0.163 EPM2A Zornitza Stark Phenotypes for gene: EPM2A were changed from to Epilepsy, progressive myoclonic 2A (Lafora) MIM#254780
Early-onset Dementia v0.161 EPM2A Zornitza Stark Mode of inheritance for gene: EPM2A was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Early-onset Dementia v0.159 Zornitza Stark HPO terms changed from to Cognitive impairment, HP:0100543
List of related panels changed from to Cognitive impairment; HP:0100543
Early-onset Dementia v0.158 ITM2B Bryony Thompson Phenotypes for gene: ITM2B were changed from to Cerebral amyloid angiopathy MONDO:0005620
Early-onset Dementia v0.156 ITM2B Bryony Thompson Mode of inheritance for gene: ITM2B was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Dementia v0.155 ITM2B Bryony Thompson reviewed gene: ITM2B: Rating: GREEN; Mode of pathogenicity: Other; Publications: 10391242, 10781099, 20385796, 33814452; Phenotypes: Cerebral amyloid angiopathy MONDO:0005620; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Early-onset Dementia v0.154 APOE Zornitza Stark changed review comment from: E4 allele association with late-onset AD.; to: E4 allele association with late-onset AD. Susceptibility allele.
Early-onset Dementia v0.154 APOE Zornitza Stark edited their review of gene: APOE: Changed rating: AMBER
Early-onset Dementia v0.153 PPIA Seb Lunke Phenotypes for gene: PPIA were changed from amyotrophic lateral sclerosis, MONDO:0004976 to amyotrophic lateral sclerosis, MONDO:0004976, PPIA-associated
Early-onset Dementia v0.151 MATR3 Bryony Thompson Phenotypes for gene: MATR3 were changed from Amyotrophic lateral sclerosis 21 MIM#606070 to Amyotrophic lateral sclerosis 21 MIM#606070; frontotemporal dementia; multisystem proteinopathy
Early-onset Dementia v0.149 MATR3 Bryony Thompson Mode of inheritance for gene: MATR3 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Dementia v0.148 MATR3 Bryony Thompson edited their review of gene: MATR3: Changed phenotypes: Amyotrophic lateral sclerosis 21 MIM#606070, frontotemporal dementia, multisystem proteinopathy; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Dementia v0.148 MATR3 Bryony Thompson changed review comment from: One family with ALS-FTD has been reported so far. A rat primary neuron model showed neurons were bidirectionally vulnerable to MATR3 levels, with pathogenic MATR3 mutants displaying enhanced toxicity.; to: Two cases/families with ALS-FTD has been reported with missense variants. An early-onset bvFTD case has been reported with a MATR3 variant 5 retrotransposition of uncertain significance. A rat primary neuron model showed neurons were bidirectionally vulnerable to MATR3 levels, with pathogenic MATR3 mutants displaying enhanced toxicity.
Early-onset Dementia v0.148 MATR3 Bryony Thompson edited their review of gene: MATR3: Changed publications: 24686783, 30015619, 28029397, 33408686; Changed phenotypes: Amyotrophic lateral sclerosis 21 MIM#606070, frontotemporal dementia
Early-onset Dementia v0.144 NIID Bryony Thompson STR: NIID was added
STR: NIID was added to Early-onset Dementia. Sources: Literature
Mode of inheritance for STR: NIID was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: NIID were set to 31178126; 31332381; 31819945; 33887199; 33943039; 32250060; 31332380; 32852534; 32989102; 34333668
Phenotypes for STR: NIID were set to Neuronal intranuclear inclusion disease MIM#603472; Oculopharyngodistal myopathy 3 MIM#619473; Tremor, hereditary essential, 6 MIM#618866
Review for STR: NIID was set to GREEN
STR: NIID was marked as clinically relevant
Added comment: NM_001364012.2:c.-164GGC[X]
Expanded repeat in NOTCH2NLC sequence is (GGC)9(GGA)2(GGC)2.
Large number of families and sporadic cases reported with expansions, with a range of neurodegenerative phenotypes, including: dementia, Parkinsonism/tremor, peripheral neuropathy, leukoencephalopathy, myopathy, motor neurone disease.
