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Hereditary neuropathy or pain disorder v7.36 CHRNA3 Dmitrijs Rots gene: CHRNA3 was added
gene: CHRNA3 was added to Hereditary neuropathy or pain disorder. Sources: Literature
Mode of inheritance for gene: CHRNA3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CHRNA3 were set to PMID: 33947782; 37161764
Phenotypes for gene: CHRNA3 were set to Familial Autonomic Ganglionopathy
Review for gene: CHRNA3 was set to GREEN
Added comment: 4 cases from 3 families are reported with biallelic LoF variants in the CHRNA3 causing familial dysautonomia:
PMID: 33947782;37161764
Sources: Literature
Hereditary neuropathy or pain disorder v7.36 SPTAN1 Arina Puzriakova Added comment: Comment on phenotypes: OMIM phenotypes accessed on 16-02-2026
Hereditary neuropathy or pain disorder v7.34 MORC2 Arina Puzriakova Added comment: Comment on phenotypes: OMIM phenotype accessed on 03-02-2026
Hereditary neuropathy or pain disorder v7.32 SPG7 Ida Ertmanska changed review comment from: Many homozygous and compound heterozygous cases reported in large spastic paraplegia cohorts, with variable symptom severity and age of onset (childhood to late adulthood).
Recurrent SPG7 variants:
SPG7: c.1529C>T, p.Ala510Val has MAF = 0.007265 in gnomAD v4.1.0 (European population), with 44 total homozygotes reported;
SPG7: c.1454_1462del, p.Arg485_Glu487del - highest frequency in gnomAD v4.1.0 = 0.0006758 (Finnish population), no homozygotes;
SPG7: c.233T>A, p.Leu78Ter - MAF = 0.002778 (South Asian population), 5 homozygotes reported.
SPG7: c.1045G>A, p.Gly349Ser -MAF = 0.002041 (European), 3 homozygotes in gnomAD.

PMID: 39978794 Jimoh et al., 2025 - Hungarian cohort - identified 25 biallelic and 33 monoallelic cases. The most common variant was p.Leu78Ter (N = 23), followed by p. Ala510Val (N = 21).

PMID: 34405107 Campins-Romeu et al., 2021 - Caucasian man with multifocal dystonia with prominent bulbar and cervical involvement; SPG7 c.1529C > T(p.Ala510Val) and c.1715C > T(p.Ala572Val) - confirmed in trans

PMID: 33598982 Estiar et al., 2021 - WES study of a Canadian cohort (585 HSP patients from 372 families and 1175 controls);
p.(Ala510Val) was found in 3.7% of index patients vs 0.8% controls. Identified 4 heterozygous SPG7 variant carriers with an additional pathogenic variant in known spasticity genes (BSCL2, TBCE, SPAST), as well as four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2).
FSP-04-053: Patient with spinocerebellar ataxia with AFG3L2: c.2114T>C, p.(Ile705Thr) and SPG7: c.376+1G>T.
FSP-01-190: Patient with spinocerebellar ataxia with CACNA1A:c.4981C>T, p.Arg1661Cys and SPG7: p.Ala510Val.
https://www.medrxiv.org/content/10.1101/2025.07.05.24312261v1 - 2025 preprint from the same group: Digenic inheritance of mutations in SPG7 and AFG3L2 causes motor neuron and cerebellar disorders


PMID: 31854126 Verdura et al., 2019 - 'A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases'
Patient with Hereditary spastic paraplegia, harbouring variants in SPG7: (c.2195T> C; p.Leu732Pro) - found by WES, and a deep intronic variant (c.286 + 853A>G) - variant activates a cryptic splice site; found by WGS. Western blot showed decreased SPG7 levels in patient's fibroblasts.

PMID: 31068484 Coarelli et al., 2019
241 spastic paraplegia cases with SPG7 variants. LoF variants correlate with spasticity-predominant phenotype. Patients with at least one p.Ala510Val variant showed a later onset and more frequent cerebellar ataxia.

PMID: 26506339 Thal et al., 2015 - Caucasian man with HSP with homozygous p.Ala510Val, affected sister also homozygous, heterozygous children unaffected. Method: WGS

PMID: 22964162 van Gassen et al., 2012 - Dutch cohort, 49 patients with homozygous or compound heterozygous SPG7 variants.

MONOALLELIC CASES:
PMID: 33774748 Bogdanova-Mihaylova et al., 2021
32 symptomatic individuals from 25 Irish families. 3 individuals reported to have heterozygous variants in SPG7; one of them subsequently found to have intronic repeat expansions in RFC1 (associated with Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome in OMIM). Heterozygous first-degree relatives of patients with recessive SPG7 variants were asymptomatic.

PMID: 32548275 Charif et al., 2020
Identified 7 new heterozygous SPG7 variants in cases with isolated optic atrophy. All patients with SPG7 presented optic disk pallor and accordingly, reduced retinal nerve fiber layer (RNFL), though visual impairment was mild in all patients. Method: targeted sequencing panel of 22 genes.

PMID: 24727571 Pfeffer et al., 2014: testing on 68 patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases.
3 relatives of compound heterozygous patients, harbouring heterozygote SPG7 mutations, had mild, late-onset cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower limbs.

Patient 25 - isolated index HSP case - heterozygous for SPG7: c.1457G>A, p.Arg486Gln - MAF in gnomAD v4 = 0.01031 (European population), 73 total homozygotes reported.

Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large family - variant not reported in gnomAD v4.1.0.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive MIM:607259 in OMIM (accessed 6th Jan 2026).; to: Many homozygous and compound heterozygous cases reported in large spastic paraplegia cohorts, with variable symptom severity and age of onset (childhood to late adulthood).
Recurrent SPG7 variants:
SPG7: c.1529C>T, p.Ala510Val has MAF = 0.007265 in gnomAD v4.1.0 (European population), with 44 total homozygotes reported;
SPG7: c.1454_1462del, p.Arg485_Glu487del - highest frequency in gnomAD v4.1.0 = 0.0006758 (Finnish population), no homozygotes;
SPG7: c.233T>A, p.Leu78Ter - MAF = 0.002778 (South Asian population), 5 homozygotes reported.
SPG7: c.1045G>A, p.Gly349Ser -MAF = 0.002041 (European), 3 homozygotes in gnomAD.

PMID: 39978794 Jimoh et al., 2025 - Hungarian cohort - identified 25 biallelic and 33 monoallelic cases. The most common variant was p.Leu78Ter (N = 23), followed by p. Ala510Val (N = 21).

PMID: 34405107 Campins-Romeu et al., 2021 - Caucasian man with multifocal dystonia with prominent bulbar and cervical involvement; SPG7 c.1529C > T(p.Ala510Val) and c.1715C > T(p.Ala572Val) - confirmed in trans

PMID: 33598982 Estiar et al., 2021 - WES study of a Canadian cohort (585 HSP patients from 372 families and 1175 controls);
p.(Ala510Val) was found in 3.7% of index patients vs 0.8% controls. Identified 4 heterozygous SPG7 variant carriers with an additional pathogenic variant in known spasticity genes (BSCL2, TBCE, SPAST), as well as four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2).
FSP-04-053: Patient with spinocerebellar ataxia with AFG3L2: c.2114T>C, p.(Ile705Thr) and SPG7: c.376+1G>T.
FSP-01-190: Patient with spinocerebellar ataxia with CACNA1A:c.4981C>T, p.Arg1661Cys and SPG7: p.Ala510Val.
https://www.medrxiv.org/content/10.1101/2025.07.05.24312261v1 - 2025 preprint from the same group: Digenic inheritance of mutations in SPG7 and AFG3L2 causes motor neuron and cerebellar disorders


PMID: 31854126 Verdura et al., 2019 - 'A deep intronic splice variant advises reexamination of presumably dominant SPG7 Cases'
Patient with Hereditary spastic paraplegia, harbouring variants in SPG7: (c.2195T> C; p.Leu732Pro) - found by WES, and a deep intronic variant (c.286 + 853A>G) - variant activates a cryptic splice site; found by WGS. Western blot showed decreased SPG7 levels in patient's fibroblasts.

PMID: 31068484 Coarelli et al., 2019
241 spastic paraplegia cases with SPG7 variants. LoF variants correlate with spasticity-predominant phenotype. Patients with at least one p.Ala510Val variant showed a later onset and more frequent cerebellar ataxia.

PMID: 26506339 Thal et al., 2015 - Caucasian man with HSP with homozygous p.Ala510Val, affected sister also homozygous, heterozygous children unaffected. Method: WGS

PMID: 22964162 van Gassen et al., 2012 - Dutch cohort, 49 patients with homozygous or compound heterozygous SPG7 variants.

MONOALLELIC CASES:
PMID: 33774748 Bogdanova-Mihaylova et al., 2021
32 symptomatic individuals from 25 Irish families. 3 individuals reported to have heterozygous variants in SPG7; one of them subsequently found to have intronic repeat expansions in RFC1 (associated with Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome in OMIM). Heterozygous first-degree relatives of patients with recessive SPG7 variants were asymptomatic.

PMID: 32548275 Charif et al., 2020
Identified 7 new heterozygous SPG7 variants in cases with isolated optic atrophy. All patients with SPG7 presented optic disk pallor and accordingly, reduced retinal nerve fiber layer (RNFL), though visual impairment was mild in all patients. Method: targeted sequencing panel of 22 genes.

PMID: 24727571 Pfeffer et al., 2014: testing on 68 patients with Progressive external ophthalmoplegia (PEO), discovered 9 patients with compound heterozygous and 6 with heterozygous variants in SPG7. Of the 6 heterozygotes, 4/6 had PEO, 4/6 had ataxia and/or spasticity, 1/6 noted to have cerebellar atrophy. 3/6 patients were heterozygous for p.Ala510Val, with variable severity and age of onset (4-60 years old). Method: WES.

PMID: 23065789 Klebe et al., 2012
Screened 135 unrelated index cases. Seq method: AFG3L2 and SPG7 sequencing only. p.Ala510Val was the most commonly detected SPG7 mutation (65%). Mostly biallelic HSP cases.
3 relatives of compound heterozygous patients, harbouring heterozygote SPG7 mutations, had mild, late-onset cerebellar signs and atrophy, or peripheral neuropathy, but no spasticity of the lower limbs.

Patient 25 - isolated index HSP case - heterozygous for SPG7: c.1457G>A, p.Arg486Gln - MAF in gnomAD v4 = 0.01031 (European population), 73 total homozygotes reported.

Novel missense SPG7 mutation at the heterozygous state (SPG7:c.1232A>C, p.Asp411Ala) was identified as the cause of isolated autosomal dominant optic neuropathy in a large family - variant not reported in gnomAD v4.1.0.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive, OMIM:607259 (accessed 8th Jan 2026). Entry for Spastic paraplegia 7 in GeneReviews (https://www.ncbi.nlm.nih.gov/books/NBK1107/) mentions that the possibility of autosomal dominant inheritance remains controversial. SPG7 link to SPG7-related spastic paraplegia (biallelic_autosomal) is classified as definitive on the Gene2Phenotype Eye disorders panel.
Hereditary neuropathy or pain disorder v7.32 SPG7 Ida Ertmanska commented on gene: SPG7: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126), as well as possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Heterozygous carriers of SPG7 variants in recessive pedigrees are usually unaffected. Based on available evidence, the mode of inheritance for SPG7 should be changed to BIALLELIC, autosomal or pseudoautosomal.
Hereditary neuropathy or pain disorder v7.29 KIF21A Ida Ertmanska commented on gene: KIF21A: Comment on list classification: There are 3 unrelated individuals with progressive peripheral neuropathy reported with de novo heterozygous missense variants localised in the second coiled‑coil domain of KIF21A. Variants in other KIF21A domains are not known to cause neuropathy. Based on available evidence, KIF21A should be promoted to Green for Hereditary neuropathy or pain disorder.
Hereditary neuropathy or pain disorder v7.29 KIF21A Alexander Rossor gene: KIF21A was added
gene: KIF21A was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: KIF21A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KIF21A were set to 39643435; 41282472
Phenotypes for gene: KIF21A were set to CFEOM; agenesis of the corpus callosum; peripheral neuropathy
Penetrance for gene: KIF21A were set to Complete
Mode of pathogenicity for gene: KIF21A 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: KIF21A was set to AMBER
Added comment: Currently only two unrelated individuals reported with peripheral neuropathy
Sources: Expert list
Hereditary neuropathy or pain disorder v7.29 CPOX Ida Ertmanska edited their review of gene: CPOX: Added comment: Comment on mode of inheritance: As reviewed by Sharon Whatley, variants in CPOX may cause autosomal dominant or autosomal recessive porphyria. Monoallelic variants in CPOX have very low clinical penetrance (<1%) and may be challenging to report as diagnostic. Hence, BIALLELIC, autosomal or pseudoautosomal MOI would be more appropriate. This gene has been tagged for MOI Expert Review. CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 20th Oct 2025).; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v7.29 ARHGAP19 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Alexander Rossor, there are multiple unrelated families reported with biallelic ARHGAP19 variants and with motor-predominant neuropathy. Hence, this gene should be promoted to green rating in the next GMS update.
Hereditary neuropathy or pain disorder v7.27 PNPT1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype last accessed on 27 October 2025.
Hereditary neuropathy or pain disorder v7.25 ARHGAP19 Alexander Rossor gene: ARHGAP19 was added
gene: ARHGAP19 was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: ARHGAP19 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ARHGAP19 were set to 41086021
Phenotypes for gene: ARHGAP19 were set to motor axonal neuropathy
Penetrance for gene: ARHGAP19 were set to Complete
Review for gene: ARHGAP19 was set to GREEN
Added comment: multiple affected families
Sources: Expert list
Hereditary neuropathy or pain disorder v7.25 PNPT1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are three additional families reported with Spinocerebellar Ataxia 25 phenotype including polyneuropathy and are identified with monoallellic PNPT1 variants. Although there was incomplete penetrance observed in previously reported cases, the evidence from these recently reported families suggests that this gene can remain green on this panel.; to: Comment on list classification: There are three additional families reported with Spinocerebellar Ataxia 25 including polyneuropathy as part of the phenotype, and they are identified with monoallellic PNPT1 variants. Although there was incomplete penetrance observed in previously reported cases, the evidence from these recently reported families suggests that this gene can remain green on this panel.
Hereditary neuropathy or pain disorder v7.25 PNPT1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are three additional families reported with Spinocerebellar Ataxia 25 phenotype including polyneuropathy and are identified with monoallellic PNPT1 variants. Although there was incomplete penetrance observed in previously reported cases, the evidence from these recently reported families suggests that this gene can remain green on this panel..; to: Comment on list classification: There are three additional families reported with Spinocerebellar Ataxia 25 phenotype including polyneuropathy and are identified with monoallellic PNPT1 variants. Although there was incomplete penetrance observed in previously reported cases, the evidence from these recently reported families suggests that this gene can remain green on this panel.
Hereditary neuropathy or pain disorder v7.25 PNPT1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are three additional families reported with Spinocerebellar Ataxia 25 phenotype including polyneuropathy and are identified with monoallellic PNPT1 variants. Although there was incomplete penetrance observed in previously reported cases, all these recently families do not show any evidence of incompletely penetrance.; to: Comment on list classification: There are three additional families reported with Spinocerebellar Ataxia 25 phenotype including polyneuropathy and are identified with monoallellic PNPT1 variants. Although there was incomplete penetrance observed in previously reported cases, the evidence from these recently reported families suggests that this gene can remain green on this panel..
Hereditary neuropathy or pain disorder v7.25 PNPT1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three additional families reported with Spinocerebellar Ataxia 25 phenotype including polyneuropathy and are identified with monoallellic PNPT1 variants. Although there was incomplete penetrance observed in previously reported cases, all these recently families do not show any evidence of incompletely penetrance.
Hereditary neuropathy or pain disorder v7.24 PNPT1 Achchuthan Shanmugasundram edited their review of gene: PNPT1: Added comment: There are additional cases reported recently:

PMID:39899068 (2025) reported a 1-year-8-month-old female proband of Brazilian descent with Spinocerebellar Ataxia 25 that presented with progressive ataxia, cerebellar atrophy, and sensory neuropathy. She was identified with a novel heterozygous truncating variant in PNPT1 (c.2068del), which she inherited from her father. Although the father was previously reported as asymptomatic, he was affected with axonal and demyelinating polyneuropathy but not ataxia upon detailed examination.

PMID:39924761 (2025) reported two unrelated families, where all individuals presented with sensory ataxic neuropathy (SAN), while some individuals developed cerebellar signs. Analysis of WGS variant data through the 100,000 Genomes Project identified two different heterozygous variants in these families. Family 1 underwent a 'quad' study and the previously reported c.2014‐3C>G variant segregated in all affected family members and was absent in all unaffected family members. Sanger sequencing confirmed segregation in two other individuals. c.2014‐3C>G is the same variant that was found in the 3-generation Australian family reported by PMID:35411967, where unaffected family members harboured the variant. A novel nonsense variant (c.2143C>T/ p.Arg715Ter) was found in both affected members of Family 2.; Changed publications to: 14705117, 35411967, 37935417, 39899068, 39924761
Hereditary neuropathy or pain disorder v7.24 PTRH2 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 24 October 2025.
Hereditary neuropathy or pain disorder v7.23 TDP1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are at least three different variants reported (two published variants including the founder-variant from the Middle East) in five unrelated families including the Sheffield case. There is also sufficient functional evidence available in support of the p.His493Arg founder variant. Hence, this gene can be promoted to green rating in the next GMS update.
Hereditary neuropathy or pain disorder v7.22 TDP1 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM accessed 24 October 2025.
Hereditary neuropathy or pain disorder v7.21 TDP1 Achchuthan Shanmugasundram changed review comment from: As reviewed before, PMID:31182267 reported three unrelated probands (two Omani families and one Saudi Arabian family) with homozygous missense variant in TDP1 gene - p.His493Arg, which has been confirmed by haplotype analysis as a founder variant. However, the allele count for this variant in gnomAD v4.1.0 is 13 and it is not found in homozygous state in any of those individuals. In addition, there is also function evidence available that showed that cells expressing TDP1 gene with H493R variant promotes mitochondrial dysfunction and mitophagy.

PMID:39576382 reported a female patient from a Pakistani family with autosomal recessive spinocerebellar ataxia with axonal neuropathy type 1, who presented with additional clinical features including congenital onset of disease, This patient was identified with novel missense variant in TDP1 - p.His478Tyr. via WES and autosomal recessive segregation was confirmed by Sanger sequencing. The allele count for this variant in gnomAD v4.1.0 is 10, of which eight were from South Asian ancestry - however, it is absent in homozygous state in the database.

As reviewed by Ian Berry and Lauren Turton, there is an additional case reported in with p.His493Arg variant and a likely LoF splicing variant, who had early adulthood onset progressive ataxia and axonal neuropathy.; to: As reviewed before, PMID:31182267 reported three unrelated probands (two Omani families and one Saudi Arabian family) with homozygous missense variant in TDP1 gene - p.His493Arg, which has been confirmed by haplotype analysis as a founder variant. However, the allele count for this variant in gnomAD v4.1.0 is 13 and it is not found in homozygous state in any of those individuals. In addition, there is also functional evidence available that showed that cells expressing TDP1 gene with H493R variant promotes mitochondrial dysfunction and mitophagy.

PMID:39576382 reported a female patient from a Pakistani family with autosomal recessive spinocerebellar ataxia with axonal neuropathy type 1, who presented with additional clinical features including congenital onset of disease. This patient was identified with a novel missense variant in TDP1 (p.His478Tyr) via WES, and autosomal recessive segregation was confirmed by Sanger sequencing. The allele count for this variant in gnomAD v4.1.0 is 10, of which eight were from South Asian ancestry - however, it is absent in homozygous state in the database.

As reviewed by Ian Berry and Lauren Turton, there is an additional case reported in with p.His493Arg variant and a likely LoF splicing variant, who had early adulthood onset progressive ataxia and axonal neuropathy.
Hereditary neuropathy or pain disorder v7.20 CPOX Ida Ertmanska changed review comment from: Comment on list classification: Both mono- and bi- allelic variants in CPOX are known to cause hereditary coproporphyria (HCP), which may sometimes result in severe abdominal pain and progressive peripheral neuropathy. However, specific neuropathy cases are rarely reported with a genetic diagnosis - biochemical tests are a much more common diagnostic route. Since CPOX is the only gene known to cause Coproporphyria, this gene may remain Green for Hereditary neuropathy or pain disorder.; to: Comment on list classification: Both mono- and bi- allelic variants in CPOX are known to cause hereditary coproporphyria (HCP), which may result in severe abdominal pain and progressive peripheral neuropathy. However, specific neuropathy cases are rarely reported with a genetic diagnosis - only 1 individual with peripheral neuropathy and a heterozygous CPOX variant is included in this review (PMID: 35228944 Upchurch et al., 2025). Biochemical testing of faecal coproporphyrin is a much more common diagnostic route. Since CPOX is the only gene known to cause Coproporphyria, this gene may remain Green for Hereditary neuropathy or pain disorder.
Hereditary neuropathy or pain disorder v7.20 CPOX Ida Ertmanska changed review comment from: HCP patients may present with acute neurovisceral attacks, characterised by severe abdominal pain and neuropsychiatric symptoms - often provoked by drugs, alcohol, or endocrine factors. Diagnosis of HCP is established based on increased faecal coproporphyrin III:I ratio when VP has been excluded by the plasma fluorescence scan wavelength (PMID: 11309681 Lamoril et al., 2001; 38940544 Aarsand et al., 2022). Acute episodes can progress to include seizures, peripheral motor neuropathy and posterior reversible encephalopathy syndrome if left untreated (PMID: 35584894 Schulenburg-Brand et al., 2022)

PMID: 11074238 Kuhnel et al., 2000
53 patients with HCP. Phenotype: abdominal pain (89% of the cohort), neurologic (33%), psychiatric (28%), cardiovascular (25%), and skin symptoms (14%).

PMID: 21103937 Hasanoglu 2011
Male infant from a Turkish consanguineous family presented with the Harderoporphyria phenotype: neonatal hyperbilirubinemia, hemolytic anemia, hepatosplenomegaly, and skin lesions when exposed to UV light. Heterozygous for c.980A>G (p.His327Arg) The patient died at 5 months old due to an apparent acute neurologic porphyric attack. Structural studies predicted that p.H327R interacts with residue W399 in the CPOX active site.

CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 21st Oct 2025).; to: HCP patients may present with acute neurovisceral attacks, characterised by severe abdominal pain and neuropsychiatric symptoms - often provoked by drugs, alcohol, or endocrine factors. Diagnosis of HCP is established based on increased faecal coproporphyrin III:I ratio when VP has been excluded by the plasma fluorescence scan wavelength (PMID: 11309681 Lamoril et al., 2001; 38940544 Aarsand et al., 2022). Acute episodes can progress to include seizures, peripheral motor neuropathy and posterior reversible encephalopathy syndrome if left untreated (PMID: 35584894 Schulenburg-Brand et al., 2022)

PMID: 8008008 Barohn et al. 1994
A 23-year-old man with no genetic diagnosis. Presented with epilepsy and a past history of abdominal pain. Electrophysiologic studies demonstrated a peripheral neuropathy with features of axonal degeneration and demyelination.

PMID: 11074238 Kuhnel et al., 2000
53 patients with HCP. Phenotype: abdominal pain (89% of the cohort), neurologic (33%), psychiatric (28%), cardiovascular (25%), and skin symptoms (14%).

PMID: 21103937 Hasanoglu 2011
Male infant from a Turkish consanguineous family presented with the Harderoporphyria phenotype: neonatal hyperbilirubinemia, hemolytic anemia, hepatosplenomegaly, and skin lesions when exposed to UV light. Heterozygous for c.980A>G (p.His327Arg) The patient died at 5 months old due to an apparent acute neurologic porphyric attack. Structural studies predicted that p.H327R interacts with residue W399 in the CPOX active site.

PMID: 24353603 Chen et al., 2013
46yo Chinese woman with a biochemical diagnosis of HCP. Phenotype: acute abdominal pain and progressive bilateral weakness and pain in the limbs. She also experienced significant muscle atrophy and decreased strength. Nerve conduction potential study revealed motor-sensory polyneuropathy. Successfully treated with hemin.

PMID: 24156084 Jiménez-Jiménez et al., 2013
44-year-old patient presenting clinically with acute ataxia who was diagnosed with HCP. Heterozygous for p.Q306X.

PMID: 35228944 Upchurch et al., 2025
26-year-old female with HCP who presented with acute ascending flaccid paralysis and respiratory failure after COVID-19 infection and was initially misdiagnosed and treated for Guillain-Barré syndrome. Patient developed progressively worsening abdominal pain; symmetric, distal-predominant, and ascending weakness developed four weeks later, associated with severe headaches and complex visual hallucinosis. Electrodiagnostic testing: profound axonal sensorimotor peripheral polyneuropathy affecting all extremities. No abnormalities on brain MRI. Successfully treated with hemin. Heterozygous for c.1070G>A (p.Cys357Tyr) - rare in gnomAD v4, Revel score = 0.9. Seq method: unknown.

CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 21st Oct 2025).
Hereditary neuropathy or pain disorder v7.20 CPOX Ida Ertmanska changed review comment from: Comment on list classification: Both mono- and bi- allelic variants in CPOX are known to cause hereditary coproporphyria, which may sometimes result in severe abdominal pain and progressive peripheral neuropathy. However, specific neuropathy cases are rarely reported with a genetic diagnosis - biochemical tests are a much more common diagnostic route. Since CPOX is the only gene known to cause Coproporphyria, this gene may remain Green for Hereditary neuropathy or pain disorder.; to: Comment on list classification: Both mono- and bi- allelic variants in CPOX are known to cause hereditary coproporphyria (HCP), which may sometimes result in severe abdominal pain and progressive peripheral neuropathy. However, specific neuropathy cases are rarely reported with a genetic diagnosis - biochemical tests are a much more common diagnostic route. Since CPOX is the only gene known to cause Coproporphyria, this gene may remain Green for Hereditary neuropathy or pain disorder.
Hereditary neuropathy or pain disorder v7.20 CPOX Ida Ertmanska changed review comment from: Comment on list classification: Both mono- and bi- allelic variants in CPOX are known to cause hereditary coproporphyria, which may sometimes result in severe abdominal pain and progressive peripheral neuropathy. However, specific neuropathy cases are not reported with a genetic diagnosis - biochemical tests are a much more common diagnostic route. Since CPOX is the only gene known to cause Coproporphyria, this gene may remain Green for Hereditary neuropathy or pain disorder.; to: Comment on list classification: Both mono- and bi- allelic variants in CPOX are known to cause hereditary coproporphyria, which may sometimes result in severe abdominal pain and progressive peripheral neuropathy. However, specific neuropathy cases are rarely reported with a genetic diagnosis - biochemical tests are a much more common diagnostic route. Since CPOX is the only gene known to cause Coproporphyria, this gene may remain Green for Hereditary neuropathy or pain disorder.
Hereditary neuropathy or pain disorder v7.20 CPOX Ida Ertmanska changed review comment from: HCP patients may present with acute neurovisceral attacks, characterised by severe abdominal pain and neuropsychiatric symptoms - often provoked by drugs, alcohol, or endocrine factors. Diagnosis of HCP is established based on increased faecal coproporphyrin III:I ratio when VP has been excluded by the plasma fluorescence scan wavelength (PMID: 11309681 Lamoril et al., 2001; 38940544 Aarsand et al., 2022). Acute episodes can progress to include seizures, peripheral motor neuropathy and posterior reversible encephalopathy syndrome if left untreated (PMID: 35584894 Schulenburg-Brand et al., 2022)

PMID: 11074238 Kuhnel et al., 2000
53 patients with HCP. Phenotype: abdominal pain (89% of the cohort), neurologic (33%), psychiatric (28%), cardiovascular (25%), and skin symptoms (14%).

CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 21st Oct 2025).; to: HCP patients may present with acute neurovisceral attacks, characterised by severe abdominal pain and neuropsychiatric symptoms - often provoked by drugs, alcohol, or endocrine factors. Diagnosis of HCP is established based on increased faecal coproporphyrin III:I ratio when VP has been excluded by the plasma fluorescence scan wavelength (PMID: 11309681 Lamoril et al., 2001; 38940544 Aarsand et al., 2022). Acute episodes can progress to include seizures, peripheral motor neuropathy and posterior reversible encephalopathy syndrome if left untreated (PMID: 35584894 Schulenburg-Brand et al., 2022)

PMID: 11074238 Kuhnel et al., 2000
53 patients with HCP. Phenotype: abdominal pain (89% of the cohort), neurologic (33%), psychiatric (28%), cardiovascular (25%), and skin symptoms (14%).

PMID: 21103937 Hasanoglu 2011
Male infant from a Turkish consanguineous family presented with the Harderoporphyria phenotype: neonatal hyperbilirubinemia, hemolytic anemia, hepatosplenomegaly, and skin lesions when exposed to UV light. Heterozygous for c.980A>G (p.His327Arg) The patient died at 5 months old due to an apparent acute neurologic porphyric attack. Structural studies predicted that p.H327R interacts with residue W399 in the CPOX active site.

CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 21st Oct 2025).
Hereditary neuropathy or pain disorder v7.20 CPOX Ida Ertmanska commented on gene: CPOX: Comment on list classification: Both mono- and bi- allelic variants in CPOX are known to cause hereditary coproporphyria, which may sometimes result in severe abdominal pain and progressive peripheral neuropathy. However, specific neuropathy cases are not reported with a genetic diagnosis - biochemical tests are a much more common diagnostic route. Since CPOX is the only gene known to cause Coproporphyria, this gene may remain Green for Hereditary neuropathy or pain disorder.
Hereditary neuropathy or pain disorder v7.20 PPOX Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotype accessed on 13 October 2025.
Hereditary neuropathy or pain disorder v7.18 PPOX Ida Ertmanska changed review comment from: Comment on mode of inheritance: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with disease onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms - including neuropathy. As reported by previous reviewers, 3 individuals with biallelic variants in PPOX presented with sensory neuropathy (PMID: 11286631 Kauppinen, 10870850 Corrigall, 8290408 Hift). Hence, the mode of inheritance should be set to 'BIALLELIC, autosomal or pseudoautosomal' for Hereditary neuropathy or pain disorder.; to: Comment on mode of inheritance: Monoallelic PPOX variants usually result in Variegate Porphyria limited to cutaneous manifestations, with disease onset in adolescence or adulthood. Biallelic variants are known to cause Variegate Porphyria with a more severe, early-onset phenotype - skin lesions, along with neurologic and/ or neurodevelopmental symptoms - including neuropathy. As reported by previous reviewers, 3 individuals with biallelic variants in PPOX presented with sensory neuropathy (PMID: 11286631 Kauppinen, 10870850 Corrigall, 8290408 Hift). Hence, the mode of inheritance should be set to 'BIALLELIC, autosomal or pseudoautosomal' for Hereditary neuropathy or pain disorder.
Hereditary neuropathy or pain disorder v7.14 XPNPEP3 Arina Puzriakova Added comment: Comment on list classification: Biallelic variants in this gene are associated with nephronophthisis, a progressive cystic kidney disorder that leads to end-stage renal disease (OMIM:613159). Extra-renal manifestations have only been reported in a subset of cases - neurological features have been reported in at least 4 unrelated families including tremor, dystonia, rhabdomyolysis, peripheral neuropathy, sensorineural hearing loss, epilepsy and cardiomyopathy. Kidney disease was present in all (PMID: 20179356; 38035175), except one case (PMID: 40953058).

In the literature, there are 2 cases with peripheral neuropathy and biallelic variants in this gene (PMID: 38035175; 40953058), however, this is not a common manifestation for this gene. One case did not have any typical renal features and therefore it's worth monitoring for similar reports. In the meantime rating as Amber awaiting further corroborating cases.
Hereditary neuropathy or pain disorder v7.13 TDP1 Achchuthan Shanmugasundram edited their review of gene: TDP1: Added comment: As reviewed before, PMID:31182267 reported three unrelated probands (two Omani families and one Saudi Arabian family) with homozygous missense variant in TDP1 gene - p.His493Arg, which has been confirmed by haplotype analysis as a founder variant. However, the allele count for this variant in gnomAD v4.1.0 is 13 and it is not found in homozygous state in any of those individuals. In addition, there is also function evidence available that showed that cells expressing TDP1 gene with H493R variant promotes mitochondrial dysfunction and mitophagy.

PMID:39576382 reported a female patient from a Pakistani family with autosomal recessive spinocerebellar ataxia with axonal neuropathy type 1, who presented with additional clinical features including congenital onset of disease, This patient was identified with novel missense variant in TDP1 - p.His478Tyr. via WES and autosomal recessive segregation was confirmed by Sanger sequencing. The allele count for this variant in gnomAD v4.1.0 is 10, of which eight were from South Asian ancestry - however, it is absent in homozygous state in the database.

As reviewed by Ian Berry and Lauren Turton, there is an additional case reported in with p.His493Arg variant and a likely LoF splicing variant, who had early adulthood onset progressive ataxia and axonal neuropathy.; Changed rating: GREEN; Changed publications to: 12244316, 15920477, 17948061, 31182267, 31723605, 39576382; Changed phenotypes to: ?Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1, OMIM:607250, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1, MONDO:0011801
Hereditary neuropathy or pain disorder v7.12 DLD Arina Puzriakova Added comment: Comment on list classification: Several cases reported with Dihydrolipoamide dehydrogenase deficiency (OMIM:246900) but only a single report linking this to a reversible sensory neuropathy (PMID:40888368). It is worth noting that neuropathy occurred without lactic acidosis or secondary vitamin deficiencies, coupled with lipid deposition in peripheral nerve biopsies. This requires validation through additional corroborative cases and therefore rating as Red until such cases emerge.
Hereditary neuropathy or pain disorder v7.11 TTC19 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Alexander Rossor, there are three unrelated patents reported with biallelic TTC19 variants and motor neuropathy. Hence, this gene can be promoted to green rating in the next GMS update.
Hereditary neuropathy or pain disorder v7.10 TTC19 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has been associated with relevant phenotype in both OMIM (MIM #615157, OMIM accessed on 30 September 2025) and Gene2Phenotype (with 'definitive' rating on the DD panel).
Hereditary neuropathy or pain disorder v7.8 TTC19 Alexander Rossor gene: TTC19 was added
gene: TTC19 was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: TTC19 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TTC19 were set to 40946707; 37927170; 25652355
Phenotypes for gene: TTC19 were set to Ataxia; apraxia; dystonia; dysarthria; necrotic brain lesions; motor axonal neuropathy
Penetrance for gene: TTC19 were set to Complete
Review for gene: TTC19 was set to GREEN
Added comment: Evidence of motor axonal neuropathy in 3 unrelated individuals.
Sources: Expert list
Hereditary neuropathy or pain disorder v7.8 XPNPEP3 Alexander Rossor gene: XPNPEP3 was added
gene: XPNPEP3 was added to Hereditary neuropathy or pain disorder. Sources: Other
Mode of inheritance for gene: XPNPEP3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: XPNPEP3 were set to 40953058
Phenotypes for gene: XPNPEP3 were set to Nephronopthisis; brain white matter lesions; sensory axonal neuropathy; recurrent rhabdomyolysis; cardiomyopathy; ataxia; hearing loss
Penetrance for gene: XPNPEP3 were set to Complete
Review for gene: XPNPEP3 was set to AMBER
Added comment: Currently sensory axonal neuropathy only reported in a single case.
Sources: Other
Hereditary neuropathy or pain disorder v7.8 DLD Alexander Rossor gene: DLD was added
gene: DLD was added to Hereditary neuropathy or pain disorder. Sources: Other
Mode of inheritance for gene: DLD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DLD were set to 40888368
Phenotypes for gene: DLD were set to hepatic dysfunction; sensory axonal neuropathy
Penetrance for gene: DLD were set to Complete
Review for gene: DLD was set to AMBER
Added comment: Single case reporting sensory axonal neuropathy therefore should be amber for now
Sources: Other
Hereditary neuropathy or pain disorder v7.8 CPOX Sharon Whatley changed review comment from: Relevant metabolic investigation: Urine porphobilinogen

PMID: 38940544 Aarsand reports that the acute porphyrias are a group of rare inborn errors of metabolism caused by abnormal functioning of haem biosynthesis enzymes and are associated with acute neurovisceral attacks characterized by severe abdominal pain and neuropsychiatric symptoms that may require highly specialized intensive care. The acute porphyrias, acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria (HCP), usually become symptomatic in early adulthood.

PMID: 11309681 Lamoril reports that HCP is the least common of the autosomal dominant, acute hepatic porphyrias. It results from pathogenic variants in the CPOX gene that encodes the mitochondrial enzyme, coproporphyrinogen oxidase.

PMID: 38940544 Aarsand and 23605133 Whatley report that HCP is an autosomal dominant disorder with an estimated prevalence of HCP in the UK as 1–2 in a million with a rough estimate of the clinical penetrance of 0.4%. Due to this low penetrance, genetic testing alone may be misleading and cause misdiagnosis. IPNET advises that biochemical testing is used to diagnose active HCP as the penetrance is so low.
PMID: 35584894 Schulenburg-Brand reviews the neuropathy that may occur in the acute porphyrias. Weakness and altered sensation are typically mild in an acute attack and improve as the pain resolves. In a small number of cases, severe, progressive peripheral neuropathy develops. Neuropathy can worsen, even after the acute pain resolves, with a Guillain-Barré like picture. Proximal muscle weakness occurs in the upper limbs and can progress to involve the legs and cause respiratory failure. Cranial nerves can be involved, with the facial, vagus and hypoglossal nerves most often affected, causing swallowing difficulties. Sensory neuropathy is less common, but can cause numbness over the torso and thighs, sometimes with severe pain. Cases gradually resolve with respiratory support, and some patients may need prolonged mechanical ventilation. After recovery, some degree of peripheral neuropathy can persist, with foot drop and wrist drop being fairly typical.

Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the CPOX gene, due to its low clinical penetrance (~0.4%).; to: Relevant metabolic investigation: Urine porphobilinogen

PMID: 38940544 Aarsand reports that the acute porphyrias are a group of rare inborn errors of metabolism caused by abnormal functioning of haem biosynthesis enzymes and are associated with acute neurovisceral attacks characterized by severe abdominal pain and neuropsychiatric symptoms that may require highly specialized intensive care. The acute porphyrias, acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria (HCP), usually become symptomatic in early adulthood.

PMID: 11309681 Lamoril reports that HCP is the least common of the autosomal dominant, acute hepatic porphyrias. It results from pathogenic variants in the CPOX gene that encodes the mitochondrial enzyme, coproporphyrinogen oxidase.

PMID: 38940544 Aarsand and 23605133 Whatley report that HCP is an autosomal dominant disorder with an estimated prevalence of HCP in the UK as 1–2 in a million with a rough estimate of the clinical penetrance of 0.4%. Due to this low penetrance, genetic testing alone may be misleading and cause misdiagnosis. IPNET advises that biochemical testing is used to diagnose active HCP as the penetrance is so low.

PMID: 35584894 Schulenburg-Brand reviews the neuropathy that may occur in the acute porphyrias. Weakness and altered sensation are typically mild in an acute attack and improve as the pain resolves. In a small number of cases, severe, progressive peripheral neuropathy develops. Neuropathy can worsen, even after the acute pain resolves, with a Guillain-Barré like picture. Proximal muscle weakness occurs in the upper limbs and can progress to involve the legs and cause respiratory failure. Cranial nerves can be involved, with the facial, vagus and hypoglossal nerves most often affected, causing swallowing difficulties. Sensory neuropathy is less common, but can cause numbness over the torso and thighs, sometimes with severe pain. Cases gradually resolve with respiratory support, and some patients may need prolonged mechanical ventilation. After recovery, some degree of peripheral neuropathy can persist, with foot drop and wrist drop being fairly typical.

Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the CPOX gene, due to its low clinical penetrance (~0.4%).
Hereditary neuropathy or pain disorder v7.8 COX18 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (four unrelated families and functional studies) for the association of biallelic COX18 variants with Charcot-Marie-Tooth disease. Hence, this gene can be promoted to green rating in the next GMS update.
Hereditary neuropathy or pain disorder v7.5 COX18 Alexander Rossor gene: COX18 was added
gene: COX18 was added to Hereditary neuropathy or pain disorder. Sources: Literature
Mode of inheritance for gene: COX18 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COX18 were set to 40830826
Phenotypes for gene: COX18 were set to peripheral neuropathy
Penetrance for gene: COX18 were set to Complete
Review for gene: COX18 was set to GREEN
Added comment: 8 individuals from 3 families
Sources: Literature
Hereditary neuropathy or pain disorder v7.3 RCC1 Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - number of cases with the same phenotype and functional support.

At least 12 unrelated families reported (PMID: 40683276) with biallelic variants in this gene associated with severe, acute-onset axonal neuropathy following infection. Eight different missense variants were identified. In vitro studies indicate that variants reduced the thermal stability of the RCC1 protein and some variants decreased GDP-to-GTP exchange activity. Patient fibroblasts under stress, revealed defects in Ran nuclear localisation and impaired nucleocytoplasmic transport. A Drosophila model demonstrated that altered Rcc1 function leads to fatal intolerance to oxidative stress.
Hereditary neuropathy or pain disorder v6.168 HMBS Sarah Leigh edited their review of gene: HMBS: Added comment: Based on review from Sharon Whatley (International Porphyria Network), the mode of inheritance of HMBS should be changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal on this panel - Hereditary neuropathy or pain disorder.; Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v6.168 HMBS Sarah Leigh Added comment: Comment on publications: Publications suggested by Sharon Whatley (International Porphyria Network): 27539938; 38940544; 35584894; 14262853; 1577472; 15534187; 31153822; 14970743; 34089223; 27558376
Hereditary neuropathy or pain disorder v6.167 RCC1 Lauren Turton gene: RCC1 was added
gene: RCC1 was added to Hereditary neuropathy or pain disorder. Sources: NHS GMS
Mode of inheritance for gene: RCC1 was set to BIALLELIC, autosomal or pseudoautosomal
Review for gene: RCC1 was set to AMBER
Added comment: Present in medrxiv, https://www.medrxiv.org/content/10.1101/2024.10.04.24314535v1. As not formally published left as amber rating.
24 individuals from 12 families with acute onset axonal neuropathy. Very severe disease in acutely unwell children. Neurological presentation was secondary to infection.
Sources: NHS GMS
Hereditary neuropathy or pain disorder v6.166 RFC1_AAGGG Sarah Leigh edited their review of STR: RFC1_AAGGG: Added comment: Pathogenicity at the RFC1_AAGGG repeat locus can result from the biallelic replacement of the benign AAAAG repeat with a variable number of AAGGG repeats (PMID: 30926972; 32040566). Furthermore, biallelic expansions of (AAAAG)exp/(AAAGG)exp, (AAAAG)exp/(AAGGG)exp or (AAAGG)exp/(AAGGG)exp were not pathogenic, therefore, it is the biallelic expansions of AAGGG that is pathogenic (PMID: 30926972). An additional pathogenic biallelic expansion :RFC1_ACAGG, was seen in was seen in two Asia-Pacific CANVAS families and a Japanese case (PMID: 33103729, 35355059).; Changed publications to: 30926972, 35883251, 36250766, 36289003, 36524104, 36478048, 32040566, 33103729, 35355059
Hereditary neuropathy or pain disorder v6.166 RFC1_AAGGG Sarah Leigh STR: RFC1_AAGGG was added
STR: RFC1_AAGGG was added to Hereditary neuropathy or pain disorder. Sources: Literature
STR, NGS Not Validated tags were added to STR: RFC1_AAGGG.
Mode of inheritance for STR: RFC1_AAGGG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for STR: RFC1_AAGGG were set to 30926972; 35883251; 36250766; 36289003; 36524104; 36478048
Phenotypes for STR: RFC1_AAGGG were set to Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome, OMIM: 614575
Review for STR: RFC1_AAGGG was set to GREEN
Added comment: RFC1 transcribed from the reverse strand, which means that the repeated sequence is the reverse compliment of the forward strand sequence.

RFC1_AAGGG is on https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r4

RFC1_AAGGG is on https://stripy.org/database

RFC1_AARRG is on DRAGON 4.02.

The coordinates of the sequence repeats shown above were obtained from DRAGON 4.02 and https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r4
The coordinates of the sequence repeats from https://stripy.org/database were 4:39348424-39348485 (hg38)
The non-pathogenic and pathogenic ranges of the sequence repeats shown above were obtained from: https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r4
And https://stripy.org/database

There is enough evidence for this STR to be green on this panel.

This STR has not been approved by NHS STR working group and is not NGS Not Validated
Sources: Literature
Hereditary neuropathy or pain disorder v6.165 VWA1_GGCGCGGAGC Sarah Leigh STR: VWA1_GGCGCGGAGC was added
STR: VWA1_GGCGCGGAGC was added to Hereditary neuropathy or pain disorder. Sources: Literature
NGS Not Validated tags were added to STR: VWA1_GGCGCGGAGC.
Mode of inheritance for STR: VWA1_GGCGCGGAGC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for STR: VWA1_GGCGCGGAGC were set to 33559681
Phenotypes for STR: VWA1_GGCGCGGAGC were set to Neuronopathy, distal hereditary motor, autosomal recessive 7, OMIM:619216; neuronopathy, distal hereditary motor, autosomal recessive 7, MONDO:0030977
Review for STR: VWA1_GGCGCGGAGC was set to GREEN
Added comment: VWA1 is transcribed from the forward strand.

VWA1_GGCGCGGAGC is on https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r4

VWA1_GGCGCGGAGC is on https://stripy.org/database

VWA1_GGCGCGGAGC is on DRAGON 4.02.

The coordinates of the sequence repeats shown above were the same on the above resources.

The non-pathogenic and pathogenic ranges of the sequence repeats shown above were obtained from: https://stripy.org/database and https://gnomad.broadinstitute.org/short-tandem-repeats?dataset=gnomad_r4

There is enough evidence for this STR to be green on this panel.

This STR has not been approved by NHS STR working group and is not NGS Not Validated
Sources: Literature
Hereditary neuropathy or pain disorder v6.164 NOTCH2NL Arina Puzriakova commented on gene: NOTCH2NL
Hereditary neuropathy or pain disorder v6.164 SPAST Sarah Leigh Added comment: Comment on publications: PMID: 39731306 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Hereditary neuropathy or pain disorder v6.163 SPAST Sarah Leigh edited their review of gene: SPAST: Added comment: Numerous heterozygous SPAST variants have been associated with Spastic paraplegia 4, autosomal dominant (OMIM:182601). PMID: 39731306 reports five homozygous SPAST variants in nine individuals from six families with spastic paraplegia and neurodegeneration. Amongst the homozygous children, all had lower limb spasticity, 5/6 had upper limb spasticity and 3/6 had severe intellectual disability. Evidence of consanguinity was evident in five of the families and the parents of the homozygous children were heterozygous for the SPAST variant found in the child, these carrier parents were asymptomatic in all but one the families studied.; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v6.163 ADPRHL2 Eleanor Williams commented on gene: ADPRHL2
Hereditary neuropathy or pain disorder v6.163 DHX9 Achchuthan Shanmugasundram Added comment: Comment on phenotypes: This gene has now been associated with relevant phenotypes in OMIM (MIM #620988).
Hereditary neuropathy or pain disorder v6.162 FGF14_TTC Sarah Leigh commented on STR: FGF14_TTC: The name of this STR has been changed from FGF14_GAA to FGF14_TTC as FGF14 is transcribed from the reverse strand of the sequence.
The coordinates for the repeated sequence have been updated to those shown in https://stripy.org/database/FGF14. Previously, the coordinates were for the whole gene, rather than the repeated sequence.
Hereditary neuropathy or pain disorder v6.161 TDP1 Sarah Leigh Added comment: Comment on publications: PMID: 39576382 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Hereditary neuropathy or pain disorder v6.160 TDP1 Sarah Leigh Added comment: Comment on list classification: This gene remains amber, as there are only two disease associated variants have been reported (PMID: 12244316;31182267;39576382)
Hereditary neuropathy or pain disorder v6.155 FMR1_CGG Sarah Leigh commented on STR: FMR1_CGG: The rating of this STR has been updated to green following NHS Genomic Medicine Service approval.
Hereditary neuropathy or pain disorder v6.154 ATXN7_CAG Sarah Leigh commented on STR: ATXN7_CAG: The rating of this STR has been updated to green following NHS Genomic Medicine Service approval.
Hereditary neuropathy or pain disorder v6.153 ATXN3_CAG Sarah Leigh commented on STR: ATXN3_CAG: The rating of this STR has been updated to green following NHS Genomic Medicine Service approval.
Hereditary neuropathy or pain disorder v6.152 ATXN2_CAG Sarah Leigh commented on STR: ATXN2_CAG: The rating of this STR has been updated to green following NHS Genomic Medicine Service approval.
Hereditary neuropathy or pain disorder v6.151 ATXN1_CAG Sarah Leigh commented on STR: ATXN1_CAG: The rating of this STR has been updated to green following NHS Genomic Medicine Service approval.
Hereditary neuropathy or pain disorder v6.151 ATXN10_ATTCT Sarah Leigh changed review comment from: The rating of this STR has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.; to: The rating of this STR has been updated to green following NHS Genomic Medicine Service approval.
Hereditary neuropathy or pain disorder v6.150 ATXN10_ATTCT Sarah Leigh commented on STR: ATXN10_ATTCT: The rating of this STR has been updated to green and the mode of inheritance set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted following NHS Genomic Medicine Service approval.
Hereditary neuropathy or pain disorder v6.150 NOP56_GGCCTG Sarah Leigh changed review comment from: The rating of this gene has been updated to green and the mode of inheritance set to following NHS Genomic Medicine Service approval. This change has been checked with NTGLH and Alex Rosser confirmed rationale for inclusion.; to: The rating of this STR has been updated to green and the mode of inheritance set to following NHS Genomic Medicine Service approval. This change has been checked with NTGLH and Alex Rosser confirmed rationale for inclusion.
Hereditary neuropathy or pain disorder v6.149 FXN_GAA Sarah Leigh commented on STR: FXN_GAA: The rating of this STR has been updated to green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval (added as per previous conversations with James Polke).
Hereditary neuropathy or pain disorder v6.149 NOP56_GGCCTG Sarah Leigh changed review comment from: The rating of this gene has been updated to green and the mode of inheritance set to following NHS Genomic Medicine Service approval.; to: The rating of this gene has been updated to green and the mode of inheritance set to following NHS Genomic Medicine Service approval. This change has been checked with NTGLH and Alex Rosser confirmed rationale for inclusion.
Hereditary neuropathy or pain disorder v6.148 MAPK8IP3 Sarah Leigh changed review comment from: The request for MAPK8IP3 to be rated as green was refused by the NHS Genomic Medicine Service. This decision was made because the phenotype associated with MAPK8IP3 variants is broader than this panel (Hereditary neuropathy or pain disorder, R78) and is covered by the Paediatric disorders (R27) and Intellectual disability (R29) panels, where MAPK8IP3 already has a green rating.; to: After NHS Genomic Medicine Service consideration, the rating of this gene has not been changed and remains amber. This decision was made because the phenotype associated with MAPK8IP3 variants is broader than this panel (Hereditary neuropathy or pain disorder, R78) and is covered by the Paediatric disorders (R27) and Intellectual disability (R29) panels, where MAPK8IP3 already has a green rating.
Hereditary neuropathy or pain disorder v6.148 TTPA Sarah Leigh commented on gene: TTPA: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Hereditary neuropathy or pain disorder v6.148 NDC1 Sarah Leigh edited their review of gene: NDC1: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v6.148 GLA Sarah Leigh commented on gene: GLA: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Hereditary neuropathy or pain disorder v6.148 FLVCR1 Sarah Leigh edited their review of gene: FLVCR1: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v6.148 FAM126A Sarah Leigh commented on gene: FAM126A: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Hereditary neuropathy or pain disorder v6.148 FAH Sarah Leigh commented on gene: FAH: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Hereditary neuropathy or pain disorder v6.148 ETFDH Sarah Leigh commented on gene: ETFDH: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Hereditary neuropathy or pain disorder v6.148 ERCC8 Sarah Leigh edited their review of gene: ERCC8: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v6.148 ERCC6 Sarah Leigh commented on gene: ERCC6: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Hereditary neuropathy or pain disorder v6.148 DMXL2 Sarah Leigh edited their review of gene: DMXL2: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v6.148 DHH Sarah Leigh edited their review of gene: DHH: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v6.148 DARS2 Sarah Leigh commented on gene: DARS2: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Hereditary neuropathy or pain disorder v6.148 CYP2U1 Sarah Leigh commented on gene: CYP2U1: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Hereditary neuropathy or pain disorder v6.148 CTDP1 Sarah Leigh commented on gene: CTDP1: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Hereditary neuropathy or pain disorder v6.148 COA7 Sarah Leigh commented on gene: COA7: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Hereditary neuropathy or pain disorder v6.148 CNTNAP1 Sarah Leigh commented on gene: CNTNAP1: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Hereditary neuropathy or pain disorder v6.148 CLP1 Sarah Leigh commented on gene: CLP1: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Hereditary neuropathy or pain disorder v6.148 CD59 Sarah Leigh commented on gene: CD59: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Hereditary neuropathy or pain disorder v6.148 CAPN1 Sarah Leigh commented on gene: CAPN1: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Hereditary neuropathy or pain disorder v6.148 C12orf65 Sarah Leigh commented on gene: C12orf65: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Hereditary neuropathy or pain disorder v6.148 BAG3 Sarah Leigh commented on gene: BAG3: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Hereditary neuropathy or pain disorder v6.148 ATP13A2 Sarah Leigh commented on gene: ATP13A2: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Hereditary neuropathy or pain disorder v6.148 ATM Sarah Leigh commented on gene: ATM: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Hereditary neuropathy or pain disorder v6.148 ATL3 Sarah Leigh commented on gene: ATL3: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Hereditary neuropathy or pain disorder v6.148 ATAD3A Sarah Leigh commented on gene: ATAD3A: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Hereditary neuropathy or pain disorder v6.148 ASAH1 Sarah Leigh commented on gene: ASAH1: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Hereditary neuropathy or pain disorder v6.148 ARSA Sarah Leigh edited their review of gene: ARSA: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v6.148 ARL6IP1 Sarah Leigh commented on gene: ARL6IP1: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Hereditary neuropathy or pain disorder v6.148 APTX Sarah Leigh edited their review of gene: APTX: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v6.148 AP5Z1 Sarah Leigh commented on gene: AP5Z1: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Hereditary neuropathy or pain disorder v6.148 AMACR Sarah Leigh edited their review of gene: AMACR: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v6.148 ADPRHL2 Sarah Leigh edited their review of gene: ADPRHL2: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v6.148 ADGRG6 Sarah Leigh edited their review of gene: ADGRG6: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v6.148 ADCY6 Sarah Leigh edited their review of gene: ADCY6: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v6.148 ADA2 Sarah Leigh edited their review of gene: ADA2: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v6.148 ABCD1 Sarah Leigh edited their review of gene: ABCD1: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Hereditary neuropathy or pain disorder v6.148 AAAS Sarah Leigh edited their review of gene: AAAS: Added comment: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v6.144 FXN_GAA Sarah Leigh STR: FXN_GAA was added
STR: FXN_GAA was added to Hereditary neuropathy or pain disorder. Sources: NHS GMS
Mode of inheritance for STR: FXN_GAA was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for STR: FXN_GAA were set to Friedreich ataxia, OMIM:229300; Friedreich ataxia 1, MONDO:0100340
Review for STR: FXN_GAA was set to GREEN
Added comment: This STR has been added to Hereditary neuropathy or pain disorder panel, on the recommendation of James Polke (Rare & Inherited Disease Genomic Laboratory, NHS North Thames GLH). Biallelic (including compound heterozygous) FXN variants, both single nucleotide and repeat expansions, have been associated with Friedreich ataxia, OMIM:229300.
The STR repeat lengths have been reviewed and confirmed by the NHS Genomic Medicine Service.
Sources: NHS GMS
Hereditary neuropathy or pain disorder v6.143 PIGG Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Christopher Record, there are six unrelated families reported with biallelic PIGG variants and hereditary motor neuropathy. Hence, this gene can be promoted to green rating in the next GMS review.
Hereditary neuropathy or pain disorder v6.139 LRP12 Sarah Leigh edited their review of gene: LRP12: Added comment: Apart from the LRP12_CGG variant, no other LRP12 variants have been associated with conditions in OMIM, G2P or Mondo.; Changed rating: RED
Hereditary neuropathy or pain disorder v6.138 LRP12_CGG Sarah Leigh Added comment: Comment on list classification: This STR is rated as amber, because it is not yet NGS validated.
Hereditary neuropathy or pain disorder v6.137 MAPK8IP3 Eleanor Williams Added comment: Comment on list classification: Promoting to amber and tagging for promotion to green, but GLH expert review is needed to decide whether there is clear enough mode of inheritance data and a strong enough association with neuropathy to report diagnostically particularly for people with isolated neuropathy presentations who are more likely to be tested via this route.
Hereditary neuropathy or pain disorder v6.131 PIGG Christopher Record gene: PIGG was added
gene: PIGG was added to Hereditary neuropathy or pain disorder. Sources: Literature
Mode of inheritance for gene: PIGG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGG were set to 39444079
Phenotypes for gene: PIGG were set to HMN
Review for gene: PIGG was set to GREEN
Added comment: Recessive variants in PIGG cause a inherited motor neuropathy with conduction block and/or temporal dispersion (39444079). This can be a pure neuropathy of part of a wider IGD syndrome to include cerebellar features, developmental delay, intellectual disability.
Sources: Literature
Hereditary neuropathy or pain disorder v6.131 LRP12_CGG Christopher Record STR: LRP12_CGG was added
STR: LRP12_CGG was added to Hereditary neuropathy or pain disorder. Sources: Literature
Mode of inheritance for STR: LRP12_CGG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: LRP12_CGG were set to 39013564
Phenotypes for STR: LRP12_CGG were set to CMT2, HMN
Review for STR: LRP12_CGG was set to GREEN
Added comment: CGG repeat expansion as cause for autosomal dominant inherited neuropathy in 44 Japanese patients
STR only
Sources: Literature
Hereditary neuropathy or pain disorder v6.131 NOTCH2NL Christopher Record gene: NOTCH2NL was added
gene: NOTCH2NL was added to Hereditary neuropathy or pain disorder. Sources: Literature
Mode of inheritance for gene: NOTCH2NL was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NOTCH2NL were set to 36948577; 37749855; 34675106
Mode of pathogenicity for gene: NOTCH2NL was set to Other
Review for gene: NOTCH2NL was set to GREEN
Added comment: [NB NOTCH2NL selected from gene drop down as NOTCH2NLC not available]
NOTCH2NLC GGC repeat expansion
Reported pure CMT in 26 cases from Japan (36948577), and 7cases from Taiwan (34675106). Chinese NOTC2NLC related NIID cohort also showed peripheral neuropathy in significant proportion (37749855). Anecdotally found in family with CMT of European ancestry (unpublished).
Phenotypes included CMT2, CMTi and HMN
Sources: Literature
Hereditary neuropathy or pain disorder v6.131 SPAST Arina Puzriakova Added comment: Comment on list classification: Axonal peripheral polyneuropathy was reported in at least 8 individuals with SPAST-related HSP (PMID:28572275) and has been recommended for this panel by Alex Rossor (UCL). The scope of this panel has now been expanded to include complex forms of neuropathy and therefore this gene can be promoted to Green at the next GMS panel update.
Hereditary neuropathy or pain disorder v6.128 OPA3 Eleanor Williams Added comment: Comment on mode of inheritance: Cases with peripheral neuropathy appear to be associated with autosomal dominant Optic atrophy 3 with cataract. This gene is also associated with a recessive condition in OMIM.
Hereditary neuropathy or pain disorder v6.127 OPA3 Eleanor Williams changed review comment from: Associated with 3-methylglutaconic aciduria, type III, OMIM:258501 (AR) and Optic atrophy 3 with cataract, OMIM:165300 (AD).

