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Hereditary neuropathy or pain disorder v3.88 RTN2 Achchuthan Shanmugasundram gene: RTN2 was added
gene: RTN2 was added to Hereditary neuropathy or pain disorder. Sources: Literature
Mode of inheritance for gene: RTN2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RTN2 were set to 38527963
Phenotypes for gene: RTN2 were set to distal hereditary motor neuropathy, MONDO:0018894
Review for gene: RTN2 was set to GREEN
Added comment: PMID:38527963 reported the identification of seven novel or ultra-rare homozygous loss-of-function RTN2 variants in 14 individuals from seven unrelated families with distal hereditary motor neuropathy.

All affected individuals (seven males and seven females, aged 9-50 years) exhibited weakness in the distal upper and lower limbs, lower limb spasticity, hyperreflexia, with an onset in the first decade of life. Nerve conduction studies revealed axonal motor neuropathy with neurogenic changes in the electromyography.

Characterisation of C. elegans RTN2 homolog loss-of-function variants demonstrated morphological and behavioural differences compared to the parental strain and treatment with an endoplasmic/sarcoplasmic reticulum Ca(2+) re-uptake inhibitor (2,5-di-tert-butylhydroquinone) rescued key phenotypic differences.

Biallelic variants in RTN2 gene have not yet been associated with any phenotypes in OMIM or Gene2Phenotype, while monoallelic variants have been associated with spastic paraplegia (MIM #604805) in OMIM.
Sources: Literature
Hereditary neuropathy or pain disorder v3.86 PDXK Achchuthan Shanmugasundram gene: PDXK was added
gene: PDXK was added to Hereditary neuropathy or pain disorder. Sources: Literature
Mode of inheritance for gene: PDXK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PDXK were set to 31187503; 32522499
Phenotypes for gene: PDXK were set to Neuropathy, hereditary motor and sensory, type VIC, with optic atrophy, OMIM:618511
Review for gene: PDXK was set to GREEN
Added comment: PMID:31187503 - Five individuals from two unrelated families were reported with biallelic PDXK variants and with primary axonal polyneuropathy and optic atrophy. This association was also supported by results from cell-based functional assays. The biochemical profile can be rescued with PLP supplementation associated with clinical improvement.

PMID:32522499 - Two affected siblings with a novel biallelic missense PDXK variant were reported with a similar phenotype as reported in PMID:31187503 with earlier onset. Functional analysis showed that this variant leads to almost complete loss of PDXK enzymatic activity and low PLP levels.

