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| Regression v0.584 | BORCS5 |
Zornitza Stark gene: BORCS5 was added gene: BORCS5 was added to Regression. Sources: Literature Mode of inheritance for gene: BORCS5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: BORCS5 were set to 40385417 Phenotypes for gene: BORCS5 were set to Lysosomal storage disease, MONDO:0002561, BORCS5-related Review for gene: BORCS5 was set to GREEN Added comment: preprint PMID 40385417, describing 12 individuals from 7 families with a spectrum of abnormalities (osteopetrosis not mentioned), suggestive of lysosomal disorder. Homozygous loss-of-function variants presented with prenatally lethal arthrogryposis multiplex congenita, brain malformations, and neuropathological evidence of diffuse neuroaxonal dystrophy. Individuals with missense variants presented differently, with microcephaly, developmental epileptic encephalopathy, intellectual disability, optic atrophy, spasticity, and progressive movement disorders. In this group, brain MRI showed diffuse hypomyelination and progressive global cerebral atrophy, consistent with neurodegeneration. Borcs5 knockout in zebrafish exhibited microcephaly, motor deficits, and seizures, mirroring the patients' clinical presentation. At the cellular level, BORCS5 loss-of-function but not missense variants, resulted in lower protein expression and impaired BORC assembly, paralleled by perinuclear lysosomal clustering. However, both loss-of-function and missense BORCS5 variants were associated with reduced total lysosomal proteolysis, reduced activity of the lysosomal hydrolases glucocerebrosidase and cathepsin B, and presence of multilamellar bodies, indicating lysosomal dysfunction. Sources: Literature |
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| Regression v0.583 | ATG2A |
Zornitza Stark gene: ATG2A was added gene: ATG2A was added to Regression. Sources: Literature Mode of inheritance for gene: ATG2A was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ATG2A were set to 40631414 Phenotypes for gene: ATG2A were set to complex neurodevelopmental disorder, ATG2A-related - MONDO:0100038 Review for gene: ATG2A was set to RED Added comment: PMID:40631414 report a 3 yo F with homozygous ATG2A missense variant (c.1372G>C (p.Gly433Ala) with developmental regression, seizures, cerebellar ataxia, and MRI-brain abnormalities (diffuse cerebral and cerebellar atrophy). Provide supportive functional evidence. Sources: Literature |
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| Regression v0.419 | NDUFAF4 |
Krithika Murali changed review comment from: 2 unrelated families reported with patient-specific functional evidence provided for each. Regression noted in one reported patient. Other reported family had two siblings unwell from birth with a relatively fulminant course. Another large family reported with recurrent decompensation episodes. PMID: 32949790 - report two siblings with facial dysmorphism and lactic acidosis diagnosed neonatally with subsequent fatal early encephalopathy with apneic episodes, irritability, central hypoventilation, liver involvement and hyperammonemia. Cerebral white matter anomalies reported in one patient and cardiomyopathy in the other. WES identified homozygous nonsense NDUFAF4 variants with absent NDUFAF4 expression in patient fibroblasts. OXPHOS assembly studies demonstrated almost undetectable levels of fully assembled complex I and complex I–containing supercomplexes and an abnormal accumulation of SCIII2IV1 supercomplexes. Morphologically, fibroblasts showed rounder mitochondria and a diminished degree of branching of the mitochondrial network. PMID: 28853723 - report one patient born at 38 weeks after IOL for IUGR. Presented age 7 months with developmental regression, growth failure and central hypotonia. Brain MRI revealed diffuse bilateral signal alterations in the basal ganglia and thalami and an EEG showed generalized slowing with multifocal spikes consistent with an epileptogenic focus. Homozygous missense NDUFAF4 variants identified. Lentiviral complementation of patient fibroblasts with wild-type NDUFAF4 rescued complex I deficiency and assembly defect PMID 18179882 - report multiple affected individuals from one family. Most presented soon after birth with severe metabolic acidosis and high plasma lactate levels. Patients who survived longer were repeatedly admitted because of exacerbation of the acidosis during intercurrent infections. One long-term survivor had profound ID. Seizures occurred in 2 individuals during decompensation episodes. Brain MRI of one patient at 16 months of age revealed severe atrophy of both gray and white matter, with demyelination, most prominent at the anterior aspects of the brain, leaving a cortical ribbon. At the occipito-parietal region there were subventricular cysts, emphasizing the ventricular walls. The cerebellum, basal ganglia, pons, and medulla were severely atrophic; to: 3 unrelated families reported with patient-specific functional evidence provided for each. Regression noted in one reported patient. Other reported family had two siblings unwell from birth with a relatively fulminant course. Another large family reported with fulminant neonatal course / longer-term survivors having recurrent decompensation episodes. PMID: 32949790 - report two siblings with facial dysmorphism and lactic acidosis diagnosed neonatally with subsequent fatal early encephalopathy with apneic episodes, irritability, central hypoventilation, liver involvement and hyperammonemia. Cerebral white matter anomalies reported in one patient and cardiomyopathy in the other. WES identified homozygous nonsense NDUFAF4 variants with absent NDUFAF4 expression in patient fibroblasts. OXPHOS assembly studies demonstrated almost undetectable levels of