Normal repeat range: 4-40, 1 control had 61 repeats and may have been a presymptomatic carrier.
Intermediate range: 41-60 identified in Parkinson's disease
Pathogenic repeat range: >=60-520
Mechanism of disease is translation of repeat expansion into a toxic polyglycine protein, identified in both mouse models and tissue samples from affected individuals.
Sources: Literature
Early-onset Dementia v0.141 NIID Bryony Thompson STR: NIID was added
STR: NIID was added to Early-onset Dementia. Sources: Literature
Mode of inheritance for STR: NIID was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: NIID were set to 31178126; 31332381; 31819945; 33887199; 33943039; 32250060; 31332380; 32852534; 32989102
Phenotypes for STR: NIID were set to Neuronal intranuclear inclusion disease MIM#603472; Oculopharyngodistal myopathy 3 MIM#619473; Tremor, hereditary essential, 6 MIM#618866
Review for STR: NIID was set to GREEN
STR: NIID was marked as clinically relevant
Added comment: NM_001364012.2:c.-164GGC[X]
Expanded repeat in NOTCH2NLC sequence is (GGC)9(GGA)2(GGC)2.
Large number of families and sporadic cases reported with expansions, with a range of neurodegenerative phenotypes, including: dementia, Parkinsonism/tremor, peripheral neuropathy, leukoencephalopathy, myopathy, motor neurone disease.
Normal repeat range: 7-60
Pathogenic repeat range: >=61-500
Mechanism of disease is translation of repeat expansion into a toxic polyglycine protein, identified in both mouse models and tissue samples from affected individuals.
Sources: Literature
Early-onset Dementia v0.135 NIID Bryony Thompson STR: NIID was added
STR: NIID was added to Early-onset Dementia. Sources: Literature
Mode of inheritance for STR: NIID was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: NIID were set to 31178126; 31332381; 31819945; 33887199; 33943039; 32250060; 31332380; 32852534; 32989102
Phenotypes for STR: NIID were set to Neuronal intranuclear inclusion disease MIM#603472; Tremor, hereditary essential, 6 MIM#618866
Review for STR: NIID was set to GREEN
STR: NIID was marked as clinically relevant
Added comment: NM_001364012.2:c.-164GGC[(66_517)] Large number of families and sporadic cases reported with expansions, with a range of neurodegenerative phenotypes, including: dementia, Parkinsonism/tremor, peripheral neuropathy, leukoencephalopathy, myopathy, motor neurone disease. Normal repeat range: 7-60 Pathogenic repeat range: >=61-500 Mechanism of disease is translation of repeat expansion into a toxic polyglycine protein, identified in both mouse models and tissue samples from affected individuals.
Sources: Literature
Early-onset Dementia v0.132 CCNF Zornitza Stark Phenotypes for gene: CCNF were changed from amyotrophic lateral sclerosis with/without frontotemporal dementia to Frontotemporal dementia and/or amyotrophic lateral sclerosis 5, MIM# 619141
Early-onset Dementia v0.131 CYLD Zornitza Stark Phenotypes for gene: CYLD were changed from Frontotemporal dementia; Amyotrophic lateral sclerosis to Frontotemporal dementia and/or amytrophic lateral sclerosis 8, MIM# 619132
Early-onset Dementia v0.130 CYLD Zornitza Stark edited their review of gene: CYLD: Changed phenotypes: Frontotemporal dementia and/or amytrophic lateral sclerosis 8, MIM# 619132
Early-onset Dementia v0.130 ATP7B Bryony Thompson edited their review of gene: ATP7B: Changed publications: 26758278, 25988284
Early-onset Dementia v0.130 SNCA Zornitza Stark Phenotypes for gene: SNCA were changed from to Dementia, Lewy body (MIM#127750); Parkinson disease 1 (MIM#168601); Parkinson disease 4 (MIM#605543)
Early-onset Dementia v0.128 SNCA Zornitza Stark Mode of inheritance for gene: SNCA was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Dementia v0.126 STUB1 Bryony Thompson edited their review of gene: STUB1: Changed phenotypes: Spinocerebellar ataxia 48 MIM#618093, cognitive impairment, Spinocerebellar ataxia, autosomal recessive 16 MIM#615768; Set current diagnostic: yes
Early-onset Dementia v0.121 TUBA4A Zornitza Stark Phenotypes for gene: TUBA4A were changed from to Amyotrophic lateral sclerosis 22 with or without frontotemporal dementia, MIM# 616208
Early-onset Dementia v0.119 TUBA4A Zornitza Stark Mode of inheritance for gene: TUBA4A was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Dementia v0.116 CHCHD10 Zornitza Stark changed review comment from: CHCHD10 is a small protein of the mitochondrial intermembrane space that is enriched at cristae junctions. It is predicted to be involved in oxidative phosphorylation or in maintenance of cristae morphology. Variants have been associated with a broad spectrum of neurological/neuromuscular phenotypes. Several large multiplex families described segregating different neurological disorders, ranging from dementia, to SMA, to myopathy. GOF mechanism has been proposed for FTD/ALS association based on a mouse model.