This gene has been associated with relevant phenotypes in OMIM (MIM #618511), but not yet in Gene2Phenotype.
Sources: Literature
Hereditary neuropathy or pain disorder v3.74 COQ7 Lucy Jackson gene: COQ7 was added
gene: COQ7 was added to Hereditary neuropathy or pain disorder. Sources: NHS GMS
Mode of inheritance for gene: COQ7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COQ7 were set to PMID: 36758993; 37077559
Phenotypes for gene: COQ7 were set to autosomal recessive distal hereditary motor neuronopathy-9 (HMNR9)
Review for gene: COQ7 was set to GREEN
Added comment: This gene is associated with autosomal recessive distal hereditary motor neuronopathy-9 (HMNR9)
Sources: NHS GMS
Hereditary neuropathy or pain disorder v3.66 PSMC3 Achchuthan Shanmugasundram gene: PSMC3 was added
gene: PSMC3 was added to Hereditary neuropathy or pain disorder. Sources: Literature
Mode of inheritance for gene: PSMC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PSMC3 were set to 32500975
Phenotypes for gene: PSMC3 were set to ?Deafness, cataract, impaired intellectual development, and polyneuropathy, OMIM:619354
Review for gene: PSMC3 was set to AMBER
Added comment: Three individuals from a single extended consanguineous Turkish pedigree was reported with early-onset and rapidly progressive deafness, early-onset cataract, severe developmental delay, severely impaired intellectual development, subcutaneous calcifications and peripheral neuropathy. They were identified with homozygous variant in PSMC3 gene (c.1127 + 337A>G). Functional studies in patient fibroblast cells suggested that the patient PSMC3 variant is responsible for proteasome failure affecting protein homeostasis under stress conditions. This is also supported by evidence from zebrafish models, where PSMC3 knockout has reproduced the human phenotype with inner ear development anomalies as well as cataracts.
Sources: Literature
Hereditary neuropathy or pain disorder v3.62 SARS Christopher Record gene: SARS was added
gene: SARS was added to Hereditary neuropathy or pain disorder. Sources: Expert Review
Mode of inheritance for gene: SARS was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SARS were set to 37706277,36088542
Phenotypes for gene: SARS were set to CMTi
Penetrance for gene: SARS were set to Complete
Review for gene: SARS was set to GREEN
Added comment: Dominant or de novo dominant plausibly causing CMT in four unrelated families. Another amino-acyl tRNA synthetase causing CMT
Sources: Expert Review
Hereditary neuropathy or pain disorder v3.60 MT-ND6 Dmitrijs Rots gene: MT-ND6 was added
gene: MT-ND6 was added to Hereditary neuropathy or pain disorder. Sources: Literature
Mode of inheritance for gene gene: MT-ND6 was set to MITOCHONDRIAL
Publications for gene: MT-ND6 were set to PMID: 20301353
Phenotypes for gene: MT-ND6 were set to LHON; peripheral neuropathy
Penetrance for gene: MT-ND6 were set to unknown
Mode of pathogenicity for gene: MT-ND6 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: MT-ND6 was set to GREEN
Added comment: Gene is associated with LHON, but GeneReviews states: "Neurologic abnormalities such as postural tremor, peripheral neuropathy, nonspecific myopathy, and movement disorders have been reported to be more common in individuals with LHON than in the general population. ".
Identified in our lab in a young patient with peripheral neuropathy phenotype only.
Sources: Literature
Hereditary neuropathy or pain disorder v3.24 Eleanor Williams Panel name changed from Hereditary neuropathy or pain disorder - NOT PMP22 copy number to Hereditary neuropathy or pain disorder
Hereditary neuropathy or pain disorder v3.23 Eleanor Williams List of related panels changed from Hereditary neuropathy NOT PMP22 copy number; R78 to Hereditary neuropathy NOT PMP22 copy number; Hereditary neuropathy or pain disorder - NOT PMP22 copy number; R78
