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| Mendeliome v0.8921 | SCA12 | Bryony Thompson Marked STR: SCA12 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8921 | SCA12 | Bryony Thompson Str: sca12 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8921 | SCA12 | Bryony Thompson Classified STR: SCA12 as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8921 | SCA12 | Bryony Thompson Str: sca12 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8920 | SCA12 |
Bryony Thompson STR: SCA12 was added STR: SCA12 was added to Mendeliome. Sources: Expert list Mode of inheritance for STR: SCA12 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for STR: SCA12 were set to 27864267; 33811808 Phenotypes for STR: SCA12 were set to Spinocerebellar ataxia 12 MIM#604326 Review for STR: SCA12 was set to GREEN STR: SCA12 was marked as clinically relevant Added comment: NM_181675.3:c.27CAG[X] Uncertain if CAG repeat encodes polyglutamine or instead effects expression of specific splice variants of the encoded phosphatase Normal: ≤32 repeats Uncertain: ~40-50 repeats have been reported, 43 repeats is the lowest reported in an established affected individual in a family with SCA12 Established pathogenic (used as diagnostic cut-off): ≥51 repeats Sources: Expert list |
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| Mendeliome v0.8914 | Bryony Thompson removed STR:SCA12 from the panel | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.8511 | CAMK4 |
Zornitza Stark gene: CAMK4 was added gene: CAMK4 was added to Mendeliome. Sources: Expert Review Mode of inheritance for gene: CAMK4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CAMK4 were set to 30262571; 33098801; 33211350 Phenotypes for gene: CAMK4 were set to Intellectual disability; Autism; Behavioral abnormality; Abnormality of movement; Dystonia; Ataxia; Chorea; Myoclonus Review for gene: CAMK4 was set to GREEN Added comment: 3 publications by Zech et al (2018, 2020 - PMIDs : 30262571, 33098801, 33211350) provide clinical details on 3 individuals, each harboring a private de novo CAMK4 variant. Overlapping features included DD, ID, behavoral issues, autism and abnormal hyperkinetic movements. Dystonia and chorea in all 3 appeared 3-20 years after initial symptoms. CAMK4 encodes Calcium/Calmodulin-dependent protein kinase IV, an important mediator of calcium-mediated activity and dynamics, particularly in the brain. It is involved in neuronal transmission, synaptic plasticity, and neuronal gene expression required for brain development and neuronal homeostasis (summary by OMIM based on Zech et al, 2018). The 473 aa enzyme has a protein kinase domain (aa 46-300) and a C-terminal autoregulatory domain (aa 305-341) the latter comprising an autoinhibitory domain (AID / aa 305-321) and a calmodulin-binding domain (CBD / aa 322-341) [NP_001735.1 / NM_001744.4 - also used below]. Variants in all 3 subjects were identified following trio-WES and were in all cases protein-truncating, mapping to exon 10 or exon 10-intron 10 junction, expected to escape NMD and cause selective abrogation of the autoinhibitory domain (aa 305-321) leading overall to gain-of-function. Variation databases include pLoF CAMK4 variants albeit in all cases usptream or downstream of this region (pLI of this gene in gnomAD: 0.51). Variants leading to selective abrogation of the autoregulatory domain have not been reported. Extensive evidence for the GoF effect of the variant has been provided in the first publication. Several previous studies have demonstrated that abrogation of the AID domain leads to consitutive activation (details below). Mouse models - though corresponding to homozygous loss of function - support a role for CAMKIV in cognitive and motor symptoms. Null mice display tremulous and ataxic movements, deficiencies in balance and sensorimotor performance associated with reduced number of Purkinje neurons (Ribar et al 2000, PMID: 11069976 - not reviewed). Wei et al (2002, PMID: 12006982 - not reviewed) provided evidence for alteration in hippocampal physiology and memory function. Heterozygous mutations in other genes for calcium/calmodulin-dependent protein kinases (CAMKs) e.g. CAMK2A/CAMK2B (encoding subunits of CAMKII) have been reported in individuals with ID. --- The proband in the first publication (PMID: 30262571) was a male with DD, ID, behavioral difficulties (ASD, autoaggression, stereotypies) and hyperkinetic movement disorder (myoclonus, chorea, ataxia) with