Two families reported with p.Ser59Leu variant and predominantly a dementia phenotype. Variant segregated with disease in 8 family members in one of the families. No variants in this gene identified in an Australian cohort study, PMID 31690696; however, good functional data including from mouse model supports gene-disease association.; to: CHCHD10 is a small protein of the mitochondrial intermembrane space that is enriched at cristae junctions. It is predicted to be involved in oxidative phosphorylation or in maintenance of cristae morphology. Variants have been associated with a broad spectrum of neurological/neuromuscular phenotypes. Several large multiplex families described segregating different neurological disorders, ranging from dementia, to SMA, to myopathy. GOF mechanism has been proposed for FTD/ALS association based on a mouse model.

Two families reported with p.Ser59Leu variant, and one with a truncating variant and predominantly a dementia phenotype. Variant segregated with disease in 8 family members in one of the families. No variants in this gene identified in an Australian cohort study, PMID 31690696; however, good functional data including from mouse model supports gene-disease association.
Early-onset Dementia v0.116 CHCHD10 Zornitza Stark edited their review of gene: CHCHD10: Changed publications: 24934289, 31690696, 30877432, 32369233, 28069311
Early-onset Dementia v0.116 TTR Zornitza Stark Phenotypes for gene: TTR were changed from to Amyloidosis, hereditary, transthyretin-related, MIM# 105210
Early-onset Dementia v0.114 TTR Zornitza Stark Mode of inheritance for gene: TTR was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Dementia v0.113 TREM2 Zornitza Stark Phenotypes for gene: TREM2 were changed from to Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy 2, MIM# 618193
Early-onset Dementia v0.111 TREM2 Zornitza Stark Mode of inheritance for gene: TREM2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Early-onset Dementia v0.110 SPG21 Zornitza Stark changed review comment from: Mast syndrome is an autosomal recessive complicated form of hereditary spastic paraplegia in which progressive spastic paraparesis is associated in more advanced cases with cognitive decline, dementia, and other neurologic abnormalities. Symptom onset usually occurs in adulthood, and the disorder is progressive with variable severity. Brain imaging shows thinning of the corpus callosum. The disorder occurs with high frequency in the Old Order Amish. Founder variant in Amish, two additional families and a mouse model.; to: Mast syndrome is an autosomal recessive complicated form of hereditary spastic paraplegia in which progressive spastic paraparesis is associated in more advanced cases with cognitive decline, dementia, and other neurologic abnormalities. Symptom onset usually occurs in adulthood, and the disorder is progressive with variable severity. Brain imaging shows thinning of the corpus callosum. The disorder occurs with high frequency in the Old Order Amish. Founder variant in Amish, two additional families and a mouse model.