PMID:28050599 - Bourne et al 2017 - 1 case - woman with cataracts, optic atrophy, lipodystrophy/lipoatrophy, and peripheral neuropathy. Exome sequencing identified a OPA3 c.235C > G p.(Leu79Val) variant that was confirmed to be de novo. The variant is not reported in gnomAD.

PMID: 31119193 - Horga et al 2019 - describe 2 families and one sporadic case with a syndromic form of OPA3-related autosomal dominant optic atrophy and cataract in which patients also show peripheral neuropathy. Heterozyous variants in OPA3 were identified c.23T>C (p.Met8Thr), c.313C>G (p.Gln105Glu) and c.313C>G (p.Gln105Glu) in each of the 3 families. In In 4 patients, the peripheral neuropathy was a major cause of disability or was severe enough to motivate the referral to specialists.

PMID:21036400 - Yu-Wai-Man et al 2011 - no patients with OPA3 variants reported, only OPA1 variants.; to: Associated with 3-methylglutaconic aciduria, type III, OMIM:258501 (AR) and Optic atrophy 3 with cataract, OMIM:165300 (AD).

PMID:28050599 - Bourne et al 2017 - 1 case - woman with cataracts, optic atrophy, lipodystrophy/lipoatrophy, and peripheral neuropathy. Exome sequencing identified a OPA3 c.235C > G p.(Leu79Val) variant that was confirmed to be de novo. The variant is not reported in gnomAD.

PMID: 31119193 - Horga et al 2019 - describe 2 families and one sporadic case with a syndromic form of OPA3-related autosomal dominant optic atrophy and cataract in which patients also show peripheral neuropathy. Heterozyous variants in OPA3 were identified c.23T>C (p.Met8Thr), c.313C>G (p.Gln105Glu) and c.313C>G (p.Gln105Glu) in each of the 3 families. In 4 patients, the peripheral neuropathy was a major cause of disability or was severe enough to motivate the referral to specialists.

PMID:21036400 - Yu-Wai-Man et al 2011 - no patients with OPA3 variants reported, only OPA1 variants.
Hereditary neuropathy or pain disorder v6.127 PRNP Arina Puzriakova Added comment: Comment on list classification: Neuropathy (predominantly sensory and autonomic) has been reported in at least 7 unrelated families with PRNP-related prion disease, which can present as an early and/or isolated feature. The scope of this panel has now been expanded to include complex forms of neuropathy and therefore this gene can be promoted to Green at the next GMS panel update.
Hereditary neuropathy or pain disorder v6.124 POLG Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Alexander Rossor, peripheral neuropathy is a well-established feature of POLG disease and hence this gene should be promoted to green rating in the next GMS update.
Hereditary neuropathy or pain disorder v6.121 POLG Achchuthan Shanmugasundram changed review comment from: PMID:25281868 reported 116 patients with genetically-defined mitochondrial disease and progressive external ophthalmoplegia, of which 16 patients had a large-fibre peripheral neuropathy. Eight of them were identified with biallelic PLOG variants and one of them was identified with POLG monoallelic variant.

PMID:33791913 reported a patient with sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO) and was identified with two novel missense variants. A systematic review of previous literature in this publication summarised a total of 35 distinct variants from POLG are reported in 63 patients with SANDO. All of them had the variants either in homozygous or compound heterozygous state.

PMID:36703500 reported gait disturbance related to sensory ataxia and oculomotor abnormalities in four patients with biallelic POLG variants. They all had sensory axonal neuropathy.

PMID:38975049 reported a retrospective study of 40 children carrying biallelic pathogenic POLG variants, of which sensorimotor axonal neuropathy was present in eight children (20%) and polyradiculoneuropathy was present in six children (15%).


; to: PMID:12975295 reported four unrelated patients with progressive external ophthalmoplegia (PEO) and with POLG variants. Of three patients with heterozygous variants, one had neuropathy and the only patient with compound heterozygous variants also had neuropathy.

PMID:15534189 reported a family with monoallelic missense variant in POLG gene and with progressive external ophthalmoplegia, neuropathy, hypogonadism, and parkinsonism.

PMID:19752458 reported 26 patients from 23 families with cerebellar ataxia plus sensory neuropathy or external ophthalmoplegia. Of these 15 patients from 11 families were identified with POLG variants, of which four patients from two families had heterozygous variants and 11 patients from nine families had either homozygous or compound heterozygous variants.

PMID:25281868 reported 116 patients with genetically-defined mitochondrial disease and progressive external ophthalmoplegia, of which 16 patients had a large-fibre peripheral neuropathy. Eight of them were identified with biallelic PLOG variants and one of them was identified with POLG monoallelic variant.

PMID:33791913 reported a patient with sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO) and was identified with two novel missense variants. A systematic review of previous literature in this publication summarised a total of 35 distinct variants from POLG are reported in 63 patients with SANDO. All of them had the variants either in homozygous or compound heterozygous state.

PMID:36703500 reported gait disturbance related to sensory ataxia and oculomotor abnormalities in four patients with biallelic POLG variants. They all had sensory axonal neuropathy.

PMID:38975049 reported a retrospective study of 40 children carrying biallelic pathogenic POLG variants, of which sensorimotor axonal neuropathy was present in eight children (20%) and polyradiculoneuropathy was present in six children (15%).

Both monoallelic and biallelic variants of this gene are associated with relevant phenotypes in OMIM and Gene2Phenotype (DD and eye panels) and OMIM records neuropathy as a clinical presentation of all but one phenotypes.
Hereditary neuropathy or pain disorder v6.120 TUBB3 Arina Puzriakova Added comment: Comment on list classification: Peripheral neuropathy has been reported >3 unrelated cases with CFEOM3A and one family with multiple mutant carriers had isolated peripheral neuropathy (PMID: 20074521). The scope of this panel has now been expanded to complex forms of neuropathy and therefore this gene can be promoted to Green at the next GMS panel update.
Hereditary neuropathy or pain disorder v6.118 POLG Achchuthan Shanmugasundram changed review comment from: PMID:25281868 reported 116 patients with genetically-defined mitochondrial disease and progressive external ophthalmoplegia, of which 16 patients had a large-fibre peripheral neuropathy. Eight of them were identified with biallelic PLOG variants and one of them was identified with POLG monoallelic variant.

PMID:33791913 reported a patient with sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO) and was identified with two novel missense variants. A systematic review of previous literature in this publication summarised a total of 35 distinct variants from POLG are reported in 63 patients with SANDO. All of them had the variants either in homozygous or compound heterozygous state.; to: PMID:25281868 reported 116 patients with genetically-defined mitochondrial disease and progressive external ophthalmoplegia, of which 16 patients had a large-fibre peripheral neuropathy. Eight of them were identified with biallelic PLOG variants and one of them was identified with POLG monoallelic variant.

PMID:33791913 reported a patient with sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO) and was identified with two novel missense variants. A systematic review of previous literature in this publication summarised a total of 35 distinct variants from POLG are reported in 63 patients with SANDO. All of them had the variants either in homozygous or compound heterozygous state.

PMID:36703500 reported gait disturbance related to sensory ataxia and oculomotor abnormalities in four patients with biallelic POLG variants. They all had sensory axonal neuropathy.

PMID:38975049 reported a retrospective study of 40 children carrying biallelic pathogenic POLG variants, of which sensorimotor axonal neuropathy was present in eight children (20%) and polyradiculoneuropathy was present in six children (15%).
Hereditary neuropathy or pain disorder v6.116 TWNK Arina Puzriakova Added comment: Comment on list classification: TWNK is associated with multiple phenotypes that feature peripheral neuropathy (Mitochondrial DNA depletion syndrome 7 (hepatocerebral type), OMIM:271245 (AR); Perrault syndrome 5, OMIM:616138 (AR); Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3, OMIM:609286 (AD)) - sufficient cases with dominant and recessive forms of disease to support the association.

The scope of this panel has now been expanded to complex forms of neuropathy and therefore this gene can be promoted to Green at the next GMS panel update.
Hereditary neuropathy or pain disorder v6.114 XPA Arina Puzriakova Added comment: Comment on list classification: Peripheral neuropathy is a reported feature in at least 8 unrelated families with xeroderma pigmentosum. The scope of this panel has now been expanded to complex forms of neuropathy and therefore this gene can be promoted to Green at the next GMS panel update.
Hereditary neuropathy or pain disorder v6.113 SOX10 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available (more than six unrelated cases) for the association of monoallelic SOX10 variants with demyelinating peripheral neuropathy. Hence, this gene can be promoted to green rating on the next GMS update.; to: Comment on list classification: There is sufficient evidence available (more than six unrelated cases) for the association of monoallelic SOX10 variants with demyelinating peripheral neuropathy. Hence, this gene can be promoted to green rating in the next GMS update.
Hereditary neuropathy or pain disorder v6.113 SOX10 Achchuthan Shanmugasundram Deleted their comment
Hereditary neuropathy or pain disorder v6.113 SOX10 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (more than six unrelated cases) for the association of monoallelic SOX10 variants with demyelinating peripheral neuropathy. Hence, this gene can be promoted to green rating on the next GMS update.
Hereditary neuropathy or pain disorder v6.112 SOX10 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (more than six unrelated cases) for the association of monoallelic SOX10 variants with demyelinating peripheral neuropathy. Hence, this gene can be promoted to green rating on the next GMS update.
Hereditary neuropathy or pain disorder v6.98 PHYH Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Alexander Rossor, peripheral neuropathy is a part of Refsum disease (MIM #266500). OMIM record lists peripheral sensorimotor neuropathy as one of the clinical manifestations. In addition, PMID:20301527 reports that polyneuropathy is present in ~70% of cases with Refsum disease.

Hence, this gene can be promoted to green rating in the next GMS update.
Hereditary neuropathy or pain disorder v6.95 HADHB Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Alexander Rossor, mitochondrial trifunctional protein deficiency 2 (MIM #620300) includes peripheral neuropathy as one of the clinical manifestations. There are more than three unrelated cases reported with neuropathy in literature. Hence, this gene can be promoted to green rating in the next GMS update.
Hereditary neuropathy or pain disorder v6.90 HADHA Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by by Alexander Rossor, mitochondrial trifunctional protein deficiency 1 (MIM #609015) includes peripheral neuropathy as one of the clinical manifestations. There are at least three unrelated cases reported with neuropathy in literature. Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: As reviewed by Alexander Rossor, mitochondrial trifunctional protein deficiency 1 (MIM #609015) includes peripheral neuropathy as one of the clinical manifestations. There are at least three unrelated cases reported with neuropathy in literature. Hence, this gene can be promoted to green rating in the next GMS update.
Hereditary neuropathy or pain disorder v6.88 HADHA Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by by Alexander Rossor, mitochondrial trifunctional protein deficiency 1 (MIM #609015) includes peripheral neuropathy as one of the clinical manifestations. There are at least three unrelated cases reported with neuropathy in literature. Hence, this gene can be promoted to green rating in the next GMS update.
Hereditary neuropathy or pain disorder v6.83 SLC13A3 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Alexander Rossor, there is only case reported with neuropathy. Hence, this gene should be rated red with current evidence.
Hereditary neuropathy or pain disorder v6.80 ZFYVE26 Arina Puzriakova Added comment: Comment on list classification: Peripheral neuropathy is a reported feature in at least 5 unrelated families with SPG15. The scope of this panel has now been expanded to complex forms of neuropathy and therefore this gene can be promoted to Green at the next GMS panel update.
Hereditary neuropathy or pain disorder v6.79 SAMD9L Eleanor Williams Added comment: Comment on list classification: Promoting to amber with a recommendation for green rating following GMS review.
Hereditary neuropathy or pain disorder v6.76 SAMD9L Eleanor Williams Mode of pathogenicity for gene: SAMD9L was changed from None to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Hereditary neuropathy or pain disorder v6.75 SAMD9L Eleanor Williams edited their review of gene: SAMD9L: Changed rating: GREEN; Changed mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Changed publications to: 32808377, 36553623, 31053103, 27259050, 28202457; Changed phenotypes to: Ataxia-pancytopenia syndrome, OMIM:159550, ataxia-pancytopenia syndrome, MONDO:0008038; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Hereditary neuropathy or pain disorder v6.75 SAMD9L Eleanor Williams commented on gene: SAMD9L
Hereditary neuropathy or pain disorder v6.66 TBCE Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is sufficient evidence available (four unrelated cases) for the promotion of this gene to green rating in the next GMS update.; to: Comment on list classification: There is sufficient evidence available (four unrelated cases) for the association of this gene with neuropathy. Hence, this gene can be promoted to green rating in the next GMS update.
Hereditary neuropathy or pain disorder v6.66 TBCE Achchuthan Shanmugasundram changed review comment from: PMID:27666369 reported six individuals from four apparently unrelated families originating from the same geographical area in Italy near Naples with a similar infantile-onset neurodegenerative disorder. They were either identified with the same homozygous p.Ile155Asn variant (five patients from three families) or with a compound heterozygous variant involving the same variant with another variant (p.Leu360Ter) in one patient. There is also functional evidence available.

This gene has been associated with relevant phenotypes in OMIM (MIM #617207) and Gene2Phenotype (with 'strong' rating on the DD panel). MIM #617207 records axonal peripheral neuropathy as one of the clinical manifestations.; to: PMID:27666369 reported six individuals from four apparently unrelated families originating from the same geographical area in Italy near Naples with a similar infantile-onset neurodegenerative disorder. They were either identified with the same homozygous p.Ile155Asn variant (five patients from three families) or with a compound heterozygous variant involving the same variant with another variant (p.Leu360Ter) in one patient. Electrophysiologic and electromyographic studies in all patients were consistent with a motor neuropathy. There is also functional evidence available.

This gene has been associated with relevant phenotypes in OMIM (MIM #617207) and Gene2Phenotype (with 'strong' rating on the DD panel). MIM #617207 records axonal peripheral neuropathy as one of the clinical manifestations.
Hereditary neuropathy or pain disorder v6.65 TBCE Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (four unrelated cases) for the promotion of this gene to green rating in the next GMS update.
Hereditary neuropathy or pain disorder v6.64 PNPT1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are three unrelated cases reported with heterozygous PNPT1 variants and sensory neuropathy. Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: There are four unrelated cases reported with heterozygous PNPT1 variants and sensory neuropathy. Hence, this gene can be promoted to green rating in the next GMS update.
Hereditary neuropathy or pain disorder v6.64 PNPT1 Achchuthan Shanmugasundram changed review comment from: PMID:14705117 reported a large family from Southeastern France with spinocerebellar ataxia with sensory involvement. Age at onset ranged from 17 months to 39 years, although most of those affected had onset in childhood. Cerebellar ataxia was always present and many patients had peripheral sensory neuropathy.

PMID:35411967 reported the identification of heterozygous splice site variants in PNPT1 in the above reported family from Southeastern France and from a 3-generation Australian family with spinocerebellar ataxia and sensory neuropathy reported in this study. All patients from the Australian family for whom information was available had an axonal sensory neuropathy with diminished or absent limb reflexes and decreased sensation. A 40-year-old French patient was also reported with heterozygous frameshift PNPT1 variant, who had onset of deafness shortly after birth and onset of gait ataxia at 23 years of age. He also had sensory neuropathy.

This gene has been associated with relevant phenotypes in OMIM (MIM #608703), which records sensory neuropathy/ axonal sensory neuropathy as clinical manifestations of the phenotype.; to: PMID:14705117 reported a large family from Southeastern France with spinocerebellar ataxia with sensory involvement. Age at onset ranged from 17 months to 39 years, although most of those affected had onset in childhood. Cerebellar ataxia was always present and many patients had peripheral sensory neuropathy.

PMID:35411967 reported the identification of heterozygous splice site variants in PNPT1 in the above reported family from Southeastern France and from a 3-generation Australian family with spinocerebellar ataxia and sensory neuropathy reported in this study. All patients from the Australian family for whom information was available had an axonal sensory neuropathy with diminished or absent limb reflexes and decreased sensation. There was evidence of incomplete penetrance in the Australian family, as two carriers in this family had sensory neuropathy without ataxia or cerebellar atrophy in their thirties. A 40-year-old French patient was also reported with heterozygous frameshift PNPT1 variant, who had onset of deafness shortly after birth and onset of gait ataxia at 23 years of age. He also had sensory neuropathy. This patient inherited the variant from an asymptomatic 80+ years old father.

PMID:37935417 reported the identification of a novel PNPT1 variant in a 3-year-old child with spinocerebellar ataxia. The child had cerebellar atrophy and psychomotor delay. At a follow up at 6 years of age, the symptoms had worsened and also presented with axonal sensory neuropathy.

Monoallelic variants in this gene have been associated with relevant phenotype in OMIM (MIM #608703), which records sensory neuropathy/ axonal sensory neuropathy as clinical manifestations of the phenotype.
Hereditary neuropathy or pain disorder v6.64 DSTYK Sarah Leigh Added comment: Comment on phenotypes: Monoallelic DSTYK variants are associated with Congenital anomalies of kidney and urinary tract 1 (OMIM:610805).
Hereditary neuropathy or pain disorder v6.62 DSTYK Sarah Leigh edited their review of gene: DSTYK: Added comment: Two DSTYK variants (as compound heterozygotes) have been associated with Spastic paraplegia 23, autosomal recessive (OMIM:270750) in 3 unrelated families of Middle Eastern origin. This combination of variants in the reported families was revealed to be founder effect by haplotype analysis (PMID: 28157540).; Changed rating: AMBER; Changed publications to: 28157540; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v6.62 DSTYK Sarah Leigh Added comment: Comment on phenotypes: Childhood onset spastic paraplegia, prominent skin pigment abnormalities (vitiligo, hyperpigmentation, diffuse lentigines), premature greying of hair, sensory predominant axonal neuropathy (mild).
Hereditary neuropathy or pain disorder v6.61 DMXL2 Sarah Leigh Added comment: Comment on phenotypes: Three brothers from a single family with Polyendocrine-polyneuropathy syndrome, OMIM:616113;polyendocrine-polyneuropathy syndrome MONDO:0014497, were homozygous for a DMXL2 variant (PMID: 25248098). Segregation between the variants and the condition was also reported in this study.
Hereditary neuropathy or pain disorder v6.60 PNPT1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated cases reported with heterozygous PNPT1 variants and sensory neuropathy. Hence, this gene can be promoted to green rating in the next GMS update.
Hereditary neuropathy or pain disorder v6.55 NFASC Achchuthan Shanmugasundram Added comment: Comment on list classification: There are at least three unrelated cases with syndromic neuropathy. Hence, this gene can be recommended for promotion to green rating in the next GMS update.
Hereditary neuropathy or pain disorder v6.52 NFASC Achchuthan Shanmugasundram commented on gene: NFASC: PMID:30850329 reported the identification of a homozygous NFASC variant (p.Val1122Glu) in two siblings from an Italian family. The patients presented with early-onset cerebellar ataxia and demyelinating neuropathy.

PMID:31501903 reported the identification of one frameshift and four different homozygous non-synonymous variants in NFASC gene in ten individuals from six unrelated families. They presented with a neurodevelopmental disorder characterised with a spectrum of central (intellectual disability, developmental delay, motor impairment, speech difficulties) and peripheral (early onset demyelinating neuropathy) neurological involvement. Neuropathy was reported in at least three patients from two different families.

This gene has been associated with relevant phenotype in OMIM (MIM #618356), which lists demyelinating sensorimotor polyneuropathy as one of the clinical manifestations observed in some of the patients.
Hereditary neuropathy or pain disorder v6.51 AP1S1 Arina Puzriakova Added comment: Comment on list classification: Neuropathy in adulthood is a feature of MEDNIK syndrome. >3 unrelated cases have been reported. The scope of this panel has now been expanded to complex forms of neuropathy and therefore this gene can be promoted to Green at the next GMS panel update.
Hereditary neuropathy or pain disorder v6.48 DHH Sarah Leigh edited their review of gene: DHH: Added comment: DHH variants have been associated with 46XY gonadal dysgenesis with minifascicular neuropathy (OMIM:607080). At least five DHH variants have been associated with in five unrelated cases of OMIM:607080.; Changed rating: GREEN
Hereditary neuropathy or pain disorder v6.48 DHH Sarah Leigh Added comment: Comment on phenotypes: DHH variants are also associated with 46XY sex reversal 7 (OMIM:233420). Neuropathy does not appear to be associated with this condition.
Hereditary neuropathy or pain disorder v6.44 DARS2 Sarah Leigh edited their review of gene: DARS2: Added comment: DARS2 variants have been associated with Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation, OMIM:611105 and as strong G2P gene for the same condition. At numerous DARS2 variants have been reported in cases of OMIM:611105 (PMID: 28334938;38790244;22677571;38549004).; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v6.43 DARS2 Sarah Leigh Added comment: Comment on phenotypes: Slowly progressive spasticity, ataxia and dorsal column dysfunction, sensory-motor axonal neuropathy, characteristic MRI findings
Hereditary neuropathy or pain disorder v6.19 PLA2G16 Eleanor Williams changed review comment from: Associated with Lipodystrophy, familial partial, type 9 620683 (AR) in OMIM where Demyelinating sensorimotor neuropathy is listed as a clinical feature.

PMID: 37919452 - Schuermans et al 2023 - 7 patients from 4 unrelated families with 3 different homozygous variants (c.16-4823_118+167del p.(Pro6ValfsTer15), c.286dupG p.(Ala96GlyfsTer16) and c.339C>A p.(Cys113Ter). All patients had generalized or partial Lipoatrophy, insulin resistance and Liver steatosis, and 6/7 showed Dyslipidemia/hypertriglyceridemia. Demyelinating peripheral neuropathy was seen in 5/7 patients from all 4 families.

Function studies with PLAAT3 inactivation in human adipose stem cells provides evidence for PLAAT3 in PPARγ-mediated adipogenesis.; to: Associated with Lipodystrophy, familial partial, type 9 620683 (AR) in OMIM where Demyelinating sensorimotor neuropathy is listed as a clinical feature.

PMID: 37919452 - Schuermans et al 2023 - 7 patients from 4 unrelated families with 3 different homozygous variants (c.16-4823_118+167del p.(Pro6ValfsTer15), c.286dupG p.(Ala96GlyfsTer16) and c.339C>A p.(Cys113Ter). All patients had generalized or partial lipoatrophy, insulin resistance and Liver steatosis, and 6/7 showed Dyslipidemia/hypertriglyceridemia. Demyelinating peripheral neuropathy was seen in 5/7 patients from all 4 families. Psychomotor retardation/intellectual disability was observed in 3/7 patients but the severity is not recorded.

Age of onset of symptoms was 19 years, 8 years, 9 months, 4 years, 4 years (not available for 2 patients).

Function studies with PLAAT3 inactivation in human adipose stem cells provides evidence for PLAAT3 in PPARγ-mediated adipogenesis.
Hereditary neuropathy or pain disorder v6.19 PLA2G16 Eleanor Williams Added comment: Comment on list classification: Promoting to amber with recommendation for green rating following GMS review. 4 cases with 3 different variants in PLAAT3 and a consistent phenotype that includes peripheral neuropathy.
Hereditary neuropathy or pain disorder v6.17 PLA2G16 Eleanor Williams commented on gene: PLA2G16: The new gene name for PLA2G16 is PLAAT3.
Hereditary neuropathy or pain disorder v6.17 PLA2G16 Eleanor Williams edited their review of gene: PLA2G16: Added comment: Associated with Lipodystrophy, familial partial, type 9 620683 (AR) in OMIM where Demyelinating sensorimotor neuropathy is listed as a clinical feature.

PMID: 37919452 - Schuermans et al 2023 - 7 patients from 4 unrelated families with 3 different homozygous variants (c.16-4823_118+167del p.(Pro6ValfsTer15), c.286dupG p.(Ala96GlyfsTer16) and c.339C>A p.(Cys113Ter). All patients had generalized or partial Lipoatrophy, insulin resistance and Liver steatosis, and 6/7 showed Dyslipidemia/hypertriglyceridemia. Demyelinating peripheral neuropathy was seen in 5/7 patients from all 4 families.

Function studies with PLAAT3 inactivation in human adipose stem cells provides evidence for PLAAT3 in PPARγ-mediated adipogenesis.; Changed phenotypes to: Associated with Lipodystrophy, familial partial, type 9, OMIM:620683, lipodystrophy, familial partial, type 9, MONDO:0958034
Hereditary neuropathy or pain disorder v6.17 PLA2G16 Eleanor Williams gene: PLA2G16 was added
gene: PLA2G16 was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: PLA2G16 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLA2G16 were set to 37919452
Added comment: Added as green by Alexander Rossor (UCL Institute of Neurology) - see https://panelapp.genomicsengland.co.uk/panels/846/gene/PLAA/
Sources: Expert list
Hereditary neuropathy or pain disorder v6.16 PLAA Eleanor Williams changed review comment from: The paper PMID:37919452 refers to gene PLAAT3, PLA2G16 and mentions transcript NM_001128203. This corresponds to the gene PLA2G16 with Ensembl ID ENSG00000176485 in the current PanelApp database and not PLAA ENSG00000137055.

Therefore this review will be copied to PLA2G16 and PLAA will have the tag 'curated_removed' added.; to: The paper PMID:37919452 refers to gene PLAAT3 previously known as PLA2G16 and mentions transcript NM_001128203. This corresponds to the gene PLA2G16 with Ensembl ID ENSG00000176485 in the current PanelApp database and not PLAA ENSG00000137055.

Therefore this review will be copied to PLA2G16 and PLAA will have the tag 'curated_removed' added.
Hereditary neuropathy or pain disorder v6.16 PLAA Eleanor Williams changed review comment from: The paper PMID:37919452 refers to gene PLAAT3, PLA2G16 and mentions transcript NM_001128203. This corresponds to the gene PLA2G16 with Ensembl ID ENSG00000176485 in the current PanelApp database and not PLAA ENSG00000137055.

Therefore this review will be copied to PLA2G16 and PLAA will have the tag 'curator_removed' added.; to: The paper PMID:37919452 refers to gene PLAAT3, PLA2G16 and mentions transcript NM_001128203. This corresponds to the gene PLA2G16 with Ensembl ID ENSG00000176485 in the current PanelApp database and not PLAA ENSG00000137055.

Therefore this review will be copied to PLA2G16 and PLAA will have the tag 'curated_removed' added.
Hereditary neuropathy or pain disorder v6.16 PLAA Eleanor Williams commented on gene: PLAA
Hereditary neuropathy or pain disorder v6.15 NDUFS6 Eleanor Williams Added comment: Comment on list classification: Promoting to amber with a recommendation for green rating following GMS review. 3 separate publications report variants in this gene in patients with peripheral neuropathies. 2 different variants are reported.
Hereditary neuropathy or pain disorder v6.14 NDUFS6 Eleanor Williams changed review comment from: Associated with Mitochondrial complex I deficiency, nuclear type 9, OMIM: 618232 (AR)

Biallelic loss of function variants are associated with severe CI deficiency and Leigh syndrome in previous reports (PubMed: 19259137 and PubMed: 15372108).

There is now phenotypic expansion with 4 families reported with a less severe phenotype. 3 families share a common variant.

PMID: 38459834 - Camila Armirola-Ricaurte et al 2024. Describe 5 patients from 3 unrelated families from Spain, Turkey and Greece. They share a homozygous NDUFS6 NM_004553.6:c.309+5G>A variant found be exome sequencing and an axonal Charcot-Marie-Tooth (CMT) neuropathy. Age of onset ranged from 1 to 10 years. In all cases the unaffected parents were heterozygous for the variant. The variant is predicted to affect splicing and in family 1 was shown to cause the expression of aberrantly spliced transcripts and negligible levels of the canonical transcript. Haplotype analysis showed that the variant lies on a shared haplotype of 0.74MB on chromosome 5 and estimate the most recent common ancestor with the haplotype would have lived 740 years ago

PMID: 38549004 – Ferreira et al 2024 – screened nearly 11,000 patients with peripheral neuropathy for variants in known mitochondrial disease genes. 1 male was found with a homozygous variant c.320_323delCAAA, p.Thr107LysfsTer40 in NDUFS6.; to: Associated with Mitochondrial complex I deficiency, nuclear type 9, OMIM: 618232 (AR)

Biallelic loss of function variants are associated with severe CI deficiency and Leigh syndrome in previous reports (PubMed: 19259137 Spiegal et al 2009 and PubMed: 15372108 Kirby et al 2004, PMID: 30948790 - Rouzier et al 2019, PMID: 22474353 Ke et al 2012).

There is now phenotypic expansion with 5 families reported with a less severe phenotype. 4 families share a common variant.

PMID: 38459834 - Armirola-Ricaurte et al 2024. Describe 5 patients from 3 unrelated families from Spain, Turkey and Greece. They share a homozygous NDUFS6 NM_004553.6:c.309+5G>A variant found be exome sequencing and an axonal Charcot-Marie-Tooth (CMT) neuropathy. Age of onset ranged from 1 to 10 years. In all cases the unaffected parents were heterozygous for the variant. The variant is predicted to affect splicing and in family 1 was shown to cause the expression of aberrantly spliced transcripts and negligible levels of the canonical transcript. Haplotype analysis showed that the variant lies on a shared haplotype of 0.74MB on chromosome 5 and estimate the most recent common ancestor with the haplotype would have lived 740 years ago

PMID: 38549004 – Ferreira et al 2024 – screened nearly 11,000 patients with peripheral neuropathy for variants in known mitochondrial disease genes. 1 male was found with a homozygous variant c.320_323delCAAA, p.Thr107LysfsTer40 in NDUFS6.