Hereditary neuropathy or pain disorder v3.11 NUDT2 Achchuthan Shanmugasundram reviewed gene: NUDT2: Rating: AMBER; Mode of pathogenicity: None; Publications: 27431290, 30059600, 33058507; Phenotypes: Intellectual developmental disorder with or without peripheral neuropathy, OMIM:619844; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v2.30 Eleanor Williams List of related panels changed from Hereditary neuropathy or pain disorder - NOT PMP22 copy number; Hereditary neuropathy NOT PMP22 copy number; R78 to Hereditary neuropathy NOT PMP22 copy number; R78
Hereditary neuropathy or pain disorder v2.29 Sarah Leigh Panel name changed from Hereditary neuropathy NOT PMP22 copy number to Hereditary neuropathy or pain disorder - NOT PMP22 copy number
List of related panels changed from R78; Hereditary neuropathy or pain disorder - NOT PMP22 copy number to Hereditary neuropathy or pain disorder - NOT PMP22 copy number; Hereditary neuropathy NOT PMP22 copy number; R78
Hereditary neuropathy or pain disorder v1.106 Eleanor Williams List of related panels changed from R78; Hereditary neuropathy or pain disorder – NOT PMP22 copy number to R78; Hereditary neuropathy or pain disorder - NOT PMP22 copy number
Hereditary neuropathy or pain disorder v1.83 SORD Sarah Leigh Tag for-review was removed from gene: SORD.
Tag Q3_21_NHS_review was removed from gene: SORD.
Hereditary neuropathy or pain disorder v1.83 SORD Sarah Leigh commented on gene: SORD: NHS Genomic Medicine Service consideration - coverage and variant calling will be compromised by pseudogene issue.
Hereditary neuropathy or pain disorder v1.83 SORD Sarah Leigh commented on gene: SORD
Hereditary neuropathy or pain disorder v1.82 SORD Sarah Leigh Source Expert Review Green was added to SORD.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hereditary neuropathy or pain disorder v1.52 TFG Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be assessed at the next GMS panel review. If the decision is made to include genes on this panel that are associated with neuropathy as part of a more complex phenotype, rather than isolated neuropathy, the MOI should be updated from 'monoallelic' only to 'both mono- and biallelic' .
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Monoallelic variants are associated with an adult-onset motor and sensory neuropathy (MIM# 604484), a disorder that is relevant to this panel. Biallelic variants cause a HSP (MIM# 615658) which also has been shown to involve peripheral neuropathy in complex cases. Both phenotypes have a sufficient number of unrelated cases (>3) reported to warrant a Green rating (updated publications list).
Hereditary neuropathy or pain disorder v1.48 SORD Arina Puzriakova Tag Q3_21_NHS_review tag was added to gene: SORD.
Hereditary neuropathy or pain disorder v1.44 SORD Sarah Leigh Publications for gene: SORD were set to 32367058; 33314640; 33397963
Hereditary neuropathy or pain disorder v1.43 SORD Sarah Leigh Phenotypes for gene: SORD were changed from Neuropathy to Sorbitol dehydrogenase deficiency with peripheral neuropathy OMIM:618912; sorbitol dehydrogenase deficiency with peripheral neuropathy MONDO:0030055
Hereditary neuropathy or pain disorder v1.37 Ivone Leong List of related panels changed from R78 to R78; Hereditary neuropathy or pain disorder – NOT PMP22 copy number
Panel version 1.36 has been signed off on 2021-08-05
Hereditary neuropathy or pain disorder v1.27 POLR3B Arina Puzriakova Phenotypes for gene: POLR3B were changed from Ataxia, spasticity, and demyelinating neuropathy to POLR3B-related neurodevelopmental disorder; Ataxia, spasticity, and demyelinating neuropathy
Hereditary neuropathy or pain disorder v1.26 POLR3B Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). Djordjevic et al. 2021 (PMID:33417887) identified different de novo POLR3B variants in 6 unrelated individuals. EMG/NCSs for 5/6 individuals revealed predominantly demyelinating sensory and motor neuropathy. Other features included ID, ataxia, spasticity.