severe generalized dystonia (onset at the age of 13y). Brain MRI demonstrated cerebellar atrophy. Extensive work-up incl. karyotyping, CMA, DYT-TOR1A, THAP1, GCH1, SCA1/2/3/6/7/8/12/17, Friedreich's ataxia and FMR1 analysis was negative.F Trio WES identified a dn splice site variant (c.981+1G>A) in the last exon-intron junction. RT-PCR followed by gel electrophoresis and Sanger in fibroblasts from an affected and control subject revealed that the proband had - as predicted by the type/location of the variant - in equal amount 2 cDNA products, a normal as well as a truncated one. Sequencing of the shortest revealed utilization of a cryptic donor splice site upstream of the mutated donor leading to a 77bp out-of-frame deletion and introduction of a premature stop codon in the last codon (p.Lys303Serfs*28). Western blot in fibroblast cell lines revealed 2 bands corresponding to the normal protein product as well as to the p.Lys303Serfs*28 although expression of the latter was lower than that of the full length protein. Several previous studies have shown that mutant CAMKIV species that lack the autoinhibitory domain are consitutively active (several Refs provided). Among others Chatila et al (1996, PMID: 8702940) studied an in vitro-engineered truncation mutant (Δ1-317 - truncation at position 317 of the protein) with functionally validated gain-of-function effect. To prove enhanced activity of the splicing variant, Zech et al assessed phosphorylation of CREB (cyclic AMP-responsive element binding protein), a downstream substrate of CAMKIV. Immunobloting revealed significant increase of CREB phosphorylation in patient fibroblasts compared to controls. Overactivation of CAMKIV signaling was reversed when cells were treated with STO-609 an inhibitor of CAMKK, the ustream activator of CAMKIV. Overall the authors demonstrated that loss of CAMKIV autoregulatory domain due to this splice variant had a gain-of-function effect. ---- Following trio-WES, Zech et al (2020 - PMID: 33098801) identified another relevant subject within cohort of 764 individuals with dystonia. This 12-y.o. male, harboring a different variant affecting the same donor site (c.981+1G>T), presented DD, ID, dystonia (onset at 3y) and additional movement disorders (myoclonus, ataxia) as well as similar behavior (ASD, autoaggression, stereotypies). [Details in suppl. p20]. ---- Finally Zech et al (2020 - PMID: 33211350) reported on a 24-y.o. woman with adolescence onset choreodystonia. Other features included DD, moderate ID, absence seizures in infancy, OCD with anxiety and later diagnosis of ASD. Trio WES revealed a dn stopgain variant (c.940C>T; p.Gln314*). Sources: Expert Review |
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| Mendeliome v0.6838 | SCA17 | Bryony Thompson Marked STR: SCA17 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6838 | SCA17 | Bryony Thompson Str: sca17 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6838 | SCA17 | Bryony Thompson Classified STR: SCA17 as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6838 | SCA17 | Bryony Thompson Str: sca17 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6837 | SCA17 |
Bryony Thompson STR: SCA17 was added STR: SCA17 was added to Mendeliome. Sources: Expert list Mode of inheritance for STR: SCA17 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for STR: SCA17 were set to 20301611; 29325606 Phenotypes for STR: SCA17 were set to Spinocerebellar ataxia 17 MIM#607136 Review for STR: SCA17 was set to GREEN STR: SCA17 was marked as clinically relevant Added comment: NM_003194.4:c.172_174[X] Mechanism of disease expected to be gain of function Normal: ≤ 40 CAG/CAA repeats Reduced-penetrance: 41-48 CAG/CAA repeats, individual may or may not develop symptoms. Full-penetrance: ≥49 CAG/CAA repeats Sources: Expert list |
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| Mendeliome v0.6835 | SCA12 | Bryony Thompson Marked STR: SCA12 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6835 | SCA12 | Bryony Thompson Str: sca12 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6835 | SCA12 | Bryony Thompson Classified STR: SCA12 as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6835 | SCA12 | Bryony Thompson Str: sca12 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6834 | SCA12 |