fully assembled complex I and complex I–containing supercomplexes and an abnormal accumulation of SCIII2IV1 supercomplexes. Morphologically, fibroblasts showed rounder mitochondria and a diminished degree of branching of the mitochondrial network. PMID: 28853723 - report one patient born at 38 weeks after IOL for IUGR. Presented age 7 months with developmental regression, growth failure and central hypotonia. Brain MRI revealed diffuse bilateral signal alterations in the basal ganglia and thalami and an EEG showed generalized slowing with multifocal spikes consistent with an epileptogenic focus. Homozygous missense NDUFAF4 variants identified. Lentiviral complementation of patient fibroblasts with wild-type NDUFAF4 rescued complex I deficiency and assembly defect PMID 18179882 - report multiple affected individuals from one family. Most presented soon after birth with severe metabolic acidosis and high plasma lactate levels. Patients who survived longer were repeatedly admitted because of exacerbation of the acidosis during intercurrent infections. One long-term survivor had profound ID. Seizures occurred in 2 individuals during decompensation episodes. Brain MRI of one patient at 16 months of age revealed severe atrophy of both gray and white matter, with demyelination, most prominent at the anterior aspects of the brain, leaving a cortical ribbon. At the occipito-parietal region there were subventricular cysts, emphasizing the ventricular walls. The cerebellum, basal ganglia, pons, and medulla were severely atrophic |
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| Regression v0.296 | TPP1 | Zornitza Stark Phenotypes for gene: TPP1 were changed from to Ceroid lipofuscinosis, neuronal, 2, MIM# 204500; MONDO:0008769 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Regression v0.293 | TPP1 | Zornitza Stark reviewed gene: TPP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 9295267, 18684116, 23418007, 26224725, 31283065; Phenotypes: Ceroid lipofuscinosis, neuronal, 2, MIM# 204500, MONDO:0008769; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Regression v0.293 | MFSD8 | Zornitza Stark Phenotypes for gene: MFSD8 were changed from to Ceroid lipofuscinosis, neuronal, 7, MIM# 610951; MONDO:0012588 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Regression v0.290 | MFSD8 | Zornitza Stark reviewed gene: MFSD8: Rating: GREEN; Mode of pathogenicity: None; Publications: 17564970, 19201763; Phenotypes: Ceroid lipofuscinosis, neuronal, 7, MIM# 610951, MONDO:0012588; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Regression v0.219 | CLCN6 |
Zornitza Stark gene: CLCN6 was added gene: CLCN6 was added to Regression. Sources: Literature Mode of inheritance for gene: CLCN6 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CLCN6 were set to 33217309 Phenotypes for gene: CLCN6 were set to Neurodegeneration with brain iron accumulation 5, MIM# 300894 Review for gene: CLCN6 was set to GREEN Added comment: Three unrelated families reported with recurrent GOF de novo c.1658A>G (p.Tyr553Cys) and severe developmental delay with pronounced generalized hypotonia, respiratory insufficiency, and variable neurodegeneration and diffusion restriction in cerebral peduncles, midbrain, and/or brainstem in MRI scans. Sources: Literature |
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| Regression v0.166 | FUS | Zornitza Stark Marked gene: FUS as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Regression v0.166 | FUS | Zornitza Stark Gene: fus has been classified as Red List (Low Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Regression v0.166 | FUS | Zornitza Stark Phenotypes for gene: FUS were changed from to Amyotrophic lateral sclerosis 6, with or without frontotemporal dementia, MIM# 608030 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Regression v0.165 | FUS | Zornitza Stark Mode of inheritance for gene: FUS was changed from Unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Regression v0.164 | FUS | Zornitza Stark Classified gene: FUS as Red List (low evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Regression v0.164 | FUS | Zornitza Stark Gene: fus has been classified as Red List (Low Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Regression v0.163 | FUS | Zornitza Stark reviewed gene: FUS: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Amyotrophic lateral sclerosis 6, with or without frontotemporal dementia, MIM# 608030; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Regression v0.162 | ISCA2 |
Zornitza Stark gene: ISCA2 was added gene: ISCA2 was added to Regression. Sources: Expert Review Mode of inheritance for gene: ISCA2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ISCA2 were set to 25539947; 29297947; 29122497; 29359243 Phenotypes for gene: ISCA2 were set to Multiple mitochondrial dysfunctions syndrome 4, MIM# 616370 Review for gene: ISCA2 was set to GREEN Added comment: Over 10 unrelated families reported with bi-allelic variants in this gene and a neurodegenerative disorder that usually results in death in early childhood. Affected individuals have normal development for the first months of life, but thereafter show progressive loss of motor and social skills with hypotonia, spasticity, and nystagmus. Patients regress to a vegetative state with lack of eye contact and speech, and poor feeding. Most patients have optic atrophy, and some may develop seizures. Brain imaging shows diffuse leukodystrophy in the subcortical region, brainstem, cerebellum, and spinal cord. Sources: Expert Review |
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| Regression v0.0 | FUS |
Zornitza Stark gene: FUS was added gene: FUS was added to Regression_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: FUS was set to Unknown |
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