PMID: 38217609 - Gangfuß et al 2024 - identified a homozygous variant (c.309 + 5 G > A) in NDUFS6 in one male patient aged 10 with axonal neuropathy accompanied by loss of small fibers in skin biopsy. The patient also showed optic atrophy and borderline intellectual disability.
Hereditary neuropathy or pain disorder v6.14 NDUFS6 Eleanor Williams changed review comment from: Associated with Mitochondrial complex I deficiency, nuclear type 9, OMIM: 618232 (AR)

Biallelic loss of function variants are associated with severe CI deficiency and Leigh syndrome. 4 families reported although 3 share a common variant.

PMID: 38459834 - Camila Armirola-Ricaurte et al 2024. Describe 5 patients from 3 unrelated families from Spain, Turkey and Greece. They share a homozygous NDUFS6 NM_004553.6:c.309+5G>A variant found be exome sequencing and an axonal Charcot-Marie-Tooth (CMT) neuropathy. Age of onset ranged from 1 to 10 years. In all cases the unaffected parents were heterozygous for the variant. The variant is predicted to affect splicing and in family 1 was shown to cause the expression of aberrantly spliced transcripts and negligible levels of the canonical transcript. Haplotype analysis showed that the variant lies on a shared haplotype of 0.74MB on chromosome 5 and estimate the most recent common ancestor with the haplotype would have lived 740 years ago

PMID: 38549004 – Ferreira et al 2024 – screened nearly 11,000 patients with peripheral neuropathy for variants in known mitochondrial disease genes. 1 male was found with a homozygous variant c.320_323delCAAA, p.Thr107LysfsTer40 in NDUFS6.; to: Associated with Mitochondrial complex I deficiency, nuclear type 9, OMIM: 618232 (AR)

Biallelic loss of function variants are associated with severe CI deficiency and Leigh syndrome in previous reports (PubMed: 19259137 and PubMed: 15372108).

There is now phenotypic expansion with 4 families reported with a less severe phenotype. 3 families share a common variant.

PMID: 38459834 - Camila Armirola-Ricaurte et al 2024. Describe 5 patients from 3 unrelated families from Spain, Turkey and Greece. They share a homozygous NDUFS6 NM_004553.6:c.309+5G>A variant found be exome sequencing and an axonal Charcot-Marie-Tooth (CMT) neuropathy. Age of onset ranged from 1 to 10 years. In all cases the unaffected parents were heterozygous for the variant. The variant is predicted to affect splicing and in family 1 was shown to cause the expression of aberrantly spliced transcripts and negligible levels of the canonical transcript. Haplotype analysis showed that the variant lies on a shared haplotype of 0.74MB on chromosome 5 and estimate the most recent common ancestor with the haplotype would have lived 740 years ago

PMID: 38549004 – Ferreira et al 2024 – screened nearly 11,000 patients with peripheral neuropathy for variants in known mitochondrial disease genes. 1 male was found with a homozygous variant c.320_323delCAAA, p.Thr107LysfsTer40 in NDUFS6.
Hereditary neuropathy or pain disorder v6.11 NDUFS6 Eleanor Williams commented on gene: NDUFS6
Hereditary neuropathy or pain disorder v6.10 NOP56_GGCCTG Arina Puzriakova commented on STR: NOP56_GGCCTG: Gene entity was recently added by Alexander Rossor (UCL Institute of Neurology) indicating that NOP56 should be green on this panel (https://panelapp.genomicsengland.co.uk/panels/846/gene/NOP56/). Adding STR as mechanism of disease is repeat expansions (GGCCTG)n rather than SNVs.

Heterozygous expansion of an intronic GGCCTG hexanucleotide repeat in the NOP56 gene causes spinocerebellar ataxia-36 (SCA36), an adult-onset slowly progressive neurodegenerative disorder. EMG in cases with skeletal muscle atrophy has shown neurogenic changes, indicating a lower motor neuropathy (PMID: 21683323). Flagging for additional GMS review to determine whether inclusion on this panel is beneficial.

Currently this STR is only included as part of the R54 Hereditary ataxia with onset in adulthood GMS panel (v7.0).
Hereditary neuropathy or pain disorder v6.9 NOP56 Arina Puzriakova Added comment: Comment on list classification: Added to this panel by Alexander Rossor (UCL Institute of Neurology). Good evidence but mechanism of disease is repeat expansions (GGCCTG)n rather than SNVs and so rating the gene entity as Red. Added STR entity instead.
Hereditary neuropathy or pain disorder v6.4 PLA2G6 Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Alexander Rossor (UCL Institute of Neurology). Biallelic variant in PLA2G6 are associated with multiple neurodegenerative phenotypes with overlapping clinical and radiologic features including Infantile neuroaxonal dystrophy (MIM# 256600), Neurodegeneration with brain iron accumulation (MIM# 610217) and Parkinson disease (MIM# 612953). Although not universal, progressive motor axonal neuropathy has been reported as an early feature in multiple patients harbouring PLA2G6 variants (PMID: 18443314; 25164370; 27882168; 29859652; 30340910). Neuropathy can present earlier than other typical features such as iron accumulation in the brain and has represented the main diagnostic feature in some cases. Therefore, there is sufficient evidence to promote this gene to Green at the next GMS panel update.
Hereditary neuropathy or pain disorder v6.2 PIEZO2 Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Alexander Rossor (UCL Institute of Neurology). Biallelic variants cause distal arthrogryposis with impaired proprioception and touch. Mild sensory axonal neuropathy has been reported in some individuals (PMID: 27653382; 27843126; 27974811). Sufficient unrelated cases to promote this gene to Green at the next GMS panel update.

Neuropathy is not a feature of dominant phenotypes associated with PIEZO2.
Hereditary neuropathy or pain disorder v5.106 MFF Achchuthan Shanmugasundram Added comment: Comment on list classification: There are only two patients reported with neuropathy so far. Hence, this gene should be rated amber with current evidence.
Hereditary neuropathy or pain disorder v5.104 MFF Achchuthan Shanmugasundram Deleted their comment
Hereditary neuropathy or pain disorder v5.104 MFF Achchuthan Shanmugasundram commented on gene: MFF: PMID:26783368 reported three patients from two unrelated families with EMPF2 and with biallelic MFF variants. Patient 1 (an Austrian boy) was identified with compound heterozygous variants (p.Leu62Profs*13; p.Arg298Ter) and had mixed form of peripheral neuropathy shown on compound muscle action potential. Patient 3 (one of two Turkish siblings) had phenotype consistent with demyelinating peripheral neuropathy, which was absent in his brother. They had homozygous p.Glu153Alafs*5 variants.

Although EMPF2 was reported in other patients (PMIDs: 22499341; 32181496; 34750646), neuropathy was not reported in them.
Hereditary neuropathy or pain disorder v5.104 MAPK8IP3 Eleanor Williams commented on gene: MAPK8IP3: Awaiting clinical feedback before deciding on rating.
Hereditary neuropathy or pain disorder v5.103 HPDL Eleanor Williams Added comment: Comment on list classification: On recommendation of clinical expert this gene has been promoted to amber and has been tagged for promotion to green subject to GMS review.
Hereditary neuropathy or pain disorder v5.98 FA2H Eleanor Williams Added comment: Comment on list classification: Promoting with amber with a recommendation for green rating as there are now 4 cases with peripheral neuropathy and variants in this gene reported.
Hereditary neuropathy or pain disorder v5.97 EXOSC3 Eleanor Williams Added comment: Comment on list classification: Promoting this gene to amber with a proposal to promote to green following NHS GMS review. There are sufficient cases with a relevant phenotype and variants in this gene.
Hereditary neuropathy or pain disorder v5.96 PTRH2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Alexander Rossor, there are multiple unrelated individuals presenting with peripheral neuropathy. Hence, this gene can be promoted to green rating in the next GMS update.
Hereditary neuropathy or pain disorder v5.93 PDHA1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Alexander Rossor, there is sufficient evidence available for the association of this gene with syndromic neuropathy and hence this gene can be promoted to green rating in the next GMS update.
Hereditary neuropathy or pain disorder v5.86 TRMT5 Arina Puzriakova Added comment: Comment on list classification: New gene added to the panel by Alexander Rossor (UCL Institute of Neurology). There is sufficient evidence to promote this gene to Green at the next GMS panel update.

Associated with relevant phenotype in OMIM, but not associated with phenotype in G2P. At least 3 variants reported in at least three cases, together with supportive functional studies.

Phenotype is characterised as a highly variable multisystemic disorder, ranging from hypotonia and GDD in infancy to exercise intolerance and muscle weakness in early adulthood. Peripheral neuropathy is a universal feature in all cases. Various other neurological features such as spasticity, cerebellar signs and seizures, and involvement of other organ systems, including the heart, pancreas, and kidney may also be observed.
Hereditary neuropathy or pain disorder v5.83 UCHL1 Arina Puzriakova Added comment: Comment on list classification: Sensorimotor neuropathy has been reported in both Spastic paraplegia 79A, autosomal dominant, OMIM:620221 and Spastic paraplegia 79B, autosomal recessive, OMIM:615491. Sufficient unrelated cases for both MOIs to promote to Green at the next GMS panel update.
Hereditary neuropathy or pain disorder v5.81 UQCRC1 Arina Puzriakova Added comment: Comment on list classification: Rating Amber based on current evidence - three unrelated individuals with Parkinson's disease and heterozygous variants identified by one group (PMID: 33141179) but results have failed to be replicated in large European and Chinese cohorts (PMIDs: 33779694; 33248804).

This matches the latest classification on other GMS panels. Furthermore, polyneuropathy was only confirmed in 1/3 families. Knock-in mice with the affected family variant did exhibit significant reductions in distal CMAP amplitudes compared to WT littermates at 12 months (but not 9 months), as well as a slightly reduced conduction velocity but preserved distal motor latency. Peripheral nerve fibre morphology showed decrease in the diameter of myelinated nerve fibres.
Hereditary neuropathy or pain disorder v5.78 VPS13D Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Alexander Rossor (UCL Institute of Neurology). There is sufficient evidence to promote this gene to Green at the next GMS panel update.

Biallelic variants in VPS13D cause a progressive spinocerebellar ataxia which can be associated with mild to moderate axonal sensorineural peripheral neuropathy. Sufficient unrelated cases to justify inclusion on the panel.
Hereditary neuropathy or pain disorder v5.77 NUDT2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available now for the promotion of this gene to green rating in the next GMS update.
Hereditary neuropathy or pain disorder v5.74 NUDT2 Achchuthan Shanmugasundram edited their review of gene: NUDT2: Added comment: As reviewed by Alexander Rossor, PMID:38141063 reported 18 patients from 10 different families with a neurological disorder typified by intellectual disability, motor developmental delay and gait disturbance and they were all identified with biallelic NUDT2 variants. 71% of these patients had sensorimotor neuropathy.; Changed publications to: 27431290, 30059600, 33058507, 38141063
Hereditary neuropathy or pain disorder v5.74 NARS Achchuthan Shanmugasundram commented on gene: NARS: The new gene name for NARS is NARS1.
Hereditary neuropathy or pain disorder v5.74 NARS Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene top green rating on the next GMS update. The MOI can be set as 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal" as there are at least three cases reported with both modes of inheritance.
Hereditary neuropathy or pain disorder v5.72 NARS Achchuthan Shanmugasundram changed review comment from: PMID:32738225 reported a total of 24 patients from 13 unrelated families with biallelic variants in the NARS1 gene and 8 unrelated patients with de novo heterozygous variants in the NARS1 gene. They presented with microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy, and ataxia. Neuropathy was present in four patients from three families with biallelic variants and three unrelated individuals with monoallelic variants.

This gene has been associated with relevant phenotypes in both OMIM (MIMs #619091 & #619092) and Gene2Phenotype (monoallelic condition with 'strong' rating and biallelic condition with 'definitive' rating on the DD panel). This gene is also present with green rating on the 'Hereditary Neuropathy - complex' panel of PanelApp Australia.; to: PMID:32738225 reported a total of 24 patients from 13 unrelated families with biallelic variants in the NARS1 gene and 8 unrelated patients with de novo heterozygous variants in the NARS1 gene. They presented with microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy, and ataxia. Neuropathy was present in four patients from three families with biallelic variants and three unrelated individuals with monoallelic variants. In addition, supportive functional data is also present.

This gene has been associated with relevant phenotypes in both OMIM (MIMs #619091 & #619092) and Gene2Phenotype (monoallelic condition with 'strong' rating and biallelic condition with 'definitive' rating on the DD panel). This gene is also present with green rating on the 'Hereditary Neuropathy - complex' panel of PanelApp Australia.
Hereditary neuropathy or pain disorder v5.71 FICD Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (three unrelated families with the same homozygous variant and functional studies) for the association of this gene with green rating in the next GMS update.
Hereditary neuropathy or pain disorder v5.70 FICD Achchuthan Shanmugasundram gene: FICD was added
gene: FICD was added to Hereditary neuropathy or pain disorder. Sources: Literature
Q3_24_promote_green tags were added to gene: FICD.
Mode of inheritance for gene: FICD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FICD were set to 36136088
Phenotypes for gene: FICD were set to Spastic paraplegia 92, autosomal recessive, OMIM:620911
Review for gene: FICD was set to GREEN
Added comment: PMID:36136088 reported three unrelated families with recurrent homozygous missense variant in FICD gene (p.Arg374His) and the patients presented with a a neurodegenerative disease of upper and lower motor neurons. A patient from one further family was identified with compound heterozygous variants in FICD gene (p.Arg374His and p.Gly370GlufsTer53).

All these patients had onset of symptoms in childhood with progressive course. Their clinical manifestations included severe lower limb spasticity and mild upper limb spasticity. In addition, nerve conduction test showed motor neuropathy in the four patients with homozygous p.Arg374His variant, whereas this test was not done in the patient with compound heterozygous variants.

Fibroblasts from patients with FICD variants have abnormally increased levels of AMPylated and thus inactivated BiP.

This gene has been associated with relevant phenotypes in OMIM (MIM #620911).
Sources: Literature
Hereditary neuropathy or pain disorder v5.69 FDXR Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Alexander Rossor (UCL Institute of Neurology). There is sufficient evidence to promote this gene to Green at the next GMS panel update.

Review by Masnada et al (2023) of 44 individuals from 35 families reported in literature with FDXR variants revealed sensorimotor peripheral polyneuropathy in more than 20% of patients. In most cases peripheral neuropathy manifests in late stages of disease but presentation since clinical onset has also been described. Other common features include optic neuropathy (93.2%) and acoustic neuropathy (50%).
Hereditary neuropathy or pain disorder v5.66 EMILIN1 Arina Puzriakova changed review comment from: Comment on list classification: This is now sufficient evidence to promote this gene to Green at the next GMS panel update. At least three unrelated families reported with heterozygous variant in the EMILIN1 gene and neuropathy.

The third family includes a proband with childhood-onset sensory-motor neuropathy and pyramidal signs (ataxic-spastic gait). Sequencing revealed two heterozygous missense variants, c.544G>A and c.546G>C, which authors renamed as c.544_546GAG>AAC (p.E182N) as the variants were in cis and located at the same protein residue. The proband's mother, carrying the same variant, presented with a milder peripheral nerve disorder, hypermobility of joints and ligamentous laxity, and moderate inflammatory arthropathy.; to: Comment on list classification: This is now sufficient evidence to promote this gene to Green at the next GMS panel update. At least three unrelated families reported with heterozygous variant in the EMILIN1 gene and neuropathy.

The third family (PMID:38963291) includes a proband with childhood-onset sensory-motor neuropathy and pyramidal signs (ataxic-spastic gait). Sequencing revealed two heterozygous missense variants, c.544G>A and c.546G>C, which authors renamed as c.544_546GAG>AAC (p.E182N) as the variants were in cis and located at the same protein residue. The proband's mother, carrying the same variant, presented with a milder peripheral nerve disorder, hypermobility of joints and ligamentous laxity, and moderate inflammatory arthropathy.
Hereditary neuropathy or pain disorder v5.66 EMILIN1 Arina Puzriakova Added comment: Comment on list classification: This is now sufficient evidence to promote this gene to Green at the next GMS panel update. At least three unrelated families reported with heterozygous variant in the EMILIN1 gene and neuropathy.