Bryony Thompson STR: SCA12 was added STR: SCA12 was added to Mendeliome. Sources: Expert list Mode of inheritance for STR: SCA12 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for STR: SCA12 were set to 29325606; 20301381 Phenotypes for STR: SCA12 were set to Spinocerebellar ataxia 12 MIM#604326 Review for STR: SCA12 was set to GREEN STR: SCA12 was marked as clinically relevant Added comment: NM_181675.3:c.27CAG[X] Uncertain if CAG repeat encodes polyglutamine or instead effects expression of specific splice variants of the encoded phosphatase Normal: ≤32 repeats Reduced penetrance: ~40-66 repeats Full penetrance: ≥66 repeats Sources: Expert list |
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| Mendeliome v0.6814 | SCA10 | Bryony Thompson Marked STR: SCA10 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6814 | SCA10 | Bryony Thompson Str: sca10 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6814 | SCA10 | Bryony Thompson Classified STR: SCA10 as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6814 | SCA10 | Bryony Thompson Str: sca10 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6813 | SCA10 |
Bryony Thompson STR: SCA10 was added STR: SCA10 was added to Mendeliome. Sources: Expert list Mode of inheritance for STR: SCA10 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for STR: SCA10 were set to 20301354 Phenotypes for STR: SCA10 were set to Spinocerebellar ataxia 10 MIM#603516 Review for STR: SCA10 was set to GREEN STR: SCA10 was marked as clinically relevant Added comment: NM_013236.2:c.1430+54822ATTCT[X] Toxic RNA gain-of-function mechanism of disease Normal alleles: 10-32 ATTCT repeats Alleles of questionable significance: 33-280 ATTCT repeats Reduced-penetrance alleles: 33-850 repeats Full-penetrance alleles: 800-4,500 ATTCT repeats Sources: Expert list |
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| Mendeliome v0.6782 | SCA1 | Bryony Thompson Marked STR: SCA1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6782 | SCA1 | Bryony Thompson Str: sca1 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6782 | SCA1 | Bryony Thompson edited their review of STR: SCA1: Changed rating: GREEN | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6782 | SCA1 | Bryony Thompson Classified STR: SCA1 as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6782 | SCA1 | Bryony Thompson Str: sca1 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.6781 | SCA1 |
Bryony Thompson STR: SCA1 was added STR: SCA1 was added to Mendeliome. Sources: Expert list Mode of inheritance for STR: SCA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for STR: SCA1 were set to 29325606; 20301363 Phenotypes for STR: SCA1 were set to Spinocerebellar ataxia 1 MIM#164400 STR: SCA1 was marked as clinically relevant Added comment: NM_000332.3:c.589_591CAG[X] Toxic protein aggregation is mechanism of disease Normal: ≤35 CAG repeats or 36-44 CAG repeats with CAT interruptions Mutable normal (intermediate): 36-38 CAG repeats without CAT interruptions Full-penetrance: ≥39 CAG repeats without CAT interruptions or ≥46 uninterrupted CAG repeats with CAT interruptions and additional CAGs Sources: Expert list |
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| Mendeliome v0.1726 | ISCA1 | Zornitza Stark Marked gene: ISCA1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1726 | ISCA1 | Zornitza Stark Gene: isca1 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1726 | ISCA1 | Zornitza Stark Classified gene: ISCA1 as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1726 | ISCA1 | Zornitza Stark Gene: isca1 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendeliome v0.1725 | ISCA1 |
Zornitza Stark gene: ISCA1 was added gene: ISCA1 was added to Mendeliome. Sources: Expert list Mode of inheritance for gene: ISCA1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ISCA1 were set to 28356563; 32092383; 31016283; 30113620; 30105122 Phenotypes for gene: ISCA1 were set to Multiple mitochondrial dysfunctions syndrome 5, MIM# 617613 Review for gene: ISCA1 was set to GREEN gene: ISCA1 was marked as current diagnostic Added comment: Multiple unrelated families reported. Severe disorder characterised by progressive neurologic deterioration beginning in early infancy. Affected individuals have essentially no psychomotor development and have early-onset seizures with neurologic decline and spasticity. Brain imaging shows severe leukodystrophy with evidence of dys- or delayed myelination. Rat model results in early lethality. Founder variant c.259G > A, p.(Glu87Lys) reported in Indian families. Sources: Expert list |
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