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| Ataxia and cerebellar anomalies - narrow panel v4.37 | MAG | Achchuthan Shanmugasundram Tag Q1_23_promote_green was removed from gene: MAG. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - narrow panel v4.37 | MAG | Eleanor Williams reviewed gene: MAG: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - narrow panel v4.35 | MAG |
Achchuthan Shanmugasundram Source Expert Review Green was added to MAG. Rating Changed from Amber List (moderate evidence) to Green List (high evidence) |
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| Ataxia and cerebellar anomalies - narrow panel v3.39 | MAG | Arina Puzriakova Entity copied from Hereditary spastic paraplegia - childhood onset v3.18 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia and cerebellar anomalies - narrow panel v3.39 | MAG |
Arina Puzriakova gene: MAG was added gene: MAG was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Yorkshire and North East GLH,London North GLH,Literature,Expert Review Amber,NHS GMS Q1_23_promote_green tags were added to gene: MAG. Mode of inheritance for gene: MAG was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MAG were set to 24482476; 26179919; 31402626; 32629324; 32340215 Phenotypes for gene: MAG were set to Spastic paraplegia 75, autosomal recessive, OMIM:616680 |
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| Ataxia and cerebellar anomalies - narrow panel v3.35 | SPTAN1 |
Achchuthan Shanmugasundram changed review comment from: Comment on classification: This gene should be rated Green as there are several unrelated cases (many more than three cases identified with different variants) from multiple ethnicities reported with ataxia and was also supported by functional studies including results from mouse model. One patient each was identified with SPTAN1 variants and was reported with ataxia from PMID:29050398 and PMID:30548380. Out of three patients identified with SPTAN1 variants and reported with Developmental and epileptic encephalopathy 5 in PMID:34590414, one patient had ataxia and another had mild ataxia. Out of 22 patients from 14 families identified with SPTAN1 variants in PMID:35150594, four unrelated patients displaying p.Lys2083del variant were reported with cerebellar ataxia, while three other patients displaying other variants (p.Arg1624Cys, p.Arg1098Cys & p.Gln2205Pro) displayed different extremes of spastic ataxia spectrum. In PMID:36331550, authors carried out SPTAN1 gene enrichment analysis in the rare disease component of the 100,000 Genomes Project and screened 100,000 Genomes Project, DECIPHER database, and GeneMatcher to identify individuals with SPTAN1 variants. Statistically significant enrichment of rare probably damaging SPTAN1 variants were identified in families with hereditary ataxia (HA) or spastic paraplegia (HSP). Out of 31 individuals identified with SPTAN1 variants, 3 were presented with complex HA/HSP and two were presented with pure HA. A 33-year old Korean woman identified with SPTAN1 variant was reported with cerebellar ataxia in PMID:36408834, being the first reported case of SPTAN1-related cerebellar ataxia. In addition, a strain of C57BL/6J mice harbouring a single point mutation in Sptan1 (c.3293G > A/ p.Arg1098Gln) with reduced CaM affinity and intrinsically enhanced sensitivity to calpain proteolysis was reported in PMID:33790315. Homozygotes are embryonically lethal and heterozygotes develop a progressive ataxia.; to: Comment on classification: This gene should be rated Green as there are several unrelated cases (many more than three cases identified with different variants) from multiple ethnicities reported with ataxia and was also supported by functional studies including results from mouse model. One patient each was identified with SPTAN1 variants and was reported with ataxia from PMID:29050398 and PMID:30548380. Out of three patients identified with SPTAN1 variants and reported with Developmental and epileptic encephalopathy 5 in PMID:34590414, one patient had ataxia and another had mild ataxia. Out of 22 patients from 14 families identified with SPTAN1 variants in PMID:35150594, four unrelated patients displaying p.Lys2083del variant were reported with cerebellar ataxia, while three other patients displaying other variants (p.Arg1624Cys, p.Arg1098Cys & p.Gln2205Pro) displayed different extremes of spastic ataxia spectrum. In PMID:36331550, authors carried out SPTAN1 gene enrichment analysis in the rare disease component of the 100,000 Genomes Project and screened 100,000 Genomes Project, DECIPHER database, and GeneMatcher to identify individuals with SPTAN1 variants. Statistically significant enrichment of rare probably damaging SPTAN1 variants were