The third family includes a proband with childhood-onset sensory-motor neuropathy and pyramidal signs (ataxic-spastic gait). Sequencing revealed two heterozygous missense variants, c.544G>A and c.546G>C, which authors renamed as c.544_546GAG>AAC (p.E182N) as the variants were in cis and located at the same protein residue. The proband's mother, carrying the same variant, presented with a milder peripheral nerve disorder, hypermobility of joints and ligamentous laxity, and moderate inflammatory arthropathy.
Hereditary neuropathy or pain disorder v5.35 ATXN7_CAG Sarah Leigh STR: ATXN7_CAG was added
STR: ATXN7_CAG was added to Hereditary neuropathy or pain disorder. Sources: NHS GMS
Q3_24_promote_green, Q3_24_NHS_review, STR tags were added to STR: ATXN7_CAG.
Mode of inheritance for STR: ATXN7_CAG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for STR: ATXN7_CAG were set to Ataxia neuropathy syndromes
Review for STR: ATXN7_CAG was set to GREEN
Added comment: ATXN7_CAG added to Hereditary neuropathy or pain disorder panel on the recommendation of Alex Rossor (UCL Institute of Neurology), who recommended its promotion to Green.
Sources: NHS GMS
Hereditary neuropathy or pain disorder v5.31 ATXN3_CAG Sarah Leigh STR: ATXN3_CAG was added
STR: ATXN3_CAG was added to Hereditary neuropathy or pain disorder. Sources: NHS GMS
Q3_24_promote_green, Q3_24_NHS_review, STR tags were added to STR: ATXN3_CAG.
Mode of inheritance for STR: ATXN3_CAG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for STR: ATXN3_CAG were set to Ataxia neuropathy syndromes
Review for STR: ATXN3_CAG was set to GREEN
Added comment: ATXN3_CAG added to Hereditary neuropathy or pain disorder panel on the recommendation of Alex Rossor (UCL Institute of Neurology), who recommended its promotion to Green.
Sources: NHS GMS
Hereditary neuropathy or pain disorder v5.28 ATXN2_CAG Sarah Leigh STR: ATXN2_CAG was added
STR: ATXN2_CAG was added to Hereditary neuropathy or pain disorder. Sources: NHS GMS
Q3_24_promote_green, Q3_24_NHS_review, STR tags were added to STR: ATXN2_CAG.
Mode of inheritance for STR: ATXN2_CAG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for STR: ATXN2_CAG were set to Ataxia neuropathy syndromes
Review for STR: ATXN2_CAG was set to GREEN
Added comment: ATXN2_CAG added to Hereditary neuropathy or pain disorder panel on the recommendation of Alex Rossor (UCL Institute of Neurology), who recommended its promotion to Green.
Sources: NHS GMS
Hereditary neuropathy or pain disorder v5.25 ATXN10_ATTCT Sarah Leigh STR: ATXN10_ATTCT was added
STR: ATXN10_ATTCT was added to Hereditary neuropathy or pain disorder. Sources: NHS GMS
Q3_24_promote_green, Q3_24_NHS_review tags were added to STR: ATXN10_ATTCT.
Mode of inheritance for STR: ATXN10_ATTCT was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for STR: ATXN10_ATTCT were set to Ataxia neuropathy syndromes
Review for STR: ATXN10_ATTCT was set to GREEN
Added comment: ATXN10_ATTCT has been added to Hereditary neuropathy or pain disorder panel on the recommendation of Alex Rossor (UCL Institute of Neurology), who recommended its promotion to Green.
Sources: NHS GMS
Hereditary neuropathy or pain disorder v5.22 FGF14_GAA Sarah Leigh edited their review of STR: FGF14_GAA: Added comment: FGF14_GAA added to Hereditary neuropathy or pain disorder panel on the recommendation of Alex Rossor (UCL Institute of Neurology), who recommended its promotion to Green.; Changed rating: GREEN
Hereditary neuropathy or pain disorder v5.22 FMR1_CGG Sarah Leigh changed review comment from: FMR1_CGG added to Hereditary neuropathy or pain disorder panel on the recommendation of Alex Rossor (UCL Institute of Neurology).; to: FMR1_CGG added to Hereditary neuropathy or pain disorder panel on the recommendation of Alex Rossor (UCL Institute of Neurology), who recommended its promotion to Green.
Hereditary neuropathy or pain disorder v5.22 FGF14_GAA Sarah Leigh Added comment: Comment on list classification: FGF14_GAA is not currently reportable, as the coordinates are not present on the analysis pipeline.
Hereditary neuropathy or pain disorder v5.20 FMR1_CGG Sarah Leigh edited their review of STR: FMR1_CGG: Added comment: FMR1_CGG added to Hereditary neuropathy or pain disorder panel on the recommendation of Alex Rossor (UCL Institute of Neurology).; Changed rating: GREEN
Hereditary neuropathy or pain disorder v5.19 ZFYVE26 Alexander Rossor edited their review of gene: ZFYVE26: Added comment: phenotypically similar to SPG11; Changed publications to: 26492578:27217339: 24833714
Hereditary neuropathy or pain disorder v5.19 XPA Alexander Rossor edited their review of gene: XPA: Added comment: PN seems otbe mostly associated with XPA- Aditional paper attached. Now that R78 inlcudes complex phenotypes should be included; Changed publications to: 2168777: 34627174
Hereditary neuropathy or pain disorder v5.19 TWNK Alexander Rossor edited their review of gene: TWNK: Added comment: Multiple reports of variants cuasing peripheral neuropathy and should be included in R78; Changed publications to: 37932750: 32281099: 32234020: 24061067: 20880070 :
Hereditary neuropathy or pain disorder v5.19 TUBB3 Alexander Rossor edited their review of gene: TUBB3: Added comment: multiple affected individuals - unrelated - should be includedin R78 now that includes complex phenotypes; Changed publications to: 34652576 : 25482575; Changed phenotypes to: ptosis, ophthalmoplegia, exotropia, facial weakness, facial dysmorphisms, and, in most cases, distal congenital joint contractures, and subsequently develop intellectual disabilities, gait disorders with proximal joint contractures, Kallmann syndrome (hypogonadotropic hypogonadism and anosmia), and a progressive peripheral neuropathy during the first decade of life
Hereditary neuropathy or pain disorder v5.19 TTPA Alexander Rossor edited their review of gene: TTPA: Added comment: Eripheral neuropathy well established part of this complex phenotype. Now that R78 inlcudes complex phenotypes this gene should be included; Changed publications to: 24369383
Hereditary neuropathy or pain disorder v5.19 SPAST Alexander Rossor commented on gene: SPAST: 23% have peripheralneuropathy and should therefore be inlcuded in R78 as this now includes complex phenotypes
Hereditary neuropathy or pain disorder v5.19 SOX10 Alexander Rossor edited their review of gene: SOX10: Added comment: now that r78 inclues complex phenotpyes should presumably be included; Changed publications to: 32150337: 29681101: 28328136
Hereditary neuropathy or pain disorder v5.19 PTRH2 Alexander Rossor edited their review of gene: PTRH2: Added comment: Peripheral neuropathy now reportedin multiple unrelated individuals and can be a presenting feature. Shouldbe green and in R78 panel; Changed rating: GREEN; Changed publications to: 25572476, 25558065: 28328138: 31057140: 27129381: 39176129: 38874107
Hereditary neuropathy or pain disorder v5.19 PRNP Alexander Rossor edited their review of gene: PRNP: Added comment: peripheral neuropathy reported as rare presentation of cjd in multiple individuals; Changed publications to: 27716661 : 24224623 : 26768678: 31953922; Changed phenotypes to: cjd, dementia, autonomic neuropathy, sensory neuropathy
Hereditary neuropathy or pain disorder v5.19 POLG Alexander Rossor edited their review of gene: POLG: Added comment: Now R78 includes complex phenotypes this needs to be included as PN well established in POLG disease; Changed publications to: 36703500 : 33791913: 25281868: 38975049; Changed phenotypes to: peripheral neuropathy, CPEO
Hereditary neuropathy or pain disorder v5.19 PHYH Alexander Rossor edited their review of gene: PHYH: Added comment: Refsums disease is a well established (historical) cause of peripheral neuropathy. It is treatable and has to be included in the R78 panel now that it includes complex phenotypes; Changed publications to: 9326940; Changed phenotypes to: Refsums diseasd; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v5.19 PDHA1 Alexander Rossor edited their review of gene: PDHA1: Added comment: PN in multiple unrelated individuals and therefore should be includedin R78 panel; Changed rating: GREEN; Changed publications to: 38497591: 36693417: 20002125; Changed phenotypes to: peripheral neuropathy, Leigh syndrome
Hereditary neuropathy or pain disorder v5.19 OPA3 Alexander Rossor edited their review of gene: OPA3: Added comment: Peripehral neuropathy reported in multiple unrelated individuals and should be included in panel; Changed publications to: 28050599: 21036400 : 31119193:
Hereditary neuropathy or pain disorder v5.19 NUDT2 Alexander Rossor edited their review of gene: NUDT2: Added comment: Recent publication attached showing peripheral neuropathy in several new unrelated individuals so should therefore be green and included in panel; Changed rating: GREEN
Hereditary neuropathy or pain disorder v5.19 NUDT2 Alexander Rossor changed review comment from: Recent publication attached showing peripheral neuropathy in several new unrelated individuals so should therefore be green and included in panel; to: Recent publication attached showing peripheral neuropathy in several new unrelated individuals so should therefore be green and included in panel
Hereditary neuropathy or pain disorder v5.19 HADHB Alexander Rossor edited their review of gene: HADHB: Added comment: PN well established part of phenotype. Multiple affected families. Now R78 includes complex phenotypes should be included; Changed publications to: 3744096: 28685493: 31521624: 24664533: 28649548: 35235001 : 37388542; Changed phenotypes to: rhabdomyloysis, hypoparathyroidism, peripheral neuropathy
Hereditary neuropathy or pain disorder v5.19 HADHA Alexander Rossor edited their review of gene: HADHA: Added comment: trifucnctional protein deificeincy, inlcudes peripheral neuropathy. NOw R78 includes complex phenotypes should be included; Changed publications to: 23868323: 28132977: 32897397; Changed phenotypes to: rhabdomyloysis, peripheral neuropathy
Hereditary neuropathy or pain disorder v5.19 GLA Alexander Rossor edited their review of gene: GLA: Added comment: small fibren europathy established feature of Fabrys; Changed publications to: 22428782; Changed phenotypes to: small fibre neuropathy, strokes, cardiomyopathy, skin disease
Hereditary neuropathy or pain disorder v5.19 FLVCR1 Alexander Rossor edited their review of gene: FLVCR1: Added comment: Multiple additional reports of association with neuropathy. Now R78 includes complex phenotypes should be included; Changed publications to: 21070897: 38405817: 32822874: 28766925: 37469134:
Hereditary neuropathy or pain disorder v5.19 FAM126A Alexander Rossor edited their review of gene: FAM126A: Added comment: Multiple unrelated patients with peripheralneuropathy. Now that R78 includes complex phneotypes needs to be included; Changed publications to: 16951682: 23998934: 21911699: 33531944: 22749724:
Hereditary neuropathy or pain disorder v5.19 FAH Alexander Rossor edited their review of gene: FAH: Added comment: Complex phneotypes now included in R78, reference of 25 patients inlcuded; Changed publications to: 33598652
Hereditary neuropathy or pain disorder v5.19 ETFDH Alexander Rossor edited their review of gene: ETFDH: Added comment: multiple families with neuropathy as part of syndrome, Now R78 includes complex phenotypes should be included; Changed publications to: 32608139: 26821934: 0587156
Hereditary neuropathy or pain disorder v5.19 ERCC8 Alexander Rossor edited their review of gene: ERCC8: Added comment: now that R78 includes complex phenotypes sould be included; Changed publications to: 25453614
Hereditary neuropathy or pain disorder v5.19 ERCC6 Alexander Rossor edited their review of gene: ERCC6: Added comment: now that R78 includes complex pheotypes should be included; Changed publications to: 25453614
Hereditary neuropathy or pain disorder v5.19 DHTKD1 Alexander Rossor commented on gene: DHTKD1: I think this gene should be removed from the panel. The original chinese family reported a lof het allele. LOF is not constrained in DHTKD!, more so recessive LOF variants in DHTKD1 cause Alpha-aminoadipic and alpha-ketoadipic aciduria and these patients do not have a peripheral neuropathy
Hereditary neuropathy or pain disorder v5.19 DARS2 Alexander Rossor edited their review of gene: DARS2: Added comment: Multiple additional unrelated individuals with variants in DARS2 and peripheral neuropathy - should now be green; Changed publications to: 28334938: 38790244: 22677571: 38549004; Changed phenotypes to: Slowly progressive spasticity, ataxia and dorsal column dysfunction, sensory-motor axonal neuropathy, characteristic MRI findings
Hereditary neuropathy or pain disorder v5.19 COA7 Alexander Rossor edited their review of gene: COA7: Added comment: Multiple additional cases now reported with peripheral neuropathy - should be green and on panle now that R78 includes complex phenotypes; Changed publications to: 29718187: 37264311: 35603692: 27683825
Hereditary neuropathy or pain disorder v5.19 CNTNAP1 Alexander Rossor edited their review of gene: CNTNAP1: Added comment: Multiple affected individuals. Now that R78 panel includes complex phenotypes should be green and on panel; Changed publications to: 28374019: 29511323: 27668699: 27782105:; Changed phenotypes to: arthrogryposis, developmental dleay, peripheral neuropathy; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v5.19 CD59 Alexander Rossor edited their review of gene: CD59: Added comment: No wthat the R78 panel includes complex phenotypees with peripheral neuropathy this should now be included in the R78 panel; Changed publications to: 23149847, 24382084
Hereditary neuropathy or pain disorder v5.19 C12orf65 Alexander Rossor edited their review of gene: C12orf65: Added comment: PN in multiple affected individuals from different families; Changed rating: GREEN; Changed publications to: 24080142: 23188110: 6303658: 24424123: 24198383; Changed phenotypes to: optic atrophy, spasticity, peripheral neuropathy; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v5.19 C12orf65 Alexander Rossor Deleted their comment
Hereditary neuropathy or pain disorder v5.19 BAG3 Alexander Rossor edited their review of gene: BAG3: Added comment: Further reports in assocation with PN since my last review, should now be green; Changed publications to: 30145633: 37989284: 37907725; Changed phenotypes to: cardiomyopathy, polyneuropathy
Hereditary neuropathy or pain disorder v5.19 VPS13D Alexander Rossor gene: VPS13D was added
gene: VPS13D was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: VPS13D was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS13D were set to 29518281: 29604224: 14681893: 11960835
Phenotypes for gene: VPS13D were set to ataxia; spasticity; peripheral neuropathy
Penetrance for gene: VPS13D were set to Complete
Review for gene: VPS13D was set to GREEN
Added comment: Sources: Expert list
Hereditary neuropathy or pain disorder v5.19 UQCRC1 Alexander Rossor gene: UQCRC1 was added
gene: UQCRC1 was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: UQCRC1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: UQCRC1 were set to 33141179
Phenotypes for gene: UQCRC1 were set to parkinsonism; peripheral neuropathy
Penetrance for gene: UQCRC1 were set to Complete
Review for gene: UQCRC1 was set to GREEN
Added comment: Sources: Expert list
Hereditary neuropathy or pain disorder v5.19 TRMT5 Alexander Rossor gene: TRMT5 was added
gene: TRMT5 was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: TRMT5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TRMT5 were set to 35342985: 26189817: 29021354
Phenotypes for gene: TRMT5 were set to develomental delay; spasticity; peripheral neuropathy
Penetrance for gene: TRMT5 were set to Complete
Review for gene: TRMT5 was set to GREEN
Added comment: Sources: Expert list
Hereditary neuropathy or pain disorder v5.19 TBCE Alexander Rossor gene: TBCE was added
gene: TBCE was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: TBCE was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBCE were set to 27666369
Phenotypes for gene: TBCE were set to encephalopathy; peripheral neuropathy
Penetrance for gene: TBCE were set to Complete
Review for gene: TBCE was set to GREEN
Added comment: Sources: Expert list
Hereditary neuropathy or pain disorder v5.19 SLC13A3 Alexander Rossor gene: SLC13A3 was added
gene: SLC13A3 was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: SLC13A3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC13A3 were set to 37290914
Phenotypes for gene: SLC13A3 were set to acute neuropathy
Penetrance for gene: SLC13A3 were set to Complete
Review for gene: SLC13A3 was set to AMBER
Added comment: one patient with neuropathy in literature
Sources: Expert list
Hereditary neuropathy or pain disorder v5.19 SAMD9L Alexander Rossor gene: SAMD9L was added
gene: SAMD9L was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: SAMD9L was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SAMD9L were set to ataxia; peripheral neuropathy; pancytopenia
Phenotypes for gene: SAMD9L were set to 32808377: 36553623 : 31053103: 27259050: 28202457
Penetrance for gene: SAMD9L were set to Complete
Review for gene: SAMD9L was set to GREEN
Added comment: Sources: Expert list
Hereditary neuropathy or pain disorder v5.19 PNPT1 Alexander Rossor gene: PNPT1 was added
gene: PNPT1 was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: PNPT1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: PNPT1 were set to 35411967: 14705117
Phenotypes for gene: PNPT1 were set to ataxia; peripheral neuropathy
Penetrance for gene: PNPT1 were set to Complete
Review for gene: PNPT1 was set to GREEN
Added comment: Sources: Expert list
Hereditary neuropathy or pain disorder v5.19 PLAA Alexander Rossor gene: PLAA was added
gene: PLAA was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: PLAA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLAA were set to 37919452
Phenotypes for gene: PLAA were set to lipodystrophy; peripheral neuropathy
Penetrance for gene: PLAA were set to Complete
Review for gene: PLAA was set to GREEN
Added comment: gene is PLAAT3
Sources: Expert list
Hereditary neuropathy or pain disorder v5.19 PLA2G6 Alexander Rossor gene: PLA2G6 was added
gene: PLA2G6 was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: PLA2G6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PLA2G6 were set to 18443314: 16783378:
Phenotypes for gene: PLA2G6 were set to Neurodegeneration with brain iron accumulation; peripheral neuropathy
Penetrance for gene: PLA2G6 were set to Complete
Review for gene: PLA2G6 was set to GREEN
Added comment: Sources: Expert list
Hereditary neuropathy or pain disorder v5.19 PIEZO2 Alexander Rossor gene: PIEZO2 was added
gene: PIEZO2 was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: PIEZO2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIEZO2 were set to 27653382
Phenotypes for gene: PIEZO2 were set to arthrodryposis; sensory neuropathy
Penetrance for gene: PIEZO2 were set to Complete
Review for gene: PIEZO2 was set to GREEN
Added comment: Sources: Expert list
Hereditary neuropathy or pain disorder v5.19 NOP56 Alexander Rossor gene: NOP56 was added
gene: NOP56 was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: NOP56 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: NOP56 were set to 22492559: 22744658: 21683323
Phenotypes for gene: NOP56 were set to ataxia; motor neuropathy
Penetrance for gene: NOP56 were set to Complete
Review for gene: NOP56 was set to GREEN
Added comment: Sources: Expert list
Hereditary neuropathy or pain disorder v5.19 NFASC Alexander Rossor gene: NFASC was added
gene: NFASC was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: NFASC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NFASC were set to 30850329: 30124836
Phenotypes for gene: NFASC were set to Developmental delay; peripheral neuropathy
Penetrance for gene: NFASC were set to Complete
Review for gene: NFASC was set to GREEN
Added comment: Sources: Expert list
Hereditary neuropathy or pain disorder v5.19 NDUFS6 Alexander Rossor gene: NDUFS6 was added
gene: NDUFS6 was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: NDUFS6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFS6 were set to 38459834 : 38549004
Phenotypes for gene: NDUFS6 were set to peripheral neuropathy; nystagmus
Penetrance for gene: NDUFS6 were set to Complete
Review for gene: NDUFS6 was set to GREEN
Added comment: Sources: Expert list
Hereditary neuropathy or pain disorder v5.19 NARS Alexander Rossor gene: NARS was added
gene: NARS was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: NARS was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: NARS were set to 32738225:
Phenotypes for gene: NARS were set to developmental delay; seizures; peripheral neuropathy
Penetrance for gene: NARS were set to Complete
Review for gene: NARS was set to GREEN
Added comment: Sources: Expert list
Hereditary neuropathy or pain disorder v5.19 MAPK8IP3 Alexander Rossor gene: MAPK8IP3 was added
gene: MAPK8IP3 was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: MAPK8IP3 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: MAPK8IP3 were set to 37462082: 30945334
Phenotypes for gene: MAPK8IP3 were set to developmental delay; motor axonal neuropathy
Penetrance for gene: MAPK8IP3 were set to Complete
Review for gene: MAPK8IP3 was set to GREEN
Added comment: Sources: Expert list
Hereditary neuropathy or pain disorder v5.19 HPDL Alexander Rossor gene: HPDL was added
gene: HPDL was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: HPDL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HPDL were set to 32707086
Phenotypes for gene: HPDL were set to developmental delay; spastic paraplegia; peripheral neuropathy
Penetrance for gene: HPDL were set to Complete
Review for gene: HPDL was set to GREEN
Added comment: 3 had peripheral neuropathy
Sources: Expert list
Hereditary neuropathy or pain disorder v5.19 FDXR Alexander Rossor gene: FDXR was added
gene: FDXR was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: FDXR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FDXR were set to 37046037: 30250212 :
Phenotypes for gene: FDXR were set to optic neuropathy; auditory neuropathy; peripheral neuropathy
Penetrance for gene: FDXR were set to Complete
Review for gene: FDXR was set to GREEN
Added comment: Sources: Expert list
Hereditary neuropathy or pain disorder v5.19 FA2H Alexander Rossor edited their review of gene: FA2H: Added comment: peripheral neuropathy now reportedin 3 additional patients; Changed rating: GREEN; Changed publications to: 22146942:31135052
Hereditary neuropathy or pain disorder v5.19 EXOSC3 Alexander Rossor gene: EXOSC3 was added
gene: EXOSC3 was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: EXOSC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXOSC3 were set to 23564332:24524299:25149867:12548734
Phenotypes for gene: EXOSC3 were set to pontocerebellar hypoplasia; motor neuropathy
Penetrance for gene: EXOSC3 were set to Complete
Review for gene: EXOSC3 was set to GREEN
Added comment: Sources: Expert list
Hereditary neuropathy or pain disorder v5.19 MFF Alexander Rossor gene: MFF was added
gene: MFF was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: MFF was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MFF were set to 26783368
Phenotypes for gene: MFF were set to encephalopathy; developmental delay; peripheral neuropathy in some
Penetrance for gene: MFF were set to Complete
Review for gene: MFF was set to GREEN
Added comment: Sources: Expert list
Hereditary neuropathy or pain disorder v5.19 DMXL2 Alexander Rossor gene: DMXL2 was added
gene: DMXL2 was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: DMXL2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DMXL2 were set to 31688942
Phenotypes for gene: DMXL2 were set to developmental encephalopathy; deafness; mild peripheral polyneuropathy; dysmorphic features
Penetrance for gene: DMXL2 were set to Complete
Review for gene: DMXL2 was set to GREEN
Added comment: Sources: Expert list
Hereditary neuropathy or pain disorder v5.19 CYP2U1 Alexander Rossor gene: CYP2U1 was added
gene: CYP2U1 was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: CYP2U1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CYP2U1 were set to 23176821
Phenotypes for gene: CYP2U1 were set to spastic paraplegia; cognitive impairment; subvlincial peripheral neuropathy
Penetrance for gene: CYP2U1 were set to Complete
Review for gene: CYP2U1 was set to GREEN
Added comment: Sources: Expert list
Hereditary neuropathy or pain disorder v5.19 CLP1 Alexander Rossor gene: CLP1 was added
gene: CLP1 was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: CLP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CLP1 were set to 24766809
Phenotypes for gene: CLP1 were set to pontocerbeelar hypoplasia, peripheral neuropathy
Penetrance for gene: CLP1 were set to Complete
Review for gene: CLP1 was set to GREEN
Added comment: Multiple affected individuals with peripheral neuropathy on ncs
Sources: Expert list
Hereditary neuropathy or pain disorder v5.19 CAPN1 Alexander Rossor gene: CAPN1 was added
gene: CAPN1 was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: CAPN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CAPN1 were set to 27153400
Phenotypes for gene: CAPN1 were set to spasticity; pes cavus; peripheral neuropathy
Penetrance for gene: CAPN1 were set to Complete
Review for gene: CAPN1 was set to GREEN
Added comment: 3 families
Sources: Expert list
Hereditary neuropathy or pain disorder v5.19 DHH Alexander Rossor edited their review of gene: DHH: Added comment: Multipel reports of this syndrome causing peripheral neuropathy. Should be added to panel; Changed rating: GREEN; Changed publications to: 29471294: 11891836: 11017805: 25927242: 33107133; Changed phenotypes to: gonadal dysgenesis, peripheral neuropathy; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v5.19 ATP13A2 Alexander Rossor gene: ATP13A2 was added
gene: ATP13A2 was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: ATP13A2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ATP13A2 were set to 28137957:
Phenotypes for gene: ATP13A2 were set to spastic paraplegia; cognitive impairment; peripheral neuropathy
Penetrance for gene: ATP13A2 were set to Complete
Review for gene: ATP13A2 was set to GREEN
Added comment: Peripheral neuropathy in individuals from 3 different families
Sources: Expert list
Hereditary neuropathy or pain disorder v5.19 ATM Alexander Rossor edited their review of gene: ATM: Added comment: Should now be included as R78 has extended its scope to include complex phenotypes that include neuropathy such as ataxia telangiectasia; Changed rating: GREEN; Changed publications to: 37553836; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v5.19 ATL3 Alexander Rossor edited their review of gene: ATL3: Added comment: 3rd indivudla reported with domintant ATL3 and neuropathy; Changed publications to: 30680846
Hereditary neuropathy or pain disorder v5.19 ATAD3A Alexander Rossor gene: ATAD3A was added
gene: ATAD3A was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: ATAD3A was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ATAD3A were set to 27640307
Phenotypes for gene: ATAD3A were set to global developmental delay; hypotonia; optic atrophy; axonal neuropathy; hypertrophic cardiomyopathy
Penetrance for gene: ATAD3A were set to Complete
Mode of pathogenicity for gene: ATAD3A was set to Other
Review for gene: ATAD3A was set to GREEN
Added comment: Both de novo and recessive. Multiple unrelated indivudals reported with axonal neuropathy
Sources: Expert list
Hereditary neuropathy or pain disorder v5.19 ASAH1 Alexander Rossor gene: ASAH1 was added
gene: ASAH1 was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: ASAH1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ASAH1 were set to 24164096: 12571787: 534421: 22703880
Phenotypes for gene: ASAH1 were set to Progressive myoclonic epilepsy; motor neuropathy
Penetrance for gene: ASAH1 were set to Complete
Review for gene: ASAH1 was set to GREEN
Added comment: multiple affected individuals with peripheral neuropathy
Sources: Expert list
Hereditary neuropathy or pain disorder v5.19 ARSA Alexander Rossor commented on gene: ARSA: Now a broad panel so this gene should be includedin R78
Hereditary neuropathy or pain disorder v5.19 ARL6IP1 Alexander Rossor changed review comment from: multiple individuals with neuropathy; to: multiple individuals with neuropathy
Hereditary neuropathy or pain disorder v5.19 APTX Alexander Rossor commented on gene: APTX: As per previous comments, complex phenotype, lots of evidence causes neuropathy as submitted i multiuple previous reviews
Hereditary neuropathy or pain disorder v5.19 AP5Z1 Alexander Rossor gene: AP5Z1 was added
gene: AP5Z1 was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: AP5Z1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AP5Z1 were set to 26085577
Phenotypes for gene: AP5Z1 were set to spasticity; ataxia; retinopathy; neuropathy; parkinsonism
Penetrance for gene: AP5Z1 were set to Complete
Review for gene: AP5Z1 was set to AMBER
Added comment: only a single patient with neuropathy
Sources: Expert list
Hereditary neuropathy or pain disorder v5.19 AP1S1 Alexander Rossor commented on gene: AP1S1: Scope of panel has been extended. 4 families with same splice site variant
Hereditary neuropathy or pain disorder v5.19 AMPD2 Alexander Rossor gene: AMPD2 was added
gene: AMPD2 was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: AMPD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AMPD2 were set to 27066553
Phenotypes for gene: AMPD2 were set to pontocerebellar hypoplasia, axonal neuropathy,
Review for gene: AMPD2 was set to AMBER
Added comment: Neuropathy in two individuals
Sources: Expert list
Hereditary neuropathy or pain disorder v5.16 AMACR Alexander Rossor gene: AMACR was added
gene: AMACR was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: AMACR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AMACR were set to 21576695; 10655068; 20821052; 18032455
Phenotypes for gene: AMACR were set to cerebellar ataxia; peripheral neuropathy; seizures; cataracts; retinitis pigmentosa
Penetrance for gene: AMACR were set to Complete
Review for gene: AMACR was set to GREEN
Added comment: multipel reports with peripheral neuropathy
Sources: Expert list
Hereditary neuropathy or pain disorder v5.16 ALDH18A1 Alexander Rossor gene: ALDH18A1 was added
gene: ALDH18A1 was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: ALDH18A1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ALDH18A1 were set to https://doi.org/10.1093/brain/awv143
Phenotypes for gene: ALDH18A1 were set to spastic paraplegia; cognitive impairment; motor neuronopathy
Penetrance for gene: ALDH18A1 were set to Complete
Review for gene: ALDH18A1 was set to AMBER
Added comment: Currently present in several members of two unrelated families
Sources: Expert list
Hereditary neuropathy or pain disorder v5.16 AFG3L2 Alexander Rossor gene: AFG3L2 was added
gene: AFG3L2 was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: AFG3L2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: AFG3L2 were set to 22022284:
Phenotypes for gene: AFG3L2 were set to spasticity, peripheral neuropathy, ptosis, oculomotor apraxia; dystonia; cerebellar atrophy; progressive myoclonic epilepsy
Penetrance for gene: AFG3L2 were set to Complete
Review for gene: AFG3L2 was set to AMBER
Added comment: I think Amber, only a single family
Sources: Expert list
Hereditary neuropathy or pain disorder v5.16 ADPRHL2 Alexander Rossor gene: ADPRHL2 was added
gene: ADPRHL2 was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: ADPRHL2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADPRHL2 were set to 30401461: 30100084
Phenotypes for gene: ADPRHL2 were set to Neurodegeneration; childhood-onset; ataxia; seizure; axonal polyneuropathy
Penetrance for gene: ADPRHL2 were set to Complete
Review for gene: ADPRHL2 was set to GREEN
Added comment: Sources: Expert list
Hereditary neuropathy or pain disorder v5.16 ADGRG6 Alexander Rossor gene: ADGRG6 was added
gene: ADGRG6 was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: ADGRG6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADGRG6 were set to 26004201
Phenotypes for gene: ADGRG6 were set to lethal congenital contracture syndrome; lack of peripheral myelination
Penetrance for gene: ADGRG6 were set to Complete
Review for gene: ADGRG6 was set to GREEN
Added comment: 4 individuals, 3 unrelated families, absence of myelinated axons on post mortem
Sources: Expert list
Hereditary neuropathy or pain disorder v5.16 ADCY6 Alexander Rossor gene: ADCY6 was added
gene: ADCY6 was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: ADCY6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADCY6 were set to 31846058: 26257172: 24319099
Phenotypes for gene: ADCY6 were set to lethal congenital contracture syndrome; loss of axons
Penetrance for gene: ADCY6 were set to Complete
Review for gene: ADCY6 was set to GREEN
Added comment: Sources: Expert list
Hereditary neuropathy or pain disorder v5.16 ADA2 Alexander Rossor gene: ADA2 was added
gene: ADA2 was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: ADA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADA2 were set to 34210540:37584090
Phenotypes for gene: ADA2 were set to VASCULITIS; AUTOINFLAMMATION; IMMUNODEFICIENCY; HEMATOLOGIC DEFECTS; peripheral neuropathy; stroke
Penetrance for gene: ADA2 were set to Complete
Review for gene: ADA2 was set to GREEN
Added comment: Sources: Expert list
Hereditary neuropathy or pain disorder v5.16 ABCD1 Alexander Rossor gene: ABCD1 was added
gene: ABCD1 was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: ABCD1 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: ABCD1 were set to https://doi.org/10.1093/brain/awt361
Phenotypes for gene: ABCD1 were set to adreno leukodystrophy; adrenomyeloneuropathy
Penetrance for gene: ABCD1 were set to Complete
Review for gene: ABCD1 was set to GREEN
Added comment: Peripheral neuropathy in 50% female carriers
Sources: Expert list
Hereditary neuropathy or pain disorder v5.16 AAAS Alexander Rossor gene: AAAS was added
gene: AAAS was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: AAAS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AAAS were set to 34796249
Phenotypes for gene: AAAS were set to ACHALASIA; ADDISONIANISM; ALACRIMA; peripheral neuropathy
Penetrance for gene: AAAS were set to Complete
Review for gene: AAAS was set to GREEN
Added comment: Sources: Expert list
Hereditary neuropathy or pain disorder v5.16 RTN2 Achchuthan Shanmugasundram commented on gene: RTN2: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Hereditary neuropathy or pain disorder v5.16 PDXK Achchuthan Shanmugasundram commented on gene: PDXK: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Hereditary neuropathy or pain disorder v5.16 HMBS Achchuthan Shanmugasundram commented on gene: HMBS: The mode of inheritance of this gene has been updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.
Hereditary neuropathy or pain disorder v5.16 COQ7 Achchuthan Shanmugasundram commented on gene: COQ7: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Hereditary neuropathy or pain disorder v5.16 CADM3 Achchuthan Shanmugasundram commented on gene: CADM3: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Hereditary neuropathy or pain disorder v5.8 LRP12 Sarah Leigh changed review comment from: A trinucleotide expansion LRP12_CGG variant has been reported in numerous unrelated Japanese individuals with either Amyotrophic lateral sclerosis 28, OMIM:620452 or Oculopharyngodistal myopathy 1, OMIM:164310 (PMID:39013564; 37339631; 31332380).
This STR has not been approved or verified by Genomics England Clinical Team or Rare Disease Analyst, it can not be added to PanelApp at present.; to: A trinucleotide expansion LRP12_CGG variant has been reported in numerous unrelated Japanese individuals with either Amyotrophic lateral sclerosis 28, OMIM:620452 or Oculopharyngodistal myopathy 1, OMIM:164310 (PMID:39013564; 37339631; 31332380).
This STR has not been approved or verified by Genomics England Clinical Team or Rare Disease Analyst, therefore, it can not be added to PanelApp at present.
Hereditary neuropathy or pain disorder v5.8 LRP12 Sarah Leigh changed review comment from: A trinucleotide expansion LRP12_CGG variant has been reported in numerous unrelated Japanese individuals with either Amyotrophic lateral sclerosis 28, OMIM:620452 or Oculopharyngodistal myopathy 1, OMIM:164310 (PMID:39013564; 37339631; 31332380). ; to: A trinucleotide expansion LRP12_CGG variant has been reported in numerous unrelated Japanese individuals with either Amyotrophic lateral sclerosis 28, OMIM:620452 or Oculopharyngodistal myopathy 1, OMIM:164310 (PMID:39013564; 37339631; 31332380).
This STR has not been approved or verified by Genomics England Clinical Team or Rare Disease Analyst, it can not be added to PanelApp at present.
Hereditary neuropathy or pain disorder v5.8 LRP12 Sarah Leigh changed review comment from: A trinucleotide expansion LRP12_CGG variant has been reported in numerous unrelated Japanese individuals with either Amyotrophic lateral sclerosis 28, OMIM:620452 or Oculopharyngodistal myopathy 1, OMIM:164310 (PMID:39013564; 37339631; 31332380).; to: A trinucleotide expansion LRP12_CGG variant has been reported in numerous unrelated Japanese individuals with either Amyotrophic lateral sclerosis 28, OMIM:620452 or Oculopharyngodistal myopathy 1, OMIM:164310 (PMID:39013564; 37339631; 31332380).
Hereditary neuropathy or pain disorder v4.11 ARSA Alexander Rossor edited their review of gene: ARSA: Added comment: Peripheral neuropathy is a well recognised feature of metachromatic leukodystrophy; Changed publications to: 31684987; Changed phenotypes to: Metachromatic leukodystrophy. Severe late infantile form with mental retardation and severe course. Regression before 30 months, adult onset, psychiatric symptoms, leukodystrophy on MRI, progressive neuropathy with SNCV, optic atrophy
Hereditary neuropathy or pain disorder v4.11 APTX Alexander Rossor edited their review of gene: APTX: Added comment: APTX recessive variants are a well established cause of cerebellar ataxia and peripheral neuropathy; Changed rating: GREEN; Changed publications to: 11176957
Hereditary neuropathy or pain disorder v4.11 SPTBN4 Sarah Leigh edited their review of gene: SPTBN4: Added comment: At least six SPTBN4 variants have been associated with OMIM:617519, which includes axonal and demyelinating peripheral neuropathy as one of the clinical features. Six SPTBN4 variants have been reported by PMID: 28540413;29861105 in five unrelated cases of OMIM:617519.; Changed rating: GREEN; Changed publications to: 28540413, 29861105; Changed phenotypes to: Neurodevelopmental disorder with hypotonia, neuropathy, and deafness, OMIM:617519; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v4.10 SLC12A6 Eleanor Williams commented on gene: SLC12A6
Hereditary neuropathy or pain disorder v4.3 SPTBN4 Arina Puzriakova edited their review of gene: SPTBN4: Added comment: The rating of this gene has been updated to Green and the mode of inheritance set to 'BIALLELIC, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.; Changed rating: GREEN
Hereditary neuropathy or pain disorder v4.3 NEMF Arina Puzriakova edited their review of gene: NEMF: Added comment: The rating of this gene has been updated to Green and the mode of inheritance set to 'BIALLELIC, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v4.3 SLC12A6 Arina Puzriakova edited their review of gene: SLC12A6: Added comment: The rating of this gene has been updated to Green and the mode of inheritance set to 'BIALLELIC, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v4.3 DHX9 Arina Puzriakova edited their review of gene: DHX9: Added comment: The rating of this gene has been updated to Green and the mode of inheritance set to 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' following NHS Genomic Medicine Service approval.; Changed rating: GREEN; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary neuropathy or pain disorder v3.94 CADM3 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by Ian Berry, there are now five unrelated families with peripheral neuropathy and with one of the two reported missense variants in heterozygous state. Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: As reviewed by Ian Berry, there are now at least nine probands with peripheral neuropathy and with one of the two reported missense variants in heterozygous state. Hence, this gene can be promoted to green rating in the next GMS update.
Hereditary neuropathy or pain disorder v3.94 CADM3 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Ian Berry, there are now five unrelated families with peripheral neuropathy and with one of the two reported missense variants in heterozygous state. Hence, this gene can be promoted to green rating in the next GMS update.
Hereditary neuropathy or pain disorder v3.91 GAN Arina Puzriakova Added comment: Comment on list classification: This gene should be promoted to Green at the next GMS panel update as the scope of this panel has now been expanded to include complex cases of neuropathy.
Biallelic variants in the GAN gene cause giant axonal neuropathy. This childhood onset polyneuropathy results in progressive neurodegeneration of both the peripheral and central nervous systems. More than 10 unrelated cases have been reported in the literature which is sufficient for making this gene Green (PMIDs: 18595793; 19231187; 20949505; 27852232; 36866531)
Hereditary neuropathy or pain disorder v3.89 RTN2 Achchuthan Shanmugasundram changed review comment from: 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 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; to: 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 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 v3.89 RTN2 Achchuthan Shanmugasundram changed review comment from: 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; to: 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 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 v3.89 RTN2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of RTN2 biallelic variants with distal hereditary motor neuropathy. Hence, this gene should be promoted to green rating in the next GMS update.
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 v3.87 PDXK Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (three unrelated cases and functional studies) for the promotion of this gene to green rating in the next GMS update.
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 v3.84 SPG7 Sarah Leigh changed review comment from: SPG7 variants have been associated with Spastic paraplegia 7, autosomal recessive (OMIM:607259) and have a definitive association with the same condition on the Eye panel at Gen2Phen. Various phenotypic features are apparent in cases of OMIM:607259. Peripheral neuropathy has been reported in at least three cases (PMID: 35096021, in the review on this panel by Williams Kirsty), and optical neuropathy has been reported in many more cases (as mentioned in PMID:35243150).; to: SPG7 variants have been associated with Spastic paraplegia 7, autosomal recessive (OMIM:607259) and have a definitive association with the same condition on the Eye panel at Gen2Phen. Various phenotypic features are apparent in cases of OMIM:607259. Peripheral neuropathy has been reported in at least three cases (PMID: 35096021, in the review on this panel by Kirsty Williams), and optical neuropathy has been reported in many more cases (as mentioned in PMID:35243150).
Hereditary neuropathy or pain disorder v3.83 SPG7 Sarah Leigh edited their review of gene: SPG7: Added comment: SPG7 variants have been associated with Spastic paraplegia 7, autosomal recessive (OMIM:607259) and have a definitive association with the same condition on the Eye panel at Gen2Phen. Various phenotypic features are apparent in cases of OMIM:607259. Peripheral neuropathy has been reported in at least three cases (PMID: 35096021, in the review on this panel by Williams Kirsty), and optical neuropathy has been reported in many more cases (as mentioned in PMID:35243150).; Changed rating: GREEN; Changed publications to: 30098094, 35637455, 35096021, 35243150, 22964162
Hereditary neuropathy or pain disorder v3.83 XK Alexander Rossor commented on gene: XK: Should be included in R78 as now inlcudes many other complex phenotype genes that can present with neuropathy
Hereditary neuropathy or pain disorder v3.83 TYMP Alexander Rossor edited their review of gene: TYMP: Added comment: Can present with neuropathy and should be included in R78 panel; Changed publications to: 21933806
Hereditary neuropathy or pain disorder v3.83 SURF1 Alexander Rossor edited their review of gene: SURF1: Added comment: Should be included as R78 now includes complex phenotype genes; Changed publications to: 27475922, 12026244, 24027061
Hereditary neuropathy or pain disorder v3.83 SPTBN4 Alexander Rossor commented on gene: SPTBN4
Hereditary neuropathy or pain disorder v3.83 SLC25A19 Alexander Rossor edited their review of gene: SLC25A19: Added comment: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46; Changed phenotypes to: Acute encephalopathic episodes and paralysis following febrile illness with almost complete recovery. Absent sensory-motor action potential during illness. Bilateral striatal necrosis on MRI. Additional chronic progressive axonal neuropathy
Hereditary neuropathy or pain disorder v3.83 SCARB2 Alexander Rossor edited their review of gene: SCARB2: Added comment: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46; Changed publications to: 21670406, 19597094
Hereditary neuropathy or pain disorder v3.83 SACS Alexander Rossor edited their review of gene: SACS: Added comment: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46; Changed publications to: 30460542
Hereditary neuropathy or pain disorder v3.83 POLR3A Alexander Rossor commented on gene: POLR3A: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46
Hereditary neuropathy or pain disorder v3.83 PNPLA6 Alexander Rossor commented on gene: PNPLA6: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46
Hereditary neuropathy or pain disorder v3.83 PMM2 Alexander Rossor edited their review of gene: PMM2: Added comment: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46; Changed phenotypes 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.
Hereditary neuropathy or pain disorder v3.83 PLP1 Alexander Rossor edited their review of gene: PLP1: Added comment: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46; Changed publications to: 12601703
Hereditary neuropathy or pain disorder v3.83 PEX7 Alexander Rossor edited their review of gene: PEX7: Added comment: Should be included in R78 as can present with neuropathy and other complex disease are now include in R78; Changed publications to: 11493716
Hereditary neuropathy or pain disorder v3.83 PEX10 Alexander Rossor edited their review of gene: PEX10: Added comment: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46; Changed publications to: 27230853, 20695019
Hereditary neuropathy or pain disorder v3.83 PDYN Alexander Rossor commented on gene: PDYN: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46
Hereditary neuropathy or pain disorder v3.83 NAGA Alexander Rossor commented on gene: NAGA: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46
Hereditary neuropathy or pain disorder v3.83 MTTP Alexander Rossor commented on gene: MTTP: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46
Hereditary neuropathy or pain disorder v3.83 MMACHC Alexander Rossor edited their review of gene: MMACHC: Added comment: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46; Changed phenotypes to: Onset infancy to adulthood, thrombotic thrombocytopenia with encephalopathy, myelopathy, renal and pulmonary complications (can be life threatening), retinitis pigmentosa, axonal motor neuropathy. Treated with high dose vitamin B12.
Hereditary neuropathy or pain disorder v3.83 LYST Alexander Rossor commented on gene: LYST: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46
Hereditary neuropathy or pain disorder v3.83 IARS2 Alexander Rossor edited their review of gene: IARS2: Added comment: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46; Changed publications to: 25130867, 28328135, 30041933, 30419932
Hereditary neuropathy or pain disorder v3.83 GBA2 Alexander Rossor commented on gene: GBA2: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46
Hereditary neuropathy or pain disorder v3.83 BCKDHB Alexander Rossor edited their review of gene: BCKDHB: Added comment: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46; Changed publications to: 18855118, 11180212; Changed phenotypes to: Maple Syrup Urine Disease, Metabolic encephalopathy, elevated branched chain amino acids in urine, acute axonal neuropathy
Hereditary neuropathy or pain disorder v3.83 B4GALNT1 Alexander Rossor commented on gene: B4GALNT1: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46
Hereditary neuropathy or pain disorder v3.83 APOA1 Alexander Rossor commented on gene: APOA1: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46
Hereditary neuropathy or pain disorder v3.83 AP1S1 Alexander Rossor Deleted their comment
Hereditary neuropathy or pain disorder v3.83 AP1S1 Alexander Rossor commented on gene: AP1S1: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46
Hereditary neuropathy or pain disorder v3.83 AGXT Alexander Rossor edited their review of gene: AGXT: Added comment: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46; Changed publications to: 4701948, 25363903
Hereditary neuropathy or pain disorder v3.83 AGTPBP1 Alexander Rossor commented on gene: AGTPBP1: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46
Hereditary neuropathy or pain disorder v3.83 ABHD12 Alexander Rossor edited their review of gene: ABHD12: Added comment: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46; Changed publications to: 29571850, 20797687
Hereditary neuropathy or pain disorder v3.83 GAN Alexander Rossor commented on gene: GAN: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46
Hereditary neuropathy or pain disorder v3.83 FXN Alexander Rossor edited their review of gene: FXN: Added comment: FA can present with a sensory neuropathy and should be included in the R78 panel. A missense may prompt testing for an expansion in the other allele.; Changed publications to: 20339857
Hereditary neuropathy or pain disorder v3.83 GALC Alexander Rossor edited their review of gene: GALC: Added comment: Can present with peripheral neuropathy and should be included in R78 panel; Changed publications to: 26840509; Changed phenotypes to: Krabbe. Spastic paraplegia, developmental delay, optic atrophy, adult onset has spastic paraplegia and sensory-motor axonal neuropathy with slow or normal conduction velocities, MRI shows leukodystrophy
Hereditary neuropathy or pain disorder v3.82 HMBS Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There is sufficient evidence available (three unrelated families) for the association of biallelic HMBS variants with peripheral neuropathy. Hence, the MOI should be updated from 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS review.
Hereditary neuropathy or pain disorder v3.79 COQ7 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (four unrelated cases) for the promotion of this gene to green rating in the next GMS review.
Hereditary neuropathy or pain disorder v3.76 COQ7 Achchuthan Shanmugasundram changed review comment from: PMID:36454683 reported three siblings of Portuguese decent with distal hereditary motor neuropathy and identified with a homozygous COQ7 variant that disrupted the start codon of the main COQ7 isoform 1 (c.3G-T).