New HGNC approved gene name is ACP33
Early-onset Dementia v0.110 SPG21 Zornitza Stark Phenotypes for gene: SPG21 were changed from to Mast syndrome, MIM# 248900
Early-onset Dementia v0.108 SPG21 Zornitza Stark Mode of inheritance for gene: SPG21 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Early-onset Dementia v0.107 SPG21 Zornitza Stark edited their review of gene: SPG21: Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Early-onset Dementia v0.107 SPG21 Zornitza Stark edited their review of gene: SPG21: Changed rating: GREEN
Early-onset Dementia v0.107 SNCB Zornitza Stark Phenotypes for gene: SNCB were changed from to Dementia, Lewy body, MIM#127750
Early-onset Dementia v0.105 SNCB Zornitza Stark Mode of inheritance for gene: SNCB was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Dementia v0.103 FUS Zornitza Stark Phenotypes for gene: FUS were changed from to Amyotrophic lateral sclerosis 6, with or without frontotemporal dementia, MIM# 608030
Early-onset Dementia v0.101 FUS Zornitza Stark Mode of inheritance for gene: FUS was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Dementia v0.100 FTL Zornitza Stark Phenotypes for gene: FTL were changed from to Neurodegeneration with brain iron accumulation 3, MIM# 606159
Early-onset Dementia v0.98 FTL Zornitza Stark Mode of inheritance for gene: FTL was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Dementia v0.97 FA2H Zornitza Stark Phenotypes for gene: FA2H were changed from to Spastic paraplegia 35, autosomal recessive, MIM# 612319
Early-onset Dementia v0.96 FA2H Zornitza Stark Mode of inheritance for gene: FA2H was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Early-onset Dementia v0.94 DCTN1 Zornitza Stark Phenotypes for gene: DCTN1 were changed from to Perry syndrome, MIM# 168605
Early-onset Dementia v0.92 DCTN1 Zornitza Stark Mode of inheritance for gene: DCTN1 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Dementia v0.91 CYP27A1 Zornitza Stark Phenotypes for gene: CYP27A1 were changed from to Cerebrotendinous xanthomatosis, MIM# 213700
Early-onset Dementia v0.90 CYP27A1 Zornitza Stark Mode of inheritance for gene: CYP27A1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Early-onset Dementia v0.89 CHCHD10 Zornitza Stark Phenotypes for gene: CHCHD10 were changed from to Frontotemporal dementia and/or amyotrophic lateral sclerosis 2, MIM# 615911
Early-onset Dementia v0.87 CHCHD10 Zornitza Stark Mode of inheritance for gene: CHCHD10 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Dementia v0.86 C19orf12 Zornitza Stark Phenotypes for gene: C19orf12 were changed from to Neurodegeneration with brain iron accumulation 4, MIM# 614298
Early-onset Dementia v0.84 C19orf12 Zornitza Stark Mode of inheritance for gene: C19orf12 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Early-onset Dementia v0.83 ATP13A2 Zornitza Stark Phenotypes for gene: ATP13A2 were changed from to Kufor-Rakeb syndrome, MIM# 606693
Early-onset Dementia v0.82 ATP13A2 Zornitza Stark Mode of inheritance for gene: ATP13A2 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Early-onset Dementia v0.81 ARSA Zornitza Stark Phenotypes for gene: ARSA were changed from to Metachromatic leukodystrophy, MIM# 250100, adult-onset
Early-onset Dementia v0.79 ARSA Zornitza Stark Mode of inheritance for gene: ARSA was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Early-onset Dementia v0.78 APOE Zornitza Stark Phenotypes for gene: APOE were changed from to Alzheimer disease 2, MIM# 104310
Early-onset Dementia v0.77 APOE Zornitza Stark Mode of inheritance for gene: APOE was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Dementia v0.76 NOTCH3 Zornitza Stark Phenotypes for gene: NOTCH3 were changed from to Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1 125310
Early-onset Dementia v0.74 NOTCH3 Zornitza Stark Mode of inheritance for gene: NOTCH3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Dementia v0.58 CST3 Bryony Thompson changed review comment from: A single missense variant L68Q causes Icelandic-type CAA, where brain haemorrhage is main presenting feature of the condition. Progressive multi-infarct dementia has been reported in at least 17 cases. Dementia has been reported as the presenting feature in 2 cases from the same family. The gene has also been reported as an Alzheimer's disease susceptibility loci, but there is modest risk associated with the homozygote (rs1064039) minor allele geneotype, combined OR 1.6.