POLR3B is listed in G2P with a 'probable' disease confidence rating for this phenotype (POLR3B-related neurodevelopmental disorder - monoallelic), but is not yet in OMIM.

Overall, there is sufficient evidence to warrant a Green rating on this panel.
Hereditary neuropathy or pain disorder v1.25 SORD James Polke reviewed gene: SORD: Rating: GREEN; Mode of pathogenicity: None; Publications: 32367058, 33875678; Phenotypes: Peripheral Neuropathy, Charcot-Marie Tooth Disease, Sorbitol dehydrogenase deficiency with peripheral neuropathy (OMIM # 618912); Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v1.23 SORD Ivone Leong Tag for-review tag was added to gene: SORD.
Hereditary neuropathy or pain disorder v1.23 SORD Ivone Leong Classified gene: SORD as Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v1.23 SORD Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics) and recommended to be Green by David Hunt (Wessex Clinical Genetics Service).

"Given that this is a potentially treatable neuropathy (https://www.ucl.ac.uk/ion/news/2020/may/sord-neuropathy-accelerated-journey-gene-identification-effective-treatment-patients), I think that SORD should be included in the ‘Hereditary neuropathy NOT PMP22 copy number’ gene panel."

There is enough evidence to support a gene-disease association and this gene should be Green at the next review.
Hereditary neuropathy or pain disorder v1.23 SORD Ivone Leong Gene: sord has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v1.22 SORD Ivone Leong Publications for gene: SORD were set to 32367058
Hereditary neuropathy or pain disorder v1.16 SPTBN4 Arina Puzriakova gene: SPTBN4 was added
gene: SPTBN4 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
for-review tags were added to gene: SPTBN4.
Mode of inheritance for gene: SPTBN4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPTBN4 were set to 28540413; 28940097; 29861105; 31230720; 31857255; 32672909
Phenotypes for gene: SPTBN4 were set to Neurodevelopmental disorder with hypotonia, neuropathy, and deafness, 617519
Review for gene: SPTBN4 was set to AMBER
Added comment: At least 11 individuals from 9 unrelated families with biallelic variants in SPTBN4 reported at present. Motor neuronopathy/axonopathy was reported in 5 unrelated families. A formal evaluation by EMG/NCS was not conducted in the rest but phenotypes did include hypotonia and hyporeflexia which could be suggestive of neuropathy.
Sources: Literature
Hereditary neuropathy or pain disorder v1.6 ACOX1 Zornitza Stark gene: ACOX1 was added
gene: ACOX1 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
Mode of inheritance for gene: ACOX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ACOX1 were set to 32169171
Phenotypes for gene: ACOX1 were set to Mitchell syndrome, MIM# 618960
Review for gene: ACOX1 was set to GREEN
gene: ACOX1 was marked as current diagnostic
Added comment: Mono-allelic variants (recurrent de novo missense, N237S) associated with Mitchell syndrome (MITCH): a progressive disorder characterised by episodic demyelination, sensorimotor polyneuropathy, and hearing loss. By contrast, bi-allelic variants cause a peroxisomal disorder characterised by neonatal hypotonia, seizures, apnoeic spells, delayed psychomotor development, and neurologic regression.
Sources: Literature
Hereditary neuropathy or pain disorder v1.4 SORD Zornitza Stark gene: SORD was added
gene: SORD was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
Mode of inheritance for gene: SORD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SORD were set to 32367058
Phenotypes for gene: SORD were set to Neuropathy
Review for gene: SORD was set to GREEN
gene: SORD was marked as current diagnostic
Added comment: 45 individuals from 38 families across multiple ancestries carrying the nonsense c.757delG
(p.Ala253GlnfsTer27) variant in SORD, in either a homozygous or compound heterozygous state .
Sources: Literature
Hereditary neuropathy or pain disorder v0.81 MTTP Louise Daugherty commented on gene: MTTP: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - syndrome with non-neurological features / Broader phenotype - Causes a progressive sensory neuropathy related to vitamin E deficiency as part of a complex multisystem disorder
Hereditary neuropathy or pain disorder v0.49 DNAJC3 Louise Daugherty commented on gene: DNAJC3: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - minor feature / Broader phenotype - ataxia & hearing loss - only 1 family in OMIM - more evidence? Complex disorder not pure neuropathy
Hereditary neuropathy or pain disorder v0.1 PTEN Ellen McDonagh gene: PTEN was added
gene: PTEN was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS,London North GLH
Mode of inheritance for gene: PTEN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: PTEN were set to Cowden syndrome 1, 158350; multifocal demyelinating motor neuropathy, macrocephaly, autism spectrum disorder and skin hamartomas
Hereditary neuropathy or pain disorder v0.1 PMM2 Ellen McDonagh gene: PMM2 was added
gene: PMM2 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS,London North GLH
Mode of inheritance for gene: PMM2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PMM2 were set to 9140401
Phenotypes for gene: PMM2 were set to Neonatal onset, leukodystrophy, abnormal serum glycoproteins, mental retardation, hypotonia, ataxia, retinitis pigmentosa, seizures, slowly progressive neuropathy with SNCV, severe infections, hepatic insufficiency and cardiomyopathy; Congenital disorder of glycosylation, type Ia, 212065
Hereditary neuropathy or pain disorder v0.1 PEX10 Ellen McDonagh gene: PEX10 was added
gene: PEX10 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS,London North GLH
Mode of inheritance for gene: PEX10 was set to
Publications for gene: PEX10 were set to 27230853; 20695019
Phenotypes for gene: PEX10 were set to Peroxisome biogenesis disorder 6A (Zellweger), 614870; Failure to thrive, facial dismorphism, agenesis of the corpus callosum, death in first year of life, axonal motor neuropathy, progressive ataxia and sensory-motor axonal neuropathy in adulthood described; Peroxisome biogenesis disorder 6B, 614871
Hereditary neuropathy or pain disorder v0.1 OPA3 Ellen McDonagh gene: OPA3 was added
gene: OPA3 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS,London North GLH
Mode of inheritance for gene: OPA3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: OPA3 were set to Infantile optic atrophy, additionally, extra pyramidal disorder (chorea), ataxia, cognitive defects, axonal sensory neuropathy, autonomic neuropathy, pseudo-obstruction; Optic atrophy 3 with cataract, 165300; 3-methylglutaconic aciduria, type III, 258501