PMID:36758993 reported two unrelated males of Chinese decent, who developed slowly progressive distal muscle weakness and atrophy at 14 to 15 years of age. They were identified with compound heterozygous variants in COQ7 gene (family 1: c.253-2A-T/ p.Leu156Gln & c.467T-A/ p.Leu156Gln; family 2: c.160C-T/ p.Arg54Trp & c.467T-G/ p.Leu156Arg).

PMID:3707755 reported three siblings of Syrian decent who presented with progressive distal limb muscle weakness and atrophy due to a length-dependent peripheral motor neuropathy. They were identified with a homozygous COQ7 variant (c.1A-G).

This gene has been associated with relevant phenotype in OMIM (MIM #620402), but not in Gene2Phenotype.; to: PMID:36454683 reported three siblings of Portuguese decent with distal hereditary motor neuropathy and identified with a homozygous COQ7 variant that disrupted the start codon of the main COQ7 isoform 1 (c.3G-T).

PMID:36758993 reported two unrelated males of Chinese decent, who developed slowly progressive distal muscle weakness and atrophy at 14 to 15 years of age. They were identified with compound heterozygous variants in COQ7 gene (family 1: c.253-2A-T/ p.Leu156Gln & c.467T-A/ p.Leu156Gln; family 2: c.160C-T/ p.Arg54Trp & c.467T-G/ p.Leu156Arg).

PMID:37077559 reported three siblings of Syrian decent who presented with progressive distal limb muscle weakness and atrophy due to a length-dependent peripheral motor neuropathy. They were identified with a homozygous COQ7 variant (c.1A-G).

This gene has been associated with relevant phenotype in OMIM (MIM #620402), but not in Gene2Phenotype.
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 v3.74 PDK3 Eleanor Williams changed review comment from: The rating of this gene has been updated togreenfollowing NHS Genomic Medicine Service approval.; to: The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Hereditary neuropathy or pain disorder v3.74 PCYT2 Achchuthan Shanmugasundram changed review comment from: PMID:35243002 reported two brothers with a novel homozygous missense variant in the first catalytic domain of PCYT2 (c.88T>G/ p.Cys30Gly). Although these two patients shared several phenotypic features with previously reported patients with syndromic spastic paraplegia including short stature, spastic tetraparesis, cerebellar ataxia, epilepsy, and cognitive decline, these were the first patients reported with axonal polyneuropathy.; to: PMID:35243002 reported two brothers with a novel homozygous missense variant in the first catalytic domain of PCYT2 (c.88T>G/ p.Cys30Gly). Although these two patients shared several phenotypic features with previously reported patients with syndromic spastic paraplegia including short stature, spastic tetraparesis, cerebellar ataxia, epilepsy, and cognitive decline, axonal polyneuropathy reported in these two brothers were not reported in any previous cases.
Hereditary neuropathy or pain disorder v3.71 EMILIN1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, there are two unrelated families in support of the association of monoallelic EMILIN1 variants with peripheral neuropathy and hence this gene should be rated amber with current evidence.
Hereditary neuropathy or pain disorder v3.68 SLC12A6 Arina Puzriakova commented on gene: SLC12A6
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 v3.65 SARS Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of SARS1 gene in this panel in the next GMS review.
Hereditary neuropathy or pain disorder v3.62 SARS Achchuthan Shanmugasundram commented on gene: SARS: Added new-gene-name tag, new approved HGNC gene symbol for SARS is SARS1.
Hereditary neuropathy or pain disorder v3.62 SARS Achchuthan Shanmugasundram changed review comment from: PMID:36088542 - Two different heterozygous missense variants within the aminoacylation domain of SARS1 gene was identified in 16 affected individuals from three unrelated families with Charcot-Marie-Tooth (CMT) disease. The mutant SerRS proteins exhibited reduced aminoacylation activity and abnormal SerRS dimerization, which suggests the impairment of total protein synthesis and induction of eIF2α phosphorylation.

PMID:37706277 - A female patient with demyelinating CMT was identified with a heterozygous variant in SARS1 gene.


Biallelic variants in this gene have already been associated with relevant phenotypes in both OMIM (MIM #617709) and Gene2Phenotype, while monoallelic variants are associated with phenotype only in Gene2Phenotype (with 'limited' rating in the DD panel).; to: PMID:36088542 - Two different heterozygous missense variants within the aminoacylation domain of SARS1 gene was identified in 16 affected individuals from three unrelated families with Charcot-Marie-Tooth (CMT) disease. The mutant SerRS proteins exhibited reduced aminoacylation activity and abnormal SerRS dimerization, which suggests the impairment of total protein synthesis and induction of eIF2α phosphorylation.

PMID:37706277 - A female patient with demyelinating CMT was identified with a heterozygous variant in SARS1 gene.

Biallelic variants in this gene have already been associated with relevant phenotypes in both OMIM (MIM #617709) and Gene2Phenotype, while monoallelic variants are associated with phenotype only in Gene2Phenotype (with 'limited' rating in the DD panel).
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 v3.60 DRP2 Eleanor Williams commented on gene: DRP2
Hereditary neuropathy or pain disorder v3.56 SYT2 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of this gene to this panel (six unrelated cases and functional studies) and this gene should therefore be promoted to green rating in the next GMS review.
Hereditary neuropathy or pain disorder v3.52 DHTKD1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence for this gene to be promoted to green rating in the next GMS review.
Hereditary neuropathy or pain disorder v3.48 SPTAN1 Sarah Leigh Added comment: Comment on mode of inheritance: Three unrelated cases have been reported with biallelic SPTAN1 variants (PMID: 31515523 & 34526651) . Neuropathy or pain was not part of the complex phenotypes that was seen in these cases.
Hereditary neuropathy or pain disorder v3.47 SPTAN1 Sarah Leigh edited their review of gene: SPTAN1: Added comment: SPTAN1 variants have been associated with Developmental and epileptic encephalopathy 5 (OMIM:613477) and as definitive Gen2Phen gene for the same condition.; Changed rating: GREEN
Hereditary neuropathy or pain disorder v3.47 SPTAN1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Hereditary neuropathy or pain disorder v3.45 AGTPBP1 Achchuthan Shanmugasundram changed review comment from: PMID:30420557 reported the identification of either homozygous or compound heterozygous variants in AGTPBP1 gene in 13 individuals from 10 unrelated families with infantile‐onset neurodegeneration. Five unrelated patients had (axonal) motor neuropathy.

This gene has been associated with relevant phenotypes in both OMIM (MIM #618276) and Gene2Phenotype (on DD panel with 'definitive' rating).; to: PMID:30420557 reported the identification of either homozygous or compound heterozygous variants in AGTPBP1 gene in 13 individuals from 10 unrelated families with infantile‐onset neurodegeneration. Five unrelated patients had (axonal) motor neuropathy. In addition, functional studies with mouse models have recapitulated the human phenotype.

This gene has been associated with relevant phenotypes in both OMIM (MIM #618276) and Gene2Phenotype (on DD panel with 'definitive' rating).
Hereditary neuropathy or pain disorder v3.45 AGTPBP1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence for this gene to be promoted to green rating at the next major review.
Hereditary neuropathy or pain disorder v3.44 DHX9 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available (three unrelated cases) for promoting this gene to green rating in the next major update.
Hereditary neuropathy or pain disorder v3.40 DNAJC3 Achchuthan Shanmugasundram changed review comment from: PMID:25466870 - Five individuals from two different families with demyelinating sensorimotor peripheral neuropathy and identified with homozygous DNAJC3 variants (family 1: c.580C>T (p.Arg194Ter); family 2: 72kb del (exons 6-12)).

PMID:28940199 - Cousin of family 1 from PMID:2546687 with the same variant and presented with demyelinating sensorimotor peripheral neuropathy.

PMID:32738013 - Two unrelated cases with homozygous splice site variants (case 1: c.393+2T>G; case 2: c.393+2T>C) in DNAJC3 and were reported with sensorimotor demyelinating and axonal polyneuropathy.

PMID:33486469 - Two unrelated patients identified with compound heterozygous (patient 1: p.Met1Val & p.Arg346Ter) or homozygous (p.Arg393Ter) variants, of which patient 1 had demyelinating peripheral sensorimotor neuropathy.

PMID:34654017 - One of two siblings identified with homozygous DNAJC3 variant (c.367_1370delAGAA; p.Lys456SerfsTer85) presented with demyelinating neuropathy among several other clinical manifestations.; to: PMID:25466870 - Five individuals from two different families with demyelinating sensorimotor peripheral neuropathy and identified with homozygous DNAJC3 variants (family 1: c.580C>T (p.Arg194Ter); family 2: 72kb del (exons 6-12)).

PMID:28940199 - Cousin of family 1 from PMID:2546687 with the same variant and presented with demyelinating sensorimotor peripheral neuropathy.

PMID:32738013 - Two unrelated cases with homozygous splice site variants (case 1: c.393+2T>G; case 2: c.393+2T>C) in DNAJC3 and were reported with sensorimotor demyelinating and axonal polyneuropathy.

PMID:33486469 - Two unrelated patients identified with compound heterozygous (patient 1: p.Met1Val & p.Arg346Ter) or homozygous (p.Arg393Ter) variants, of which patient 1 had demyelinating peripheral sensorimotor neuropathy.

PMID:34654017 - One of two siblings identified with homozygous DNAJC3 variant (c.367_1370delAGAA; p.Lys456SerfsTer85) presented with demyelinating neuropathy.
Hereditary neuropathy or pain disorder v3.40 DNAJC3 Achchuthan Shanmugasundram changed review comment from: PMID:25466870 - Five individuals from two different families with demyelinating sensorimotor peripheral neuropathy and identified with homozygous DNAJC3 variants (family 1: c.580C>T (p.Arg194Ter); family 2: 72kb del (exons 6-12)).

PMID:28940199 - Cousin of family 1 from PMID:2546687 with the same variant and presented with demyelinating sensorimotor peripheral neuropathy.

PMID:32738013 - Two unrelated cases with homozygous splice site variants (case 1: c.393+2T>G; case 2: c.393+2T>C) in DNAJC3 and were reported with sensorimotor demyelinating and axonal polyneuropathy among several clinical manifestations.

PMID:33486469 - Two unrelated patients identified with compound heterozygous (patient 1: p.Met1Val & p.Arg346Ter) or homozygous (p.Arg393Ter) variants, of which patient 1 had demyelinating peripheral sensorimotor neuropathy.

PMID:34654017 - One of two siblings identified with homozygous DNAJC3 variant (c.367_1370delAGAA; p.Lys456SerfsTer85) presented with demyelinating neuropathy among several other clinical manifestations.; to: PMID:25466870 - Five individuals from two different families with demyelinating sensorimotor peripheral neuropathy and identified with homozygous DNAJC3 variants (family 1: c.580C>T (p.Arg194Ter); family 2: 72kb del (exons 6-12)).

PMID:28940199 - Cousin of family 1 from PMID:2546687 with the same variant and presented with demyelinating sensorimotor peripheral neuropathy.

PMID:32738013 - Two unrelated cases with homozygous splice site variants (case 1: c.393+2T>G; case 2: c.393+2T>C) in DNAJC3 and were reported with sensorimotor demyelinating and axonal polyneuropathy.

PMID:33486469 - Two unrelated patients identified with compound heterozygous (patient 1: p.Met1Val & p.Arg346Ter) or homozygous (p.Arg393Ter) variants, of which patient 1 had demyelinating peripheral sensorimotor neuropathy.

PMID:34654017 - One of two siblings identified with homozygous DNAJC3 variant (c.367_1370delAGAA; p.Lys456SerfsTer85) presented with demyelinating neuropathy among several other clinical manifestations.
Hereditary neuropathy or pain disorder v3.39 DNAJC3 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are six unrelated families with DNAJC3 biallelic variants and presenting with demyelinating sensorimotor peripheral neuropathy. Hence, this gene can be promoted to Green at the next GMS review.
Hereditary neuropathy or pain disorder v3.36 PPOX Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: Comment on mode of inheritance: There are at least three cases of variegate porphyria reported with biallelic variants in PPOX gene and sensory neuropathy. Hence, the MOI should be updated from "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted" to "BOTH monoallelic and biallelic, autosomal or pseudoautosomal" in the next GMS review.
Hereditary neuropathy or pain disorder v3.35 ITPR3 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Hereditary neuropathy or pain disorder v3.31 NTRK1 Achchuthan Shanmugasundram changed review comment from: I agree with Zornitza Stark that it is a complex phenotype. However, neuropathy has been associated with the phenotype in sufficient number of cases and been reviewed by several expert reviewers. Hence, the rating should remain as Green.

This gene has been associated with relevant phenotypes in both OMIM (MIM #256800) and Gene2Phenotype (with 'definitive' rating in DD and skin panels.; to: I agree with Zornitza Stark that it is a complex phenotype. However, neuropathy has been associated with the phenotype in sufficient number of cases and been reviewed by several expert reviewers. Hence, the rating should remain as Green.

This gene has been associated with relevant phenotypes in both OMIM (MIM #256800) and Gene2Phenotype (with 'definitive' rating in DD and skin panels).
Hereditary neuropathy or pain disorder v3.30 MYH14 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are four families reported with the same variant (p.Arg941Leu) and with supporting functional studies characterising this variant. As the reported cases came from both Korean and North American families, it is not likely to be a founder variant. Hence, this gene can be promoted to GREEN rating at the next GMS update.
Hereditary neuropathy or pain disorder v3.21 UBA1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence (at least nine unrelated cases and supportive functional evidence) available for this gene to be promoted to GREEN at the next major review.
Hereditary neuropathy or pain disorder v3.18 UBA1 Achchuthan Shanmugasundram changed review comment from: As reported in PMID:18179898 and reviewed in OMIM, X-linked spinal muscular atrophy-2 (SMAX2) is characterised by neonatal onset of severe hypotonia, areflexia, and multiple congenital contractures, known as arthrogryposis, associated with loss of anterior horn cells and infantile death. Variants in UBA1 gene ( p.Asn577Asn in three families, and p.Met539Ile and p.Ser547Gly in one family each) were identified in five of screened X-linked spinal muscular atrophy families.

Additional unrelated cases with variants in UBA1 gene are reported in PMIDs: 23518311, 26028276, 31932168 & 32181232.

This gene has been reported with relevant phenotypes in OMIM (MIM #301830).; to: As reported in PMID:18179898 and reviewed in OMIM, X-linked spinal muscular atrophy-2 (SMAX2) is characterised by neonatal onset of severe hypotonia, areflexia, and multiple congenital contractures, known as arthrogryposis, associated with loss of anterior horn cells and infantile death. Variants in UBA1 gene ( p.Asn577Asn in three families, and p.Met539Ile and p.Ser547Gly in one family each) were identified in five of screened X-linked spinal muscular atrophy families.

Additional unrelated cases with variants in UBA1 gene are reported in PMIDs: 23518311, 26028276, 31932168 & 32181232.

This gene has been reported with relevant phenotypes in OMIM (MIM #301830).
Hereditary neuropathy or pain disorder v3.18 VAPB Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence (>3 unrelated cases & functional studies from mouse models) for this gene to be promoted to GREEN at the next major review.
Hereditary neuropathy or pain disorder v3.15 DRP2 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark (Australian Genomics), there is sufficient evidence (3 unrelated cases and functional studies) for this gene to be promoted to GREEN at the next major review.
Hereditary neuropathy or pain disorder v3.12 GBF1 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark (Australian Genomics) and Dmitrijs Rots (RadboudUMC), this gene should be promoted to GREEN at the next major review as there are four unrelated families identified with monoallelic (2 de novo and 2 dominant) variants in GBF1 gene and reported with distal hereditary motor neuropathies (HMNs)/ axonal Charcot-Marie-Tooth neuropathy (CMT2).
Hereditary neuropathy or pain disorder v3.11 GBF1 Achchuthan Shanmugasundram commented on gene: GBF1: GBF1 is associated with relevant phenotype (MIM #606483) in OMIM, but not in Gene2Phenotype.
Hereditary neuropathy or pain disorder v3.9 SPG7 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as definitive Gen2Phen gene. Numerous biallelic SPG7 variants have been reported (PMIDs: 9635427; 16534102; 17646629; 18200586, 20186691; 22571692) and at least five monoallelic SPG7 variants have been associated with Spastic paraplegia 7, autosomal recessive, OMIM:607259 (PMIDs: 18200586; 22571692). For this reason, the mode of inheritance for this gene should be BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form) autosomal or pseudoautosomal; to: Associated with OMIM:607259 and as definitive Gen2Phen gene for the same condition. Numerous biallelic SPG7 variants have been reported (PMIDs: 9635427; 16534102; 17646629; 18200586, 20186691; 22571692) and at least five monoallelic SPG7 variants have been associated with Spastic paraplegia 7, autosomal recessive, OMIM:607259 (PMIDs: 18200586; 22571692). For this reason, the mode of inheritance for this gene should be BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form) autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v3.9 SPG7 Sarah Leigh commented on gene: SPG7
Hereditary neuropathy or pain disorder v3.6 TDP1 Achchuthan Shanmugasundram changed review comment from: As reviewed by Ian Berry (Leeds Genetics Laboratory), there are now three unrelated families reported in literature with Spinocerebellar ataxia with axonal neuropathy-1 (SCAN1) and identified with homozygous variant in TDP1 gene. However, all three families are of Arab descent (one family from Saudi Arabia and two families from Oman) and they presented with the same homozygous variant (p.His493Arg).

This gene has been associated with phenotypes in OMIM (MIM #607250), but not in Gene2Phenotype.; to: As reviewed by Ian Berry (Leeds Genetics Laboratory), there are now three unrelated families reported in literature with Spinocerebellar ataxia with axonal neuropathy-1 (SCAN1) and identified with homozygous variant in TDP1 gene. However, all three families are of Arab descent (one family from Saudi Arabia and two families from Oman) and they presented with the same homozygous variant (p.His493Arg).

There are a number of functional studies characterising the function of H493R variant in vitro (PMIDs:15920477, 17948061 & 31723605).

This gene has been associated with phenotypes in OMIM (MIM #607250), but not in Gene2Phenotype.
Hereditary neuropathy or pain disorder v3.6 TDP1 Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene can now be promoted to AMBER as there are three unrelated cases. The "founder-effect" tag has been added as they are all of Middle Eastern descent and harboured the same homozygous variant. Hence, it cannot be promoted to green rating.
Hereditary neuropathy or pain disorder v2.25 SCO2 Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene should be rated GREEN as there are four unrelated cases identified with CMT type 4 (axonal polyneuropathy).
Hereditary neuropathy or pain disorder v2.22 SCO2 Achchuthan Shanmugasundram Deleted their comment
Hereditary neuropathy or pain disorder v2.22 SCO2 Achchuthan Shanmugasundram commented on gene: SCO2: As reviewed by Zornitza Stark, PMID:29351582 reported two unrelated cases with compound heterozygous variants in SCO2 gene (p.Glu140Lys/ p.Pro169Thr and p.Asp135Gly/ p.Arg171Gln). These two patients presented with axonal polyneuropathy (Charcot-Marie-Tooth disease type 4). They developed predominantly motor neuropathy, survived infancy, and have not yet developed the cardiomyopathy that causes death in early infancy in previously reported patients associated with Mitochondrial complex IV deficiency, nuclear type 2 (MIM #604377).

PMID:31844624 reported two siblings with homozygous missense variant in SCO2 gene (p.Arg255Trp) who presented with cerebellar ataxia, progressive peripheral axonal neuropathy and long survival. Similarly, homozygous variant p.Gly121Arg was identified in two brothers in PMID:35112411 and they were reported with axonal motor neuropathy like the other cases.