Sources: Expert list; to: A single missense variant L68Q causes Icelandic-type CAA, where brain haemorrhage is main presenting feature of the condition. Progressive multi-infarct dementia has been reported in at least 17 cases. Dementia has been reported as the presenting feature in 2 cases from the same family. The gene has also been reported as an Alzheimer's disease susceptibility loci, but there is modest risk associated with the homozygote (rs1064039) minor allele genotype, combined OR 1.6.
Sources: Expert list
Early-onset Dementia v0.58 CST3 Bryony Thompson changed review comment from: A single missense variant L68Q causes Icelandic-type CAA, where brain haemorrhage is main presenting feature of the condition. Progressive multi-infarct dementia has been reported in at least 17 cases. Dementia has been reported as the presenting feature in 2 cases from the same family. The gene has also been reported as an Alzheimer's disease susceptibility loci, but the combined OR for the homozygote (rs1064039) minor allele is modest risk at 1.6.
Sources: Expert list; to: A single missense variant L68Q causes Icelandic-type CAA, where brain haemorrhage is main presenting feature of the condition. Progressive multi-infarct dementia has been reported in at least 17 cases. Dementia has been reported as the presenting feature in 2 cases from the same family. The gene has also been reported as an Alzheimer's disease susceptibility loci, but there is modest risk associated with the homozygote (rs1064039) minor allele geneotype, combined OR 1.6.
Sources: Expert list
Early-onset Dementia v0.58 CST3 Bryony Thompson gene: CST3 was added
gene: CST3 was added to Early-onset Dementia. Sources: Expert list
Mode of inheritance for gene: CST3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CST3 were set to 22435454; 8866434; 2602413; 8108423
Phenotypes for gene: CST3 were set to Cerebral amyloid angiopathy MIM#105150
Mode of pathogenicity for gene: CST3 was set to Other
Review for gene: CST3 was set to GREEN
Added comment: A single missense variant L68Q causes Icelandic-type CAA, where brain haemorrhage is main presenting feature of the condition. Progressive multi-infarct dementia has been reported in at least 17 cases. Dementia has been reported as the presenting feature in 2 cases from the same family. The gene has also been reported as an Alzheimer's disease susceptibility loci, but the combined OR for the homozygote (rs1064039) minor allele is modest risk at 1.6.
Sources: Expert list
Early-onset Dementia v0.56 MAPT Zornitza Stark Phenotypes for gene: MAPT were changed from to Supranuclear palsy, progressive (MIM# 601104) AD; Supranuclear palsy, progressive atypical (MIM# 260540) AR
Early-onset Dementia v0.54 MAPT Zornitza Stark Mode of inheritance for gene: MAPT was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Early-onset Dementia v0.52 GBA Zornitza Stark Phenotypes for gene: GBA were changed from to {Lewy body dementia, susceptibility to} (MIM# 127750)
Early-onset Dementia v0.50 GBA Zornitza Stark Mode of inheritance for gene: GBA was changed from Unknown to Other
Early-onset Dementia v0.45 ATN1 Bryony Thompson gene: ATN1 was added
gene: ATN1 was added to Early-onset Dementia. Sources: Expert list
Mode of inheritance for gene: ATN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ATN1 were set to 7633415
Phenotypes for gene: ATN1 were set to Dentatorubral-pallidoluysian atrophy MIM#125370
Mode of pathogenicity for gene: ATN1 was set to Other
Review for gene: ATN1 was set to GREEN
Added comment: DRPLA contains various combinations of myoclonus, seizures, ataxia, choreoathetosis, and dementia, and is only caused by trinucleotide repeat expansion. Mean age of onset is 30 years of age. From OMIM: In 22 patients unstable expansion of a CAG unit in the DRPLA gene was identified. Each patient was a heterozygote with 1 allele in the normal range (8-25 repeat units) and a second expanded allele with the range of 54-68 repeat units. There were no overlaps in the number of CAG repeat units between control chromosomes and DRPLA chromosomes.