identified in families with hereditary ataxia (HA) or spastic paraplegia (HSP). Out of 31 individuals identified with SPTAN1 variants, five (from three families) were presented with complex HA/HSP and two were presented with pure HA. A 33-year old Korean woman identified with SPTAN1 variant was reported with cerebellar ataxia in PMID:36408834, being the first reported case of SPTAN1-related cerebellar ataxia. In addition, a strain of C57BL/6J mice harbouring a single point mutation in Sptan1 (c.3293G > A/ p.Arg1098Gln) with reduced CaM affinity and intrinsically enhanced sensitivity to calpain proteolysis was reported in PMID:33790315. Homozygotes are embryonically lethal and heterozygotes develop a progressive ataxia. |
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| Ataxia and cerebellar anomalies - narrow panel v3.16 | NPTX1 |
Dmitrijs Rots gene: NPTX1 was added gene: NPTX1 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature Mode of inheritance for gene: NPTX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: NPTX1 were set to 34788392; 35285082; 35560436 Phenotypes for gene: NPTX1 were set to Ataxia Penetrance for gene: NPTX1 were set to unknown Mode of pathogenicity for gene: NPTX1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: NPTX1 was set to GREEN Added comment: Multiple individiuals with de novo or inherited (segregating with the phenotype) NPTX1 reported in the literature with both late and infantile-onset ataxia. Enough evidence for green. The phenotype is described in 34788392 as: "The NPTX1-associated phenotype consists of a late-onset, slowly progressive, cerebellar ataxia, with downbeat nystagmus, cognitive impairment reminiscent of cerebellar cognitive affective syndrome, myoclonic tremor and mild cerebellar vermian atrophy on brain imaging." Sources: Literature |
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| Ataxia and cerebellar anomalies - narrow panel v3.11 | SLC25A46 |
Achchuthan Shanmugasundram changed review comment from: Comment on classification of this gene: The rating for this gene should be GREEN, as this gene has been implicated in ataxia, as identified from biallelic loss-of-function variants from at least 8 unrelated individuals/ families from multiple ethnicities and supported by results from animal models. Two brothers of consanguineous parents of Pakistani origin were identified with homozygous variant in SLC25A46 (c.413T>G./ p.Leu138Arg). The younger of the two brothers was presented with balancing difficulties in infancy, prominent myoclonus, cerebellar ataxia, profound visual loss, rod cone dysfunction, exotropia, difficulty initiating saccades, mild spasticity, and axonal sensory-motor neuropathy leading to trophic changes. He also developed scoliosis and had cerebellar atrophy as well as T2/FLAIR (fluid-attenuated inversion recovery) hyperintensities and cavitations in the cerebellum. The older brother was mildly affected with similar clinical manifestations (PMID:27430653). A study on patients from three North African families (Two siblings from Tunisian family and two unrelated Algerians) showed that the previously reported variant c.1018C>T/ p.Arg340Cys (displayed in Tunisian siblings and one Algerian patient) was associated with childhood onset, optic atrophy, gait and speech difficulties and wasting of the lower limbs, and the Algerian patient with the novel variant p.Trp160Ser did not present with optic atrophy, while all patients were presented with ataxia (PMID:28558379). Similarly, ataxia was also observed in Sardinian (p.Arg340Cys) and Palestinian (c.1005A>T/ p.Glu335Asp) patients from Abrams et al, 2015 (PMID:26168012). A six year old boy with homozygous missense variant c.770G>A (p.Arg257Gln) was reported with optic atrophy, peripheral neuropathy, ataxia, but not cerebellar atrophy (PMID:30178502). p.Arg340Cys variant was also identified in the eleven year old male patient and in other unaffected family members, and the patient was presented with insidious onset, progressive vision loss and swaying since 8 years of age. The other presentations were gait ataxia, torticollis to left and tilt to right, head tremors and myoclonus (PMID:33816684). Mouse models with loss-of-function mutation or lacking SLC25A46 gene manifest the main clinical features identified in patients such as ataxia, optic atrophy, cerebellar hypoplasia and peripheral neuropathy which were completely rescued by expression of human ortholog (PMID:28376086; PMID:28934388). The results suggest that the gene loss causes degeneration in neurons by affecting mitochondrial dynamics and energy production. Loss-of-function in cultured cells and in zebrafish also led to increased mitochondrial connectivity, while severely affecting the