Autosomal recessive variants in this gene have been associated with Mitochondrial complex IV deficiency, nuclear type 2 (MIM #604377) in OMIM and Gene2Phenotype, which primarily has a cardiac phenotype. The axonal neuropathy phenotype without cardiac presentation has not yet been recorded in these resources.
Hereditary neuropathy or pain disorder v2.18 TFG Eleanor Williams commented on gene: TFG
Hereditary neuropathy or pain disorder v2.18 SH3TC2 Eleanor Williams commented on gene: SH3TC2
Hereditary neuropathy or pain disorder v2.18 KIF1A Eleanor Williams commented on gene: KIF1A
Hereditary neuropathy or pain disorder v2.18 FIG4 Eleanor Williams commented on gene: FIG4
Hereditary neuropathy or pain disorder v2.18 CPOX Eleanor Williams commented on gene: CPOX
Hereditary neuropathy or pain disorder v2.9 TECPR2 Mafalda Gomes changed review comment from: Neuser et al. (2021) report 17 unrelated cases with a biallelic pathogenic variants in TECPR2. The study also includes 11 previously reported patients. The core manifestations in these individuals are global developmental delay/intellectual disability, muscular hypotonia, ataxia, hyporeflexia, respiratory infections, and central/nocturnal hypopnea. Peripheral neuropathy was present in two-thirds of all individuals. The majority of the pathogenic variants identified are truncating variants; however, missense variants were also found, predominantly located in the N-terminal and C-terminal regions. The TECPR2 gene is implicated in the autophagy pathway, which is critical to the development and function of the central nervous system. Loss?of?function variants in several genes of the autophagy pathway lead to both neurodevelopmental and neurodegenerative diseases. In summary, this gene should be promoted to GREEN in this panel, with autosomal recessive mode of inheritance.; to: Neuser et al. (2021) report 17 unrelated cases with a biallelic pathogenic variants in TECPR2. The study also includes 11 previously reported patients. The core manifestations in these individuals are global developmental delay/intellectual disability, muscular hypotonia, ataxia, hyporeflexia, respiratory infections, and central/nocturnal hypopnea. Peripheral neuropathy was present in two-thirds of all individuals. The majority of the pathogenic variants identified are truncating variants; however, missense variants were also found, predominantly located in the N-terminal and C-terminal regions. The TECPR2 gene is implicated in the autophagy pathway, which is critical to the development and function of the central nervous system. Loss of function variants in several genes of the autophagy pathway lead to both neurodevelopmental and neurodegenerative diseases. In summary, this gene should be promoted to GREEN in this panel, with autosomal recessive mode of inheritance.
Hereditary neuropathy or pain disorder v2.7 MYH14 Dmitrijs Rots reviewed gene: MYH14: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments; Publications: 31231018; Phenotypes: Neuropathy; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Hereditary neuropathy or pain disorder v2.3 CADM3 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). To date only one paper reports three families with the same missense variant in CADM3. A separate report and/or another variant causing disease would help corroborate this association and so rating Amber for now with a 'watchlist' tag.
Hereditary neuropathy or pain disorder v1.105 FAM126A Eleanor Williams commented on gene: FAM126A
Hereditary neuropathy or pain disorder v1.103 SLC5A6 Sarah Leigh edited their review of gene: SLC5A6: Added comment: Associated with relevant phenotype in OMIM and as limited Gen2Phen gene. At least 6 variants have been reported in at least 4 unrelated cases. Supportive functional studies and targeted therapeutic interventionyielded clinical improvement in four of the five patients (PMID: 35013551).; Changed rating: GREEN; Changed publications to: 35013551; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v1.103 SLC5A6 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Hereditary neuropathy or pain disorder v1.101 TAZ Arina Puzriakova commented on gene: TAZ
Hereditary neuropathy or pain disorder v1.101 MARS Arina Puzriakova commented on gene: MARS
Hereditary neuropathy or pain disorder v1.101 C1orf194 Eleanor Williams commented on gene: C1orf194
Hereditary neuropathy or pain disorder v1.100 SETX Sarah Leigh Added comment: Comment on phenotypes: SETX variants are also associated with Amyotrophic lateral sclerosis 4, juvenile, OMIM:602433, but this condition is not relevant to this narrow panel.
Hereditary neuropathy or pain disorder v1.99 SETX Sarah Leigh Added comment: Comment on publications: PMID: 25025039 - a likely pathogenic variant in SETX reported in a sporadic case with CMT2 and spasticity. Found with a REEP1 variant, and the authors assume digenic pathogenicity.;PMID:25802885 - Identifiy one previously reported variant and three novel variants in 4 families. Report the variants found in CMT patients are likely nonpathogenic due to bioinformatics analysis. Report SETX c.7640T>C is a nonpathogenic rare variant
Hereditary neuropathy or pain disorder v1.97 OPA1 Arina Puzriakova Added comment: Comment on list classification: It has now been agreed that all genes causing neuropathy as a key feature of a phenotype, even if in the context of other syndromic symptoms, should be included on this panel to minimise the risk of missing cases. For this reason it would now be appropriate to rate this gene as Green on R78.
Hereditary neuropathy or pain disorder v1.96 OPA1 Arina Puzriakova Added comment: Comment on mode of inheritance: Updated from 'monoallelic' only to 'both mono- and biallelic'. Biallelic variants cause Behr syndrome (MIM# 210000) which is also associated with axonal sensorimotor peripheral neuropathy (PMID: 20157015; 25012220; 25146916). Sufficient cases have been reported to rate as green for both inheritance patterns.
Hereditary neuropathy or pain disorder v1.88 PCYT2 Dmitrijs Rots gene: PCYT2 was added
gene: PCYT2 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
Mode of inheritance for gene: PCYT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PCYT2 were set to PMID: 35243002
Review for gene: PCYT2 was set to AMBER
Added comment: Two brother with axonal neuropathy reported in PMID: 35243002. In the same study, after reviewing previously published cases, other individuals (2/10) had sensory deficit / neuropathy: "Of 5 previously reported adult patients (age range of 20–59 years),2-6 nerve conduction studies were performed in 2 of them and reported as normal.3,4 Clinically, one of them had hypopallesthesia of the ankles,4 and the other had loss of vibration sense in the lower limbs and mild loss of proprioception in the feet".
Sources: Literature
Hereditary neuropathy or pain disorder v1.88 SLC12A6 Sarah Leigh commented on gene: SLC12A6: The to_be_confirmed_NHSE tag has been added, as further NHSE review is required.
Hereditary neuropathy or pain disorder v1.88 SPTBN4 Sarah Leigh commented on gene: SPTBN4
Hereditary neuropathy or pain disorder v1.88 NEMF Sarah Leigh commented on gene: NEMF
Hereditary neuropathy or pain disorder v1.88 AR_CAG Ivone Leong commented on STR: AR_CAG
Hereditary neuropathy or pain disorder v1.88 MME Ivone Leong Tag Q4_21_expert_review was removed from gene: MME.
Tag Q4_21_MOI was removed from gene: MME.
Tag Q4_21_NHS_review was removed from gene: MME.
Hereditary neuropathy or pain disorder v1.88 VWA1 Sarah Leigh commented on gene: VWA1: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Hereditary neuropathy or pain disorder v1.88 POLR3B Sarah Leigh commented on gene: POLR3B
Hereditary neuropathy or pain disorder v1.88 PIGB Sarah Leigh commented on gene: PIGB
Hereditary neuropathy or pain disorder v1.88 MME Sarah Leigh commented on gene: MME
Hereditary neuropathy or pain disorder v1.88 HEXB Sarah Leigh commented on gene: HEXB
Hereditary neuropathy or pain disorder v1.88 HEXA Sarah Leigh commented on gene: HEXA
Hereditary neuropathy or pain disorder v1.88 GSN Sarah Leigh commented on gene: GSN
Hereditary neuropathy or pain disorder v1.88 C1orf194 Sarah Leigh commented on gene: C1orf194: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Hereditary neuropathy or pain disorder v1.87 MME Ivone Leong Mode of inheritance for gene MME was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
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 PNKP Sarah Leigh commented on gene: PNKP: The rating of this gene has been updated following NHS Genomic Medicine Service approval.
Hereditary neuropathy or pain disorder v1.83 SORD Sarah Leigh commented on gene: SORD
Hereditary neuropathy or pain disorder v1.80 SLC12A6 Sarah Leigh edited their review of gene: SLC12A6: Added comment: In reviewing SLC12A6 on the Intellectual disabily panel, it was suggested that this gene should be green on this panel (source NHS Genomic Medicine Service).; Changed rating: GREEN
Hereditary neuropathy or pain disorder v1.80 SLC5A6 Ian Berry gene: SLC5A6 was added
gene: SLC5A6 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS
Mode of inheritance for gene: SLC5A6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC5A6 were set to PMID: 35013551
Phenotypes for gene: SLC5A6 were set to motor neuropathy
Penetrance for gene: SLC5A6 were set to Complete
Review for gene: SLC5A6 was set to GREEN
Added comment: Five individuals reported including three siblings with identical genotypes. Targeted therapy with biotin (therapeutic in other manifestations of this gene and in other biotin transporter deficiencies) improved phenotype in patients.
Sources: NHS GMS
Hereditary neuropathy or pain disorder v1.79 PDK3 Arina Puzriakova Added comment: Comment on list classification: At least two variants in three unrelated families reported (founder effect ruled out), as well as functional analyses conducted in patient fibroblasts, cell lines, and animal model. This supports a rating upgrade on this panel from Amber to Green at the next GMS panel update (tagged).
Hereditary neuropathy or pain disorder v1.78 MME Arina Puzriakova Tag Q4_21_expert_review tag was added to gene: MME.
Hereditary neuropathy or pain disorder v1.78 MME Arina Puzriakova Added comment: Comment on mode of inheritance: Heterozygous variants have been identified in >10 individuals with late-onset CMT2T. However, some variants have been found in control databases and family studies indicate incomplete penetrance, suggesting heterozygous variants only confer susceptibility. Nonetheless, sufficient cases have been reported in literature and both MOIs are listed in OMIM for this phenotype, and so inclusion of monoallelic inheritance on this panel will first be flagged for GMS review.
Hereditary neuropathy or pain disorder v1.78 MME Arina Puzriakova Mode of inheritance for gene: MME was changed from BIALLELIC, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v1.77 MME Arina Puzriakova Tag adult-onset tag was added to gene: MME.
Tag Q4_21_MOI tag was added to gene: MME.
Hereditary neuropathy or pain disorder v1.77 MME Arina Puzriakova Publications for gene: MME were set to 26991897; 27588448
Hereditary neuropathy or pain disorder v1.76 MME Arina Puzriakova Phenotypes for gene: MME were changed from Charcot-Marie-Tooth disease, axonal, type 2T, 617017 to Charcot-Marie-Tooth disease, axonal, type 2T, OMIM:617017
Hereditary neuropathy or pain disorder v1.75 MME Arina Puzriakova Tag Q4_21_NHS_review tag was added to gene: MME.
Hereditary neuropathy or pain disorder v1.73 HEXB Arina Puzriakova Added comment: Comment on list classification: Neuropathy has been described in Sandhoff disease, particularly in adult-onset cases where this can be an initial finding and other symptoms may be more mild. Sufficient unrelated cases of neuropathy due to variants in this gene have been reported in literature (>3). Overall HEXB should be promoted to Green at the next GMS panel update.
Hereditary neuropathy or pain disorder v1.70 HEXA Arina Puzriakova Added comment: Comment on list classification: Neuronopathy and peripheral neuropathy have been described in Tay-Sachs disease, particularly in adult-onset cases where this can be an initial finding and other symptoms may be more mild. Sufficient unrelated cases of neuropathy due to variants in this gene have been reported in literature (>3). Overall HEXA should be promoted to Green at the next GMS panel update.
Hereditary neuropathy or pain disorder v1.68 MME Lindsey Vialard reviewed gene: MME: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 27588448, 33144514; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal; Current diagnostic: yes
Hereditary neuropathy or pain disorder v1.68 RFC1 Eleanor Williams commented on gene: RFC1: Copied this gene from the Hereditary ataxia - adult onset panel so that it is noted that the STR associated with this gene is relevant to the panel, NOT SNV/indels or deletions covering this gene. In PMID: 33969391 - Curro et al 2021 - they found that 43 patients (34%) with sensory neuropathy had biallelic AAGGG repeat expansions in RFC1and in none with sensory-motor neuropathy.
Hereditary neuropathy or pain disorder v1.67 HEXA Evan Reid gene: HEXA was added
gene: HEXA was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
Mode of inheritance for gene: HEXA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HEXA were set to PMID: 28739864; 18642377
Penetrance for gene: HEXA were set to Complete
Review for gene: HEXA was set to GREEN
Added comment: Both HEXA and HEXB autosomal recessive mutations can be associated with a late onset motor neuropathy, sometimes quite mild and sometimes resembling ALS. We missed diagnosis of a patient with a late onset motor neuropathy as HEXB is not on the neuropathy panel. I would suggest that HEXA and HEXB should both be included on this panel.
Sources: Literature
Hereditary neuropathy or pain disorder v1.65 FXN Arina Puzriakova Added comment: Comment on mode of inheritance: Updated MOI to 'Biallelic' as monoallelic variants have not been associated with disease. Patients either harbour a homozygous expansion or are compound heterozygous for an expansion and a point mutation.
Hereditary neuropathy or pain disorder v1.64 TECPR2 Dmitrijs Rots gene: TECPR2 was added
gene: TECPR2 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
Mode of inheritance for gene: TECPR2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TECPR2 were set to PubMed: 33847017
Phenotypes for gene: TECPR2 were set to Hereditary sensory and autonomic neuropathy
Penetrance for gene: TECPR2 were set to unknown
Review for gene: TECPR2 was set to GREEN
Added comment: Neuser et al. (2021) reported clinical findings in 17 patients, including 2 sib pairs, from 15 families segregating HSAN9.
Sources: Literature
Hereditary neuropathy or pain disorder v1.63 COX20 Zornitza Stark gene: COX20 was added
gene: COX20 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
Mode of inheritance for gene: COX20 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: COX20 were set to 33751098
Phenotypes for gene: COX20 were set to Neuropathy
Review for gene: COX20 was set to GREEN
gene: COX20 was marked as current diagnostic
Added comment: Well established association with mitochondrial disease, presentation with neuropathy reported PMID 33751098
Sources: Literature
Hereditary neuropathy or pain disorder v1.63 AIFM1 Arina Puzriakova commented on gene: AIFM1
Hereditary neuropathy or pain disorder v1.62 ABCA1 Arina Puzriakova commented on gene: ABCA1
Hereditary neuropathy or pain disorder v1.62 PIGB Arina Puzriakova Added comment: Comment on list classification: Axonal degenerative polyneuropathy and demyelinating sensorimotor polyneuropathy are observed in the more severely affected individuals with biallelic variants in this gene. There are sufficient cases with a relevant phenotype (5 individuals from 3 families) to rate as Green at the next GMS panel update.
Hereditary neuropathy or pain disorder v1.60 C1orf194 Sarah Leigh edited their review of gene: C1orf194: Added comment: This green review is based on the review of Alexander Rossor (UCL Institute of Neurology), 8 Mar 2021, which was entered in error on the entry for C1orf94. The review is as follows: Two unrelated families, knock in mouse with relevant phenotype. Functional evidence for one variant only. Sources: Expert list.; Changed rating: GREEN
Hereditary neuropathy or pain disorder v1.60 C1orf194 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Hereditary neuropathy or pain disorder v1.59 C1orf94 Sarah Leigh Added comment: Comment on list classification: Curator deletion of this gene from this panel.
This gene has been added to this panel in error. The publications, phenotype and reviews are appropriate for C1orf194 and not for C1orf94.
Hereditary neuropathy or pain disorder v1.58 C1orf94 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Hereditary neuropathy or pain disorder v1.57 C1orf94 Sarah Leigh changed review comment from: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. At least 2 variants reported, together with a supportive mouse knock-out model.; to: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. At least 2 variants reported, together with a supportive mouse knock-out model (PMID: 31199454; 32592472).
Hereditary neuropathy or pain disorder v1.55 JAG1 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). Sullivan et al., 2020 (PMID:32065591) report two unrelated families with segregation, presenting vocal fold paresis. Knock in mouse model showed slight but nonsignificant reduction in compound muscle action potential and morphological assessments of the recurrent laryngeal nerve were normal. Mice did however display an increased frequency of axons with focally folded myelin. Notably, variants in JAG1 are associated with several phenotypes that have not included neuropathy and there was no history of cardiac, kidney, or liver disease in affected individuals in either of the two families discussed here (possibly different mechanisms of pathogenesis but further investigation may be warranted).

At this point there is not enough evidence to add this gene as diagnostic-grade; however, additional cases would corroborate this gene-disease association - rating Amber with 'watchlist' tag.
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 v1.46 FIG4 Sarah Leigh Deleted their comment
Hereditary neuropathy or pain disorder v1.45 FIG4 Sarah Leigh Added comment: Comment on phenotypes: Amyotrophic lateral sclerosis 11 OMIM:612577; amyotrophic lateral sclerosis type 11 MONDO:0012945; Charcot-Marie-Tooth disease, type 4J, OMIM:611228; Charcot-Marie-Tooth disease type 4J MONDO:0012640;Yunis Varon syndrome OMIM:216340;Yunis-Varon syndromeMONDO:0008995
Hereditary neuropathy or pain disorder v1.41 VWA1 Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Hereditary neuropathy or pain disorder v1.35 KIF1A Arina Puzriakova Added comment: Comment on mode of inheritance: Biallelic variants are associated with autonomic-sensory neuropathy (MIM# 614213). KIF1A is also associated HSP type 30 (MIM# 610357) which can be inherited recessively or dominantly, as well as NESCAV syndrome (MIM# 614255) caused by heterozygous variants in this gene - both monoallelic conditions have been shown to include peripheral sensorimotor neuropathy.

For this reason, the MOI could be changed from 'biallelic' to 'both mono- and biallelic' if it is decided to include genes on this panel that cause neuropathy as part of a more complex phenotype (tagged for GMS review)
Hereditary neuropathy or pain disorder v1.34 GSN Ivone Leong Added comment: Comment on list classification: New gene added by Dmitrijs Rots (RadboudUMC). This gene is associated with a phenotype in OMIM and Gene2Phenotype. There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Hereditary neuropathy or pain disorder v1.30 GSN Dmitrijs Rots gene: GSN was added
gene: GSN was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
Mode of inheritance for gene: GSN was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GSN were set to PMID: 33499149; 26339870
Phenotypes for gene: GSN were set to Amyloidosis; cranial neuropathy; peripheral neuropathy; cutis laxa; cardiomyopathy; arrhytmia
Penetrance for gene: GSN were set to Complete
Review for gene: GSN was set to GREEN
gene: GSN was marked as current diagnostic
Added comment: Causes Amyloidosis, Finnish type with multisystem involvement. Peripheral and cranial neuropathy each reported in >70% of patients from >200 big cohort from Finland. PMID:26339870.
Sources: Literature
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 CADM3 Zornitza Stark gene: CADM3 was added
gene: CADM3 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
Mode of inheritance for gene: CADM3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CADM3 were set to 33889941
Phenotypes for gene: CADM3 were set to Charcot-Marie-Tooth disease
Review for gene: CADM3 was set to AMBER
Added comment: Three families reported with the same missense variant in CADM3, p.Tyr172Cys (one family de novo), with functional work in mice to show reduced expression of the mutant protein in axons and abnormal axonal organization.
Sources: Literature
Hereditary neuropathy or pain disorder v1.25 PIGB Dmitrijs Rots gene: PIGB was added
gene: PIGB was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
Mode of inheritance for gene: PIGB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PIGB were set to 31256876
Phenotypes for gene: PIGB were set to intellectual disability; developmental delay; epilepsy; axonal neuropathy
Penetrance for gene: PIGB were set to Complete
Review for gene: PIGB was set to GREEN
gene: PIGB was marked as current diagnostic
Added comment: Murakami et al., reported 10 cases with biallelic PIGB variants with complex and severe phenotype, of whom 4 had peripheral neuropathy.
Sources: Literature
Hereditary neuropathy or pain disorder v1.25 VWA1 Ian Berry gene: VWA1 was added
gene: VWA1 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS
Mode of inheritance for gene: VWA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VWA1 were set to PMID: 33559681
Phenotypes for gene: VWA1 were set to axonal hereditary motor neuropathy; myopathy
Penetrance for gene: VWA1 were set to unknown
Review for gene: VWA1 was set to GREEN
gene: VWA1 was marked as current diagnostic
Added comment: 17 individuals from 15 families, recurrent 10bp repeat allele causative in all patients. Detected in 100K so clearly tractable by WGS.
Sources: NHS GMS
Hereditary neuropathy or pain disorder v1.25 DHX9 Arina Puzriakova Added comment: Comment on list classification: Rating this gene as Red, but with a watchlist tag, until more evidence is available.
Hereditary neuropathy or pain disorder v1.24 DHX9 Arina Puzriakova gene: DHX9 was added
gene: DHX9 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Other
watchlist tags were added to gene: DHX9.
Mode of inheritance for gene: DHX9 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: DHX9 were set to Adult-onset axonal neuropathy
Added comment: Conference poster (Genomics of Rare Disease 2021) - 'DExH-box helicase 9 (DHX9) is a candidate hereditary axonal neuropathy gene' by Fatih et al, Baylor College of Medicine -

Report three unrelated individuals with adult-onset axonal neuropathy (age of onset: 41, 49, and 12 years old, respectively). Clinical features include limb weakness (3), muscle atrophy (2), diminished sensation in feet (2; plus in hands in 1 individual), ataxic gait (1), and painful neuropathy (1). All subjects exhibited neurogenic changes on EMG, and 2 cases also had normal or absent motor and sensory NCV.
Exome sequencing revealed distinct heterozygous variants in the DHX9 gene ([c.2537A>G, p.Asp846Gly]; [c.2510G>C, p.Arg837Thr]; [c.3763G>A, p.Ala1255Thr]). Segregation data was only available for one case, showing de novo occurrence. No functional data presented.

These variants have to be validated and currently DHX9 is deemed a candidate gene. No other publications in relation to this gene and phenotype are available in PubMed at this time.

Baylor College of Medicine POC: Dr. Daniel Calame, [email protected]
Sources: Other
Hereditary neuropathy or pain disorder v1.23 SPTAN1 Zornitza Stark gene: SPTAN1 was added
gene: SPTAN1 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
Mode of inheritance for gene: SPTAN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SPTAN1 were set to 20493457; 22258530; 32811770
Phenotypes for gene: SPTAN1 were set to Hereditary motor neuropathy
Review for gene: SPTAN1 was set to GREEN
gene: SPTAN1 was marked as current diagnostic
Added comment: Gene previously associated with DEE.

PMID 32811770: 13 affected individuals from 4 families reported (nonsense variants) with AD distal hereditary motor neuropathy. Variable penetrance was noted and phenotype severity differs greatly between patients. Functional studies show NMD and reduced protein levels in patient cells.
Sources: Literature
Hereditary neuropathy or pain disorder v1.23 C12orf65 Catherine Snow commented on gene: C12orf65
Hereditary neuropathy or pain disorder v1.23 POLR3B Zornitza Stark gene: POLR3B was added
gene: POLR3B was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
Mode of inheritance for gene: POLR3B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: POLR3B were set to 33417887
Phenotypes for gene: POLR3B were set to Ataxia, spasticity, and demyelinating neuropathy
Review for gene: POLR3B was set to GREEN
Added comment: Note biallelic variants cause a leukodystrophy.

New MOI and new phenotype reported in PMID: 33417887: Six unrelated individuals with de novo missense variants and ataxia, spasticity, variable intellectual disability and epilepsy, and predominantly demyelinating sensory motor peripheral neuropathy.
Protein modeling and proteomic analysis shows variants caused aberrant association of individual enzyme subunits rather than affecting overall enzyme assembly or stability.
Sources: Literature
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 v1.21 PNKP Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
Hereditary neuropathy or pain disorder v1.18 UBA5 Arina Puzriakova gene: UBA5 was added
gene: UBA5 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
Mode of inheritance for gene: UBA5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: UBA5 were set to 32179706
Phenotypes for gene: UBA5 were set to Hypomyelinating neuropathy
Added comment: Note that UBA5 variants have been associated with a range of neurological phenotypes including epilepsy, ID and ataxia.

PMID: 32179706 (2020) - Five affected individuals from a consanguineous family presenting with a severe congenital neuropathy causing early death in infancy. Some in vitro functional data included. Due to early mortality, unclear whether additional features previously associated with UBA5 variants would have developed.
Sources: Literature
Hereditary neuropathy or pain disorder v1.17 SPTBN4 Arina Puzriakova Added comment: Comment on list classification: Following discussion with Helen Brittain (Genomics England Clinical Team) it has been agreed to add this gene as Amber, awaiting review by the GMS specialist group (added 'for-review' tag).

Although neuropathy is reported in at least 5 unrelated cases with biallelic SPTBN4 variants, the phenotype relevance requires review due to the more limited scope of this panel.
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 v1.15 ITPR3 Zornitza Stark gene: ITPR3 was added
gene: ITPR3 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
Mode of inheritance for gene: ITPR3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ITPR3 were set to 32949214
Phenotypes for gene: ITPR3 were set to Charcot-Marie-Tooth disease
Review for gene: ITPR3 was set to AMBER
Added comment: Two unrelated families reported: variant segregated in four affected individuals in one family and was de novo in the second family where there was a single affected person. Some evidence for dominant-negative effect.
Sources: Literature
Hereditary neuropathy or pain disorder v1.15 NUDT2 Arina Puzriakova Added comment: Comment on list classification: Rating Amber as only 2 unrelated cases harbouring the same variant reported at present
Hereditary neuropathy or pain disorder v1.14 NUDT2 Arina Puzriakova commented on gene: NUDT2: Comment on tags: added 'founder-effect' tag - although authors state that they do not believe p.Ala63GlnfsTer3 to be a founder variant (one family of Mexican descent while the other of Cajun descent), this was not confirmed by haplotype analysis. Also added 'watchlist' tag in anticipation of further publications/clinical evidence to support association with this phenotype.
Hereditary neuropathy or pain disorder v1.13 NUDT2 Arina Puzriakova gene: NUDT2 was added
gene: NUDT2 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
watchlist, founder-effect tags were added to gene: NUDT2.
Mode of inheritance for gene: NUDT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NUDT2 were set to 27431290; 30059600; 33058507
Phenotypes for gene: NUDT2 were set to Sensorimotor polyneuropathy; Muscular hypotonia; Intellectual disability; no OMIM number
Review for gene: NUDT2 was set to AMBER
Added comment: - PMID: 33058507 (2020) - Three patients from two families harbouring the same homozygous variant (c.186del, p.Ala63GlnfsTer3). Affected individuals present distal upper and lower extremity weakness due to a sensorimotor polyneuropathy with demyelinating and/or axonal features.
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A further 4 Saudi families (7 affected individuals) with a different homozygous NUDT2 variant (c.34C> T, p.Arg12) have been published elsewhere (PMID: 27431290, 30059600), however neuropathy was not reported in these cases.
Sources: Literature
Hereditary neuropathy or pain disorder v1.12 NEMF Arina Puzriakova Added comment: Comment on list classification: Rating Amber but there is sufficient evidence to promote to Green at the next GMS panel update (added 'for-review' tag) - axonal neuropathy reported in all formally assessed cases (at least 4 with biallelic variants)
Hereditary neuropathy or pain disorder v1.11 NEMF Arina Puzriakova Added comment: Comment on mode of inheritance: Set MOI to 'Biallelic' as only 1 case with a monoallelic variant described at present. The 'watchlist' tag has been added while further evidence is gathered to establish whether or not there is a wider association with monoallelic variants and disease.
Hereditary neuropathy or pain disorder v1.10 NEMF Arina Puzriakova gene: NEMF was added
gene: NEMF was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
watchlist, for-review tags were added to gene: NEMF.
Mode of inheritance for gene: NEMF was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NEMF were set to 32934225; 33048237
Phenotypes for gene: NEMF were set to Hypotonia; Axonal neuropathy; Ataxia; Abnormal brain imaging; Global developmental delay; Intellectual disability; Kyphosis; Scoliosis; Tremor; Respiratory distress
Review for gene: NEMF was set to GREEN
Added comment: Currently not associated with any phenotype in OMIM (last edited on 04/01/2017) or Gene2Phenotype.

Gene added and expert reviewed on Intellectual Disability panel:
https://panelapp.genomicsengland.co.uk/panels/285/gene/NEMF/


- PMID: 32934225 (2020) - 8 individuals from 6 families with a juvenile neuromuscular disease due to biallelic NEMF variants. A ninth individual with similar presentation was found to harbor a single NEMF missense SNV as de novo event.

Features incl. hypotonia (4/8 with biallelic variant (B) | 1/1 monoallelic (M)), DD/ID (7/8B | 0/1M) with speech delay as universal feature (8/8B | 1/1M), axonal neuropathy (3/3B | 1/1M), ataxia (3/8B | 0/1M). Other findings included tremor (1/7B | 1/1M), abnormal brain imaging (2/6B / ?/1M), kyphosis/scoliosis (4/8B | 0/1M), respiratory distress (1/8B | 0/1M). The authors provide evidence that mice homozygous for Nemf missense mutations display progressive motor phenotypes, exhibit neurogenic atrophy and progressive axonal degeneration.