Sources: Expert list
Early-onset Dementia v0.40 Bryony Thompson Panel types changed to Victorian Clinical Genetics Services; Melbourne Genomics; Royal Melbourne Hospital; Rare Disease
Early-onset Dementia v0.38 PINK1 Bryony Thompson Mode of inheritance for gene: PINK1 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Early-onset Dementia v0.37 PRKN Bryony Thompson Phenotypes for gene: PRKN were changed from to Parkinson disease, juvenile, type 2 MIM#600116
Early-onset Dementia v0.36 PRKN Bryony Thompson Mode of inheritance for gene: PRKN was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Early-onset Dementia v0.35 SPG11 Bryony Thompson Phenotypes for gene: SPG11 were changed from to Spastic paraplegia 11, autosomal recessive MIM#604360; Charcot-Marie-Tooth disease, axonal, type 2X MIM#616668; Amyotrophic lateral sclerosis 5, juvenile MIM#602099
Early-onset Dementia v0.34 SPG11 Bryony Thompson Mode of inheritance for gene: SPG11 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Early-onset Dementia v0.33 VPS13A Bryony Thompson Phenotypes for gene: VPS13A were changed from to Choreoacanthocytosis MIM#200150
Early-onset Dementia v0.33 VPS13A Bryony Thompson Mode of inheritance for gene: VPS13A was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Early-onset Dementia v0.32 VPS35 Bryony Thompson Mode of inheritance for gene: VPS35 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early-onset Dementia v0.31 VPS35 Bryony Thompson Phenotypes for gene: VPS35 were changed from to {Parkinson disease 17} MIM#614203; Cognitive decline
Early-onset Dementia v0.30 VAPB Bryony Thompson Phenotypes for gene: VAPB were changed from to Amyotrophic lateral sclerosis 8 MIM#608627; Spinal muscular atrophy, late-onset, Finkel type MIM#182980
Early-onset Dementia v0.29 MATR3 Bryony Thompson Phenotypes for gene: MATR3 were changed from to Amyotrophic lateral sclerosis 21 MIM#606070
Early-onset Dementia v0.28 MATR3 Bryony Thompson Mode of inheritance for gene: MATR3 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early-onset Dementia v0.27 PARK7 Bryony Thompson Mode of inheritance for gene: PARK7 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal
Early-onset Dementia v0.26 LRRK2 Bryony Thompson Mode of inheritance for gene: LRRK2 was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early-onset Dementia v0.18 ANG Bryony Thompson Classified gene: ANG as Red List (low evidence)
Early-onset Dementia v0.18 ANG Bryony Thompson Added comment: Comment on list classification: Not a prominent ALS-FTD phenotype
Early-onset Dementia v0.18 ANG Bryony Thompson Gene: ang has been classified as Red List (Low Evidence).
Early-onset Dementia v0.16 WDR45 Bryony Thompson changed review comment from: De novo variants identified in 5 cases with static encephalopathy of childhood with neurodegeneration in adulthood (SENDA), which included dementia as a feature.
Sources: Expert list; to: De novo variants identified in 5 female cases with static encephalopathy of childhood with neurodegeneration in adulthood (SENDA), which included dementia as a feature.
Sources: Expert list
Early-onset Dementia v0.7 PRKN Bryony Thompson edited their review of gene: PRKN: Changed rating: GREEN
Early-onset Dementia v0.1 ANG Bryony Thompson reviewed gene: ANG: Rating: RED; Mode of pathogenicity: None; Publications: 19153377; Phenotypes: Amyotrophic lateral sclerosis 9 MIM#611895; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Early-onset Dementia v0.1 Zornitza Stark Panel name changed from Early-onset Dementia_MGHA_VCGS to Early-onset Dementia
Panel types changed to Victorian Clinical Genetics Services; Melbourne Genomics
Early-onset Dementia v0.0 ANG Zornitza Stark gene: ANG was added
gene: ANG was added to Early-onset Dementia_MGHA_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services,Melbourne Genomics Health Alliance Complex Neurology Flagship
Mode of inheritance for gene: ANG was set to Unknown