development and maintenance of neurons in the zebrafish (PMID:26168012). SLC25A46 has been associated with neuropathy, hereditary motor and sensory, type VIB in OMIM and Gene2Phenotype and with pontocerebellar hypoplasia, type 1E in OMIM.; to: Comment on classification of this gene: The rating for this gene should be GREEN, as this gene has been identified to be implicated in cerebellar ataxia (MONDO:0000437) from biallelic loss-of-function variants from at least 8 unrelated individuals/ families and in pontocerebellar hypoplasia, type 1E (MIM# 619303) from biallelic loss-of-function variants from at least 6 unrelated individuals/ families. These cases were from multiple ethnicities and were supported by results from animal models. In addition, this gene has also been identified to be implicated in cerebellar hypoplasia from monoallelic loss-of-function variants from a family of three siblings. As we currently do not have three unrelated cases for monoallelic inheritance, this gene is assigned only to biallelic MOI. Cerebellar ataxia: Two brothers of consanguineous parents of Pakistani origin were identified with homozygous variant in SLC25A46 (c.413T>G./ p.Leu138Arg). The younger of the two brothers was presented with balancing difficulties in infancy, prominent myoclonus, cerebellar ataxia, profound visual loss, rod cone dysfunction, exotropia, difficulty initiating saccades, mild spasticity, and axonal sensory-motor neuropathy leading to trophic changes. He also developed scoliosis and had cerebellar atrophy as well as T2/FLAIR (fluid-attenuated inversion recovery) hyperintensities and cavitations in the cerebellum. The older brother was mildly affected with similar clinical manifestations (PMID:27430653). A study on patients from three North African families (Two siblings from Tunisian family and two unrelated Algerians) showed that the previously reported variant c.1018C>T/ p.Arg340Cys (displayed in Tunisian siblings and one Algerian patient) was associated with childhood onset, optic atrophy, gait and speech difficulties and wasting of the lower limbs, and the Algerian patient with the novel variant p.Trp160Ser did not present with optic atrophy, while all patients were presented with ataxia (PMID:28558379). Similarly, ataxia was also observed in Sardinian (p.Arg340Cys) and Palestinian (c.1005A>T/ p.Glu335Asp) patients from Abrams et al, 2015 (PMID:26168012). A six year old boy with homozygous missense variant c.770G>A (p.Arg257Gln) was reported with optic atrophy, peripheral neuropathy, ataxia, but not cerebellar atrophy (PMID:30178502). p.Arg340Cys variant was also identified in the eleven year old male patient and in other unaffected family members, and the patient was presented with insidious onset, progressive vision loss and swaying since 8 years of age. The other presentations were gait ataxia, torticollis to left and tilt to right, head tremors and myoclonus (PMID:33816684). Cerebellar hypoplasia: Four infants from two different families with homozygous variants (family 1: c.1022T>C/ p.Leu341Pro; family 2: deletion of exon 1) were reported to have died soon after birth with a profound neurodevelopmental disorder associated with congenital pontocerebellar hypoplasia (PMID:27543974). The phenotypes are similar to a female infant from the United States with pontocerebellar atrophy who died at age 15 weeks. This infant reported by Abram et al (2015) exhibited compound heterozygous variants (c.882_885dupTTAC/ p.Asn296fs*297 & c.998C>T/ p.Pro333Leu) (PMID:26168012). Four infants from two unrelated families of German and Italian descent were reported with PCH1E. All died in the first days or weeks of life. The German infants were identified with homozygous variant c.736A>T (p.Arg246Ter) and the Italian infants were identified with compound heterozygous variants c.42C>G (p.Tyr14Ter) & 462+ 1G>A (PMID:28653766). Two siblings with bi-allelic compound heterozygous variants (a splicing variant - c.385-1G > A and a deletion) had a fulminant neonatal course. The mother of these siblings exhibited a heterozygous c.385-1G > A allele and the father had an 80-kb deletion spanning SLC25A46 and TMEM232 genes. Pontocerebellar hypoplasia was reported by postmortem brain CT imaging in one of the siblings (PMID:35012485). Barth (1993) reported a Dutch family in which three siblings died within the first day of life due to lack of spontaneous respiration and profound muscle weakness (PMID:8147499). Although these infants displayed similarities to the clinical indications described by Wan et al, 2016 (PMID:27543974), they were identified to possess heterozygous variant leading to a premature stop codon (c.691C>T/ p.Arg231Ter) in exon 8 of the SLC25A46 gene (PMID:28637197). Functional studies: Mouse models with loss-of-function mutation or lacking SLC25A46 gene manifest the main clinical features identified in patients such as ataxia, optic atrophy, cerebellar hypoplasia and peripheral neuropathy which were completely rescued by expression of human ortholog (PMID:28376086; PMID:28934388). The results suggest that the gene loss causes degeneration in neurons by affecting mitochondrial dynamics and energy production. Loss-of-function in cultured cells and in zebrafish also led to increased mitochondrial connectivity, while severely affecting the development and maintenance of neurons in the zebrafish (PMID:26168012). SLC25A46 has been associated with neuropathy, hereditary motor and sensory, type VIB in OMIM and Gene2Phenotype and with pontocerebellar hypoplasia, type 1E in OMIM. |
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| Ataxia and cerebellar anomalies - narrow panel v2.226 | ATG7 |
Zornitza Stark gene: ATG7 was added gene: ATG7 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Literature Mode of inheritance for gene: ATG7 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ATG7 were set to 34161705 Phenotypes for gene: ATG7 were set to Spinocerebellar ataxia, SCAR31, MIM#619422 Review for gene: ATG7 was set to GREEN Added comment: 12 individuals from 5 unrelated families reported with a complex neurodevelopmental disorder and bi-allelic variants in this gene. Age range from 21 months to 71 years of age. Main clinical features included axial hypotonia, variably impaired intellectual development with poor or absent speech, and delayed walking (up to 7 years of age) or inability to walk. All had ataxia, often with tremor or dyskinesia, as well as dysarthria associated with cerebellar hypoplasia on brain imaging. Most had optic atrophy, and some had ptosis, chronic progressive external ophthalmoplegia, retinopathy, and strabismus; 1 had early-onset cataracts. The more severely affected individuals had spastic paraplegia and inability to walk. Functional data including mouse model. Sources: Literature |
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| Ataxia and cerebellar anomalies - narrow panel v2.12 | SLC25A46 |
Zornitza Stark gene: SLC25A46 was added gene: SLC25A46 was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list Mode of inheritance for gene: SLC25A46 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC25A46 were set to 30178502; 26168012; 27543974; 27430653; 27390132; 28934388; 28558379 Phenotypes for gene: SLC25A46 were set to Neuropathy, hereditary motor and sensory, type VIB, MIM# 616505 Review for gene: SLC25A46 was set to GREEN gene: SLC25A46 was marked as current diagnostic Added comment: Hereditary motor and sensory neuropathy type VIB is an autosomal recessive complex progressive neurologic disorder characterized mainly by early-onset optic atrophy resulting in progressive visual loss and peripheral axonal sensorimotor neuropathy with highly variable age at onset and severity. Affected individuals also have cerebellar or pontocerebellar atrophy on brain imaging, and they show abnormal movements, such as ataxia, dysmetria, and myoclonus. At least 10 unrelated families reported, supportive functional data. Sources: Expert list |
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| Ataxia and cerebellar anomalies - narrow panel v2.12 | RORA |
Zornitza Stark gene: RORA was added gene: RORA was added to Ataxia and cerebellar anomalies - narrow panel. Sources: Expert list Mode of inheritance for gene: RORA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: RORA were set to 29656859 Phenotypes for gene: RORA were set to Intellectual developmental disorder with or without epilepsy or cerebellar ataxia, MIM# 618060 Review for gene: RORA was set to GREEN gene: RORA was marked as current diagnostic Added comment: 11 unrelated individuals with syndromic intellectual disability and de novo variants in this gene. Severity varied from mild borderline intellectual disability with mild speech delay or normal speech, through to severe cognitive impairment with poor or absent speech. Most had ataxia, hypotonia, poor coordination, and/or mild tremor, suggesting cerebellar dysfunction. Three individuals had documented cerebellar hypoplasia or pontocerebellar atrophy on brain imaging. Seven had seizures of variable types, including neonatal myoclonic, tonic-clonic, multifocal, generalized, and absence. Five were diagnosed with autism spectrum disorder. More variable features included strabismus, esotropia, nystagmus, and oculomotor apraxia. Postulated that some variants exert dominant-negative effect resulting in a more severe phenotype than the LoF variants. Sources: Expert list |
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