- PMID: 33048237 (2020) - 13 affected individuals from 5 unrelated families presenting with a spectrum of central and peripheral neurological involvement. Peripheral systemic neurological manifestations such as impaired eye movements, limb weakness, and axonal polyneuropathy were found in families 1, 2 and 5 - however, only 2 sibs from family 2 had a precise diagnosis for polyneuropathies. Knockdown studies in cultured mouse primary cortical neurons showed a significant decrease in axon length and impaired synapse development.
Sources: Literature
Hereditary neuropathy or pain disorder v1.8 GBF1 Zornitza Stark gene: GBF1 was added
gene: GBF1 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
Mode of inheritance for gene: GBF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GBF1 were set to 32937143
Phenotypes for gene: GBF1 were set to Axonal Neuropathy
Review for gene: GBF1 was set to GREEN
gene: GBF1 was marked as current diagnostic
Added comment: Four unrelated families with individuals affected by sporadic or dominant Distal hereditary motor neuropathies (HMNs) or axonal Charcot-Marie-Tooth neuropathy (CMT2). 3 missense variants (1 de novo) and 1 nonsense variant (de novo). Age of onset varied from childhood (nonsense variant) to 50s. Authors observed marked increase in Golgi fragmentation in primary fibroblasts derived from all affected individuals.
Sources: Literature
Hereditary neuropathy or pain disorder v1.8 C1orf194 Arina Puzriakova changed review comment from: PMID: 32592472 (2020) - Another knockout mouse model by same research group, demonstrating defects in motor and sensory functions, myelination abnormalities, peripheral nerve loss and muscle atrophy.; to: PMID: 32592472 (2020) - An additional knockout mouse model by same research group, demonstrating defects in motor and sensory functions, myelination abnormalities, peripheral nerve loss and muscle atrophy.
Hereditary neuropathy or pain disorder v1.8 C1orf194 Arina Puzriakova edited their review of gene: C1orf194: Added comment: PMID: 32592472 (2020) - Another knockout mouse model by same research group, demonstrating defects in motor and sensory functions, myelination abnormalities, peripheral nerve loss and muscle atrophy.; Changed publications: 32592472; Changed phenotypes: Charcot-Marie-Tooth
Hereditary neuropathy or pain disorder v1.7 C1orf194 Arina Puzriakova Added comment: Comment on list classification: This is has been added with an Amber rating, in accordance with the expert review by Zornitza Stark.
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 v1.6 SLC12A6 Sarah Leigh commented on gene: SLC12A6: For-review tag has been added as it maybe appropriate to change the MOI to BOTH monoallelic and biallelic, autosomal or pseudoautosomal at the next major review, to ensure that de novo heterozgous variants are identified.
Hereditary neuropathy or pain disorder v1.6 SLC12A6 Sarah Leigh commented on gene: SLC12A6
Hereditary neuropathy or pain disorder v1.5 YARS Sarah Leigh commented on gene: YARS
Hereditary neuropathy or pain disorder v1.5 EMILIN1 Zornitza Stark gene: EMILIN1 was added
gene: EMILIN1 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
Mode of inheritance for gene: EMILIN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: EMILIN1 were set to 31978608; 26462740
Phenotypes for gene: EMILIN1 were set to Peripheral neuropathy; aortic aneurysm
Review for gene: EMILIN1 was set to AMBER
Added comment: Missense mutations identified in two families. First family, proband presented with ascending and descending aortic aneurysms, bilateral lower leg and foot sensorimotor peripheral neuropathy, arthropathy, and increased skin elasticity. Variant segregated with disease in the affected proband, mother, and son. Second family, father and three affected children showed amyotrophy and weakness of the distal lower limbs, dating back to early childhood. Some functional studies performed in patient fibroblasts and zebrafish, however these were not conclusive as the two missense mutations are at different locations within the protein.
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 v1.4 C1orf194 Zornitza Stark gene: C1orf194 was added
gene: C1orf194 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
Mode of inheritance for gene: C1orf194 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: C1orf194 were set to 31199454
Phenotypes for gene: C1orf194 were set to Charcot-Marie-Tooth disease, intermediate or demyelinating
Review for gene: C1orf194 was set to AMBER
Added comment: Two unrelated families with missense variants, one with intermediate CMT, the other with demyelinating CMT. Different phenotypic manifestations may relate to different mechanism, but this remains to be fully elucidated. Supportive mouse model.
Sources: Literature
Hereditary neuropathy or pain disorder v1.4 JAG1 Zornitza Stark gene: JAG1 was added
gene: JAG1 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
Mode of inheritance for gene: JAG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: JAG1 were set to 32065591; 25707699
Phenotypes for gene: JAG1 were set to Peripheral neuropathy
Mode of pathogenicity for gene: JAG1 was set to Other
Review for gene: JAG1 was set to GREEN
Added comment: Two unrelated families reported with CMT type 2. Affected individuals in both families exhibited severe vocal fold paresis, a rare feature of peripheral nerve disease that can be life-threatening. Studies of mutant protein posttranslational modification and localization indicated that the mutations (p.Ser577Arg, p.Ser650Pro) impair protein glycosylation and reduce JAG1 cell surface expression. Mice harboring heterozygous CMT2-associated mutations exhibited mild peripheral neuropathy, and homozygous expression resulted in embryonic lethality by midgestation. Pre-existing rat model.
Sources: Literature
Hereditary neuropathy or pain disorder v1.4 VAPB Zornitza Stark gene: VAPB was added
gene: VAPB was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Expert list
Mode of inheritance for gene: VAPB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: VAPB were set to 15372378; 32162544; 28993872; 28173107; 26566915
Phenotypes for gene: VAPB were set to Adult proximal spinal muscular atrophy, autosomal dominant; dHMN/dSMA; Spinal muscular atrophy, late-onset, Finkel type, MIM# 182980
Review for gene: VAPB was set to GREEN
Added comment: p.P56S variant found in multiple families from different ethnicities but additional variant also reported; functional data.
Sources: Expert list
Hereditary neuropathy or pain disorder v1.4 UBA1 Zornitza Stark gene: UBA1 was added
gene: UBA1 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Expert list
Mode of inheritance for gene: UBA1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: UBA1 were set to 18179898
Phenotypes for gene: UBA1 were set to Spinal muscular atrophy, X-linked 2, infantile MIM#301830
Review for gene: UBA1 was set to GREEN
gene: UBA1 was marked as current diagnostic
Added comment: Five families reported, gene is Green on the Paediatric motor neuropathies panel.
Sources: Expert list
Hereditary neuropathy or pain disorder v1.4 SCO2 Zornitza Stark gene: SCO2 was added
gene: SCO2 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Expert list
Mode of inheritance for gene: SCO2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SCO2 were set to 29351582
Phenotypes for gene: SCO2 were set to axonal Charcot-Marie-Tooth disease
Review for gene: SCO2 was set to AMBER
Added comment: Two unrelated cases with compound heterozygous variants and a CMT phenotype. Cardiomyopathy not present.
Sources: Expert list
Hereditary neuropathy or pain disorder v1.0 WARS Louise Daugherty commented on gene: WARS: Added new-gene-name tag, new approved HGNC gene symbol for WARS is WARS1
Hereditary neuropathy or pain disorder v1.0 GARS Louise Daugherty Deleted their comment
Hereditary neuropathy or pain disorder v1.0 GARS Louise Daugherty commented on gene: GARS: Added new-gene-name tag, new approved HGNC gene symbol for GARS is GARS1
Hereditary neuropathy or pain disorder v1.0 AARS Louise Daugherty commented on gene: AARS: Added new-gene-name tag, new approved HGNC gene symbol for AARS is AARS1
Hereditary neuropathy or pain disorder v1.0 SEPT9 Louise Daugherty commented on gene: SEPT9: Added new-gene-name tag, new approved HGNC gene symbol for SEPT9 is SEPTIN9
Hereditary neuropathy or pain disorder v0.107 ABCA1 Louise Daugherty changed review comment from: Comment on list classification: Changed from Amber to Green - is a very rare condition, the primary feature can be neuropathy so if abnormalities of lipids or tonsils are missed or not present the diagnosis will not be made. However if there is a second panel to go to after the primary neuropathy panel and it is on it then it should still be diagnosed as long as a patient with primary neuropathy only would still be eligible for the more syndromic panel.; to: Comment on list classification: Changed from Amber to Green - recommendation from Genomics England clinical ream - is a very rare condition, the primary feature can be neuropathy so if abnormalities of lipids or tonsils are missed or not present the diagnosis will not be made. However if there is a second panel to go to after the primary neuropathy panel and it is on it then it should still be diagnosed as long as a patient with primary neuropathy only would still be eligible for the more syndromic panel.
Hereditary neuropathy or pain disorder v0.107 ABCA1 Louise Daugherty Added comment: Comment on list classification: Changed from Amber to Green - is a very rare condition, the primary feature can be neuropathy so if abnormalities of lipids or tonsils are missed or not present the diagnosis will not be made. However if there is a second panel to go to after the primary neuropathy panel and it is on it then it should still be diagnosed as long as a patient with primary neuropathy only would still be eligible for the more syndromic panel.
Hereditary neuropathy or pain disorder v0.106 VCP Louise Daugherty Added comment: Comment on list classification: Downgraded from Green to Amber from recommendation from Alex Rossor - only two published cases of VCP and neuropathy. P.Glu185Lys is absent form GNOMAD but p.Glu185Asp is present 4 times. I don’t think there have been any more cases. Might it be better as Amber for neuropathy?
Hereditary neuropathy or pain disorder v0.104 AR_CAG Louise Daugherty Added comment: Comment on list classification: changed rating : It was agreed that the 10 STRs submitted by Alex Rossor should be on the WGS panel only, with the exception of AR, which should be on both- so this STR was upgraded to Green - R78 has no mention of age in the directory, and will mostly be used for non-syndromic adult cases.
Hereditary neuropathy or pain disorder v0.92 FBXO38 Louise Daugherty changed review comment from: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope but limited evidence / SMA - limited evidence, some functional work but not strong - Amber? 2 families one very large segregating gene, possibly green if test Group supports rating?; to: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope but limited evidence / SMA - limited evidence, some functional work but not strong - Amber? 2 families one very large segregating gene, possibly green if test Group supports rating?
Hereditary neuropathy or pain disorder v0.91 DNAJB2 Louise Daugherty changed review comment from: Gene rated Green : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart)/ New evidence/re-evaluation of evidence - promotion to Green? Reviewed initially as Amber due to single reported variant in 2016, however now multiple case series Frontiers in Molecular biosciences doi: 10.3389/fmolb.2016.00081 cites 10 cases (PMID: 28018906); to: Gene rated Green : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart)/ New evidence/re-evaluation of evidence - promotion to Green? Reviewed initially as Amber due to single reported variant in 2016, however now multiple case series Frontiers in Molecular biosciences doi: 10.3389/fmolb.2016.00081 cites 10 cases (PMID: 28018906) recessive CMT/ HMN.
Hereditary neuropathy or pain disorder v0.91 DNAJB2 Louise Daugherty changed review comment from: Gene rated Green : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart)/ New evidence/re-evaluation of evidence - promotion to Green? Reviewed initially as Amber due to single reported variant in 2016, however now multiple case series Frontiers in Molecular biosciences doi: 10.3389/fmolb.2016.00081 cites 10 cases. ; to: Gene rated Green : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart)/ New evidence/re-evaluation of evidence - promotion to Green? Reviewed initially as Amber due to single reported variant in 2016, however now multiple case series Frontiers in Molecular biosciences doi: 10.3389/fmolb.2016.00081 cites 10 cases (PMID: 28018906)
Hereditary neuropathy or pain disorder v0.91 DNAJB2 Louise Daugherty changed review comment from: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart)/ Green for larger panel only as main phenotype is distal SMA; AR to provide further references; to: Gene rated Green : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart)/ New evidence/re-evaluation of evidence - promotion to Green? Reviewed initially as Amber due to single reported variant in 2016, however now multiple case series Frontiers in Molecular biosciences doi: 10.3389/fmolb.2016.00081 cites 10 cases.
Hereditary neuropathy or pain disorder v0.90 AR_CAG Louise Daugherty STR: AR_CAG was added
STR: AR_CAG was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Expert Review
STR tags were added to STR: AR_CAG.
Mode of inheritance for STR: AR_CAG was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Phenotypes for STR: AR_CAG were set to Spinal and bulbar muscular atrophy or Kennedy diseases 313200
Review for STR: AR_CAG was set to GREEN
Added comment: New Green STR submitted by Alex Rossor (UCL Institute of Neurology) on behalf of London North GLH for GMS Neurology specialist test group. This STR has been rated Amber until further discussion with the Neurology Test Group on 21st June 2019- although appropriate to have on this panel, they can be more late-onset, this panel is used for children so needs further discussion with the GLHs and Genomics England Clinical team before upgrading to Green.
Sources: Expert Review
Hereditary neuropathy or pain disorder v0.86 ZFYVE26 Louise Daugherty commented on gene: ZFYVE26: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart): Extension of panel scope - HSP with neuropathy / Broader phenotype: HSP
Hereditary neuropathy or pain disorder v0.86 XRCC1 Louise Daugherty commented on gene: XRCC1: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart): Extension of panel scope but limited evidence / Broader phenotype: SCA26, 2 cases in OMIM
Hereditary neuropathy or pain disorder v0.86 XPA Louise Daugherty commented on gene: XPA: 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: XP/de Sanctis-Cacchione syndrome - does only this form of XP have neurological features?
Hereditary neuropathy or pain disorder v0.86 XK Louise Daugherty commented on gene: XK: 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: McLeod syndrome, note adult onset
Hereditary neuropathy or pain disorder v0.86 VPS13A Louise Daugherty commented on gene: VPS13A: 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: Choreoacanthocytosis
Hereditary neuropathy or pain disorder v0.86 VCP Louise Daugherty edited their review of gene: VCP: Added comment: Gene rated Green : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart): Extension of panel scope - minor feature / Broader phenotype: ALS+/-FTD; unclear whether also causes CMT - Amber? Very rare but I think include as Green as reasonable evidence for distal myopathy/neuropathy; Changed rating: GREEN
Hereditary neuropathy or pain disorder v0.86 TWNK Louise Daugherty commented on gene: TWNK: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart): Extension of panel scope - minor feature / Broader phenotype: mitochondrial, comment that neuropathy is not common
Hereditary neuropathy or pain disorder v0.86 TTPA Louise Daugherty commented on gene: TTPA: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart): Extension of panel scope - ataxia with neuropathy / Broader phenotype: ataxia with vitamin E deficiency More likely to present as ataxia on ataxia panel
Hereditary neuropathy or pain disorder v0.86 TRPA1 Louise Daugherty commented on gene: TRPA1: 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 / Episodic pain syndrome - within scope of panel? Only 1 family in OMIM Agree not enough evidence
Hereditary neuropathy or pain disorder v0.86 SURF1 Louise Daugherty commented on gene: SURF1: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart): Extension of panel scope - mitochondrial / Broader phenotype: Leigh syndrome with neuropathy
Hereditary neuropathy or pain disorder v0.86 SUCLA2 Louise Daugherty commented on gene: SUCLA2: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart): Extension of panel scope - minor feature / Broader phenotype: Leigh-like syndrome, neuropathy 'in a minority of patients'
Hereditary neuropathy or pain disorder v0.86 SPG7 Louise Daugherty commented on gene: SPG7: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart): Extension of panel scope - minor feature / Broader phenotype submitted by Alex Rossor, but 2 reviews say no clear association with neuropathy
Hereditary neuropathy or pain disorder v0.86 SPAST Louise Daugherty commented on gene: SPAST: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart): Extension of panel scope - HSP with neuropathy / Broader phenotype (HSP)
Hereditary neuropathy or pain disorder v0.86 SOX10 Louise Daugherty commented on gene: SOX10: 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: PERIPHERAL DEMYELINATING NEUROPATHY, CENTRAL DYSMYELINATION, WAARDENBURG SYNDROME, AND HIRSCHSPRUNG DISEASE; PCWH (Shah-Waardenburg syndrome, neurologic variant)
Hereditary neuropathy or pain disorder v0.86 SLC25A46 Louise Daugherty commented on gene: SLC25A46: 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: Optic atrophy and progressive visual loss in the 1st decade, then spasticity, cerebellar ataxia, sensory-motor axonal neuropathy
Hereditary neuropathy or pain disorder v0.86 SLC25A19 Louise Daugherty commented on gene: SLC25A19: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart): Extension of panel scope - epilepsy/encephalopathy with neuropathy / Broader phenotype: episodic encephalopathy with progressive axonal neuropathy; common mutation in Amish and 1 other unrelated family in OMIM
Hereditary neuropathy or pain disorder v0.86 SCYL1 Louise Daugherty commented on gene: SCYL1: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart): Extension of panel scope but limited evidence / Overlap: SCA21 - 2 cases in OMIM, sufficient evidence?
Hereditary neuropathy or pain disorder v0.86 SCN10A Louise Daugherty edited their review of gene: SCN10A: Added comment: Gene rated Green : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart): Extension of panel scope - syndrome with non-neurological features / Episodic pain syndrome - within scope of panel? 2 cases het missense variants (1 segregating in 2 family members) and functional evidence in OMIM - sufficient for Green if within scope? If SCN9A is on the panel then this and similar genes should be on too. Recommend Green; Changed rating: GREEN
Hereditary neuropathy or pain disorder v0.86 SCARB2 Louise Daugherty commented on gene: SCARB2: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart): Extension of panel scope - minor feature / Broader phenotype: epilepsy and renal failure, 'rarely' sensorimotor neuropathy
Hereditary neuropathy or pain disorder v0.86 PTRH2 Louise Daugherty commented on gene: PTRH2: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart): Extension of panel scope but limited evidence / Broad phenotype but limited evidence? Only 2 cases in OMIM
Hereditary neuropathy or pain disorder v0.86 PTPN11 Louise Daugherty commented on gene: PTPN11: 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 / Broad phenotype - Noonan syndrome - is hypertrophic neuropathy an important feature?
Hereditary neuropathy or pain disorder v0.86 PTEN Louise Daugherty commented on gene: PTEN: 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 / Broad phenotype - is neuropathy a common feature?
Hereditary neuropathy or pain disorder v0.86 PRKCG Louise Daugherty commented on gene: PRKCG: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart): Extension of panel scope - minor feature / Neuropathy rare feature - Amber
Hereditary neuropathy or pain disorder v0.86 POLR3A Louise Daugherty commented on gene: POLR3A: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart): Extension of panel scope - ataxia with neuropathy / Broader phenotype: spastic ataxia with abnormal nerve conduction in 8/14 cases
Hereditary neuropathy or pain disorder v0.86 PNPLA6 Louise Daugherty commented on gene: PNPLA6: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart): Extension of panel scope - minor feature / Broader phenotype: Natalie no evidence of clear association with neuropathy
Hereditary neuropathy or pain disorder v0.86 PNKP Louise Daugherty commented on gene: PNKP: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart): Extension of panel scope but limited evidence / Broader phenotype: good evidence for ataxia/oculomotor apraxia, less for more severe phenotype
Hereditary neuropathy or pain disorder v0.86 PMM2 Louise Daugherty commented on gene: PMM2: 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: CDG1a
Hereditary neuropathy or pain disorder v0.86 PLP1 Louise Daugherty commented on gene: PLP1: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart): Extension of panel scope - minor feature / Broader phenotype: Pelizaeus-Merbacher/Spastic paraplegia 2 - is neuropathy a feature?
Hereditary neuropathy or pain disorder v0.86 PEX10 Louise Daugherty commented on gene: PEX10: 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: Zellweger, is neuropathy only associated with this gene?
Hereditary neuropathy or pain disorder v0.86 PDYN Louise Daugherty commented on gene: PDYN: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart): Extension of panel scope - minor feature / Broader phenotype: SCA with mild neuropathy
Hereditary neuropathy or pain disorder v0.86 OPA3 Louise Daugherty commented on gene: OPA3: 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: 3-methylglutaconic aciduria type III
Hereditary neuropathy or pain disorder v0.86 OPA1 Louise Daugherty commented on gene: OPA1: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart): Extension of panel scope - mitochondrial / Broader mitochondrial phenotype
Hereditary neuropathy or pain disorder v0.86 NAGA Louise Daugherty commented on gene: NAGA: 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: Schindler disease
Hereditary neuropathy or pain disorder v0.84 ZFYVE26 Louise Daugherty commented on gene: ZFYVE26: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.84 XRCC1 Louise Daugherty commented on gene: XRCC1: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.84 XPA Louise Daugherty commented on gene: XPA: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.84 XK Louise Daugherty commented on gene: XK: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.84 VPS13A Louise Daugherty commented on gene: VPS13A: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.84 VCP Louise Daugherty commented on gene: VCP: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.84 TWNK Louise Daugherty commented on gene: TWNK: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.84 TTPA Louise Daugherty commented on gene: TTPA: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.84 TRPA1 Louise Daugherty commented on gene: TRPA1: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.84 SURF1 Louise Daugherty commented on gene: SURF1: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.84 SUCLA2 Louise Daugherty commented on gene: SUCLA2: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.84 SPG7 Louise Daugherty commented on gene: SPG7: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.84 SPAST Louise Daugherty commented on gene: SPAST: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.84 SOX10 Louise Daugherty commented on gene: SOX10: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.84 SLC25A46 Louise Daugherty commented on gene: SLC25A46: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.84 SLC25A19 Louise Daugherty commented on gene: SLC25A19: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.84 SCYL1 Louise Daugherty commented on gene: SCYL1: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.84 SCN10A Louise Daugherty commented on gene: SCN10A: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.84 SCARB2 Louise Daugherty commented on gene: SCARB2: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.84 PTRH2 Louise Daugherty commented on gene: PTRH2: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.84 PTPN11 Louise Daugherty commented on gene: PTPN11: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.84 PTEN Louise Daugherty commented on gene: PTEN: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.84 PRKCG Louise Daugherty commented on gene: PRKCG: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.84 POLR3A Louise Daugherty commented on gene: POLR3A: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.84 PNPLA6 Louise Daugherty commented on gene: PNPLA6: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.84 PNKP Louise Daugherty commented on gene: PNKP: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.84 PMM2 Louise Daugherty commented on gene: PMM2: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.84 PLP1 Louise Daugherty commented on gene: PLP1: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.84 PEX10 Louise Daugherty commented on gene: PEX10: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.84 PDYN Louise Daugherty commented on gene: PDYN: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.84 OPA3 Louise Daugherty commented on gene: OPA3: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.84 OPA1 Louise Daugherty commented on gene: OPA1: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.84 NAGA Louise Daugherty commented on gene: NAGA: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.83 SLC25A19 Louise Daugherty Deleted their comment
Hereditary neuropathy or pain disorder v0.82 MYH14 Louise Daugherty commented on gene: MYH14: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - minor feature / Hearing loss enough evidence for Green; 1 family with hearing loss & neuropathy in literature, are there additional unpublished families?
Hereditary neuropathy or pain disorder v0.82 MYH14 Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
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 v0.81 MTTP Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.80 MT-TL1 Louise Daugherty commented on gene: MT-TL1: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - mitochondrial / Broader phenotype but mitochondrial gene (MELAS) - discuss
Hereditary neuropathy or pain disorder v0.80 MT-TL1 Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.79 MT-RNR1 Louise Daugherty commented on gene: MT-RNR1: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - mitochondrial / Broader phenotype but mitochondrial gene - discuss
Hereditary neuropathy or pain disorder v0.79 MT-RNR1 Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.78 MMACHC Louise Daugherty commented on gene: MMACHC: 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 - methylmalonic acidemia & homcysteinuria
Hereditary neuropathy or pain disorder v0.78 MMACHC Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.77 LYST Louise Daugherty commented on gene: LYST: 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 - Chediak-Higashi (albinism, immune deficiency)
Hereditary neuropathy or pain disorder v0.77 LYST Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.76 KCNA2 Louise Daugherty commented on gene: KCNA2: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - ataxia with neuropathy / Broader phenotype - epilepsy & ataxia, neuropathy only in one family - is neuropathy a consistent feature?
Hereditary neuropathy or pain disorder v0.76 KCNA2 Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.75 IARS2 Louise Daugherty commented on gene: IARS2: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - mitochondrial / Broader phenotype
Hereditary neuropathy or pain disorder v0.75 IARS2 Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.74 PPOX Louise Daugherty commented on gene: PPOX: Gene rated Green : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - syndrome with non-neurological features / Broader phenotype: variegate porphyria. As per CPOX usually presents more acutely but management implications. Promote to Green as management implications
Hereditary neuropathy or pain disorder v0.74 PPOX Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.73 HMBS Louise Daugherty commented on gene: HMBS: Gene rated Green : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - syndrome with non-neurological features / Broader phenotype - acute intermittent porphyria As per CPOX usually presents more acutely but management implications. Promote to Green as management implications
Hereditary neuropathy or pain disorder v0.73 CPOX Louise Daugherty changed review comment from: Gene rated Green : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - syndrome with non-neurological features / Broader phenotype - porphyria, can present similar to AIP according to Alex Promote to Green as management implications; to: Gene rated Green : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - syndrome with non-neurological features / Broader phenotype - porphyria, can present similar to AIP according to Alex Rossor. Promote to Green as management implications
Hereditary neuropathy or pain disorder v0.73 HMBS Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.72 HADHB Louise Daugherty commented on gene: HADHB: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - mitochondrial / Broader phenotype - mitochondrial trifunctional protein deficiency
Hereditary neuropathy or pain disorder v0.72 HADHB Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.71 HADHA Louise Daugherty commented on gene: HADHA: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - mitochondrial / Broader phenotype - mitochondrial trifunctional protein deficiency
Hereditary neuropathy or pain disorder v0.71 HADHA Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.70 GJC2 Louise Daugherty commented on gene: GJC2: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - HSP with neuropathy / Broader phenotype - HSP/hypomyelinating leucodystrophy with neuropathy
Hereditary neuropathy or pain disorder v0.70 GJC2 Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.69 GBA2 Louise Daugherty commented on gene: GBA2: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - HSP with neuropathy / Broader phenotype - HSP with neuropathy
Hereditary neuropathy or pain disorder v0.69 GBA2 Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.68 TYMP Louise Daugherty commented on gene: TYMP: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.68 TYMP Louise Daugherty Added comment: Comment on list classification: Gene included in a list of complex neuropathy syndrome genes recommended to be downgraded for R78 panel (list submitted by Alex Rossor 15th July 2019)
Hereditary neuropathy or pain disorder v0.67 TUBB3 Louise Daugherty commented on gene: TUBB3: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.67 TUBB3 Louise Daugherty Added comment: Comment on list classification: Gene included in a list of complex neuropathy syndrome genes recommended to be downgraded for R78 panel (list submitted by Alex Rossor 15th July 2019)
Hereditary neuropathy or pain disorder v0.66 SLC12A6 Louise Daugherty Added comment: Comment on list classification: Gene included in a list of complex neuropathy syndrome genes recommended to be downgraded for R78 panel (list submitted by Alex Rossor 15th July 2019)
Hereditary neuropathy or pain disorder v0.65 SLC12A6 Louise Daugherty commented on gene: SLC12A6: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.65 SACS Louise Daugherty Added comment: Comment on list classification: Gene included in a list of complex neuropathy syndrome genes recommended to be downgraded for R78 panel (list submitted by Alex Rossor 15th July 2019)
Hereditary neuropathy or pain disorder v0.64 SACS Louise Daugherty commented on gene: SACS: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.64 POLG Louise Daugherty Added comment: Comment on list classification: Gene included in a list of complex neuropathy syndrome genes recommended to be downgraded for R78 panel (list submitted by Alex Rossor 15th July 2019)
Hereditary neuropathy or pain disorder v0.63 POLG Louise Daugherty commented on gene: POLG: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.63 PHYH Louise Daugherty commented on gene: PHYH: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.63 PEX7 Louise Daugherty commented on gene: PEX7: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.63 PDHA1 Louise Daugherty commented on gene: PDHA1: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.63 GLA Louise Daugherty commented on gene: GLA: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.63 GAN Louise Daugherty commented on gene: GAN: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.63 PHYH Louise Daugherty Added comment: Comment on list classification: Gene included in a list of complex neuropathy syndrome genes recommended to be downgraded for R78 panel (list submitted by Alex Rossor 15th July 2019)
Hereditary neuropathy or pain disorder v0.62 PEX7 Louise Daugherty Added comment: Comment on list classification: Gene included in a list of complex neuropathy syndrome genes recommended to be downgraded for R78 panel (list submitted by Alex Rossor 15th July 2019)
Hereditary neuropathy or pain disorder v0.61 PDHA1 Louise Daugherty Added comment: Comment on list classification: Gene included in a list of complex neuropathy syndrome genes recommended to be downgraded for R78 panel (list submitted by Alex Rossor 15th July 2019)
Hereditary neuropathy or pain disorder v0.60 GLA Louise Daugherty Added comment: Comment on list classification: Gene included in a list of complex neuropathy syndrome genes recommended to be downgraded for R78 panel (list submitted by Alex Rossor 15th July 2019)
Hereditary neuropathy or pain disorder v0.59 GAN Louise Daugherty Added comment: Comment on list classification: Gene included in a list of complex neuropathy syndrome genes recommended to be downgraded for R78 panel (list submitted by Alex Rossor 15th July 2019)
Hereditary neuropathy or pain disorder v0.58 GALC Louise Daugherty commented on gene: GALC: 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 - Krabbe disease
Hereditary neuropathy or pain disorder v0.58 GALC Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.57 FXN Louise Daugherty commented on gene: FXN: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - ataxia with neuropathy / Rate as Green if STR Green Should be on ataxia panels
Hereditary neuropathy or pain disorder v0.57 FXN Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.56 FLVCR1 Louise Daugherty commented on gene: FLVCR1: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - ataxia with neuropathy / Broader phenotype - ataxia & RP. Agree more suited to ataxia panel
Hereditary neuropathy or pain disorder v0.56 FLVCR1 Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.55 FBXO38 Louise Daugherty commented on gene: FBXO38: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope but limited evidence / SMA - limited evidence, some functional work but not strong - Amber? 2 families one very large segregating gene, possibly green if test Group supports rating?
Hereditary neuropathy or pain disorder v0.55 FBXO38 Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.54 FAM126A Louise Daugherty commented on gene: FAM126A: 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: leukodystrophy
Hereditary neuropathy or pain disorder v0.54 FAM126A Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.53 FAH Louise Daugherty commented on gene: FAH: 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: Tyrosinemia, acute episodes of neuropathy similar to AIP
Hereditary neuropathy or pain disorder v0.53 FAH Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.52 ETFDH Louise Daugherty commented on gene: ETFDH: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - minor feature / Broader phenotype: Glutaric acidemia IIc - minor feature
Hereditary neuropathy or pain disorder v0.52 ETFDH Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.51 ERCC8 Louise Daugherty commented on gene: ERCC8: 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 - Cockayne syndrome
Hereditary neuropathy or pain disorder v0.51 ERCC8 Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.50 ERCC6 Louise Daugherty commented on gene: ERCC6: 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 - Cockayne syndrome
Hereditary neuropathy or pain disorder v0.50 ERCC6 Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.49 ELP1 Louise Daugherty changed review comment from: Gene rated Green : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - syndrome with non-neurological features / Familial dysautonomia - appropriate for panel Keep green; to: Gene rated Green : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - syndrome with non-neurological features / Familial dysautonomia - appropriate for panel. autonomic neuropathy - relevant to both panels (narrow and broad). Keep green
Hereditary neuropathy or pain disorder v0.49 ELP1 Louise Daugherty commented on gene: ELP1: Gene rated Green : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - syndrome with non-neurological features / Familial dysautonomia - appropriate for panel Keep green
Hereditary neuropathy or pain disorder v0.49 ELP1 Louise Daugherty edited their review of gene: ELP1: Added comment: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.; Changed rating: GREEN
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 v0.49 DNAJC3 Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.48 CYP27A1 Louise Daugherty changed review comment from: Gene rated Green : From feedback from Genomics England Clinical team (Anna de Burca). Although Extension of panel scope - syndrome with non-neurological features / Broader phenotype - cerebrotendinous xanthomatosis, it was noted that it was good to pick up early; to: Gene rated Green : From feedback from Genomics England Clinical team (Anna de Burca). Although Extension of panel scope - syndrome with non-neurological features / Broader phenotype - cerebrotendinous xanthomatosis, it was noted that it was good to pick up early so advised Green rating over Amber for R57 panel
Hereditary neuropathy or pain disorder v0.48 CYP27A1 Louise Daugherty changed review comment from: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca). Extension of panel scope - syndrome with non-neurological features / Broader phenotype - cerebrotendinous xanthomatosis; to: Gene rated Green : From feedback from Genomics England Clinical team (Anna de Burca). Although Extension of panel scope - syndrome with non-neurological features / Broader phenotype - cerebrotendinous xanthomatosis, it was noted that it was good to pick up early
Hereditary neuropathy or pain disorder v0.47 DEGS1 Louise Daugherty commented on gene: DEGS1: 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 - leukodystrophy with neuropathy
Hereditary neuropathy or pain disorder v0.47 DEGS1 Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.46 DARS2 Louise Daugherty commented on gene: DARS2: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - mitochondrial / Mitochondrial gene - extension to phenotype to include isolated neuropathy
Hereditary neuropathy or pain disorder v0.46 DARS2 Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.45 CYP27A1 Louise Daugherty commented on gene: CYP27A1: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca). Extension of panel scope - syndrome with non-neurological features / Broader phenotype - cerebrotendinous xanthomatosis
Hereditary neuropathy or pain disorder v0.45 CYP27A1 Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.44 CTDP1 Louise Daugherty commented on gene: CTDP1: 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 (dysmorphic, cataract) - founder mutation in Roma populations, intronic
Hereditary neuropathy or pain disorder v0.44 CTDP1 Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.42 CPOX Louise Daugherty edited their review of gene: CPOX: Added comment: Gene rated Green : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - syndrome with non-neurological features / Broader phenotype - porphyria, can present similar to AIP according to Alex Promote to Green as management implications; Changed rating: GREEN
Hereditary neuropathy or pain disorder v0.42 CPOX Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.41 COA7 Louise Daugherty commented on gene: COA7: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart) Extension of panel scope - ataxia with neuropathy / Broader phenotype - SCA with axonal neuropathy
Hereditary neuropathy or pain disorder v0.41 COA7 Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.40 WARS Louise Daugherty edited their review of gene: WARS: Added comment: Gene rated Green : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). New evidence/re-evaluation of evidence - promotion to Green/ Additional evidence: 3 cases in literature with same variant on diff haplotypes and postulated dom neg effect; Changed rating: GREEN
Hereditary neuropathy or pain disorder v0.40 VRK1 Louise Daugherty changed review comment from: Gene rated Green: From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart)
New evidence/re-evaluation of evidence - promotion to Green / Additional evidence: PMID:30847374 cites 2 other cases with neuropathy & unpublished evidence; to: Gene rated Amber: From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart)
New evidence/re-evaluation of evidence - promotion to Green / Additional evidence: PMID:30847374 cites 2 other cases with neuropathy & unpublished evidence.
Hereditary neuropathy or pain disorder v0.39 VRK1 Louise Daugherty commented on gene: VRK1: Gene rated Green: From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart)
New evidence/re-evaluation of evidence - promotion to Green / Additional evidence: PMID:30847374 cites 2 other cases with neuropathy & unpublished evidence
Hereditary neuropathy or pain disorder v0.38 TRIM2 Louise Daugherty commented on gene: TRIM2: Gene rated Green : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). New evidence/re-evaluation of evidence - promotion to Green / Consider for Green with functional data? 2 families with missense variants; no new publications since 2015
Hereditary neuropathy or pain disorder v0.38 SYT2 Louise Daugherty changed review comment from: Gene rated Red : From feedback from Genomics England Clinical team (Anna de Burca). Congenital myasthenia gene; currently Green on Congenital myaesthenic syndrome Panel so recommend leave as Red on the R78 panel, but promote to Green on larger panel for WGS; to: Gene rated Red : From feedback from Genomics England Clinical team (Anna de Burca). 3 families and functional data according to Natalie's review but more of a myastheia phenotype but overlaps with CMT . Congenital myasthenia gene; currently Green on Congenital myaesthenic syndrome Panel so recommend leave as Red on the R78 panel, but promote to Green on larger panel for WGS.
Hereditary neuropathy or pain disorder v0.37 SYT2 Louise Daugherty changed review comment from: Gene rated Red : From feedback from Genomics England Clinical team (Anna de Burca). Congenital myasthenia gene; currently Red on congenital myasthenic syndrome panel but Oxford have given Green review for that panel so suggest promote on the congenital myasthenic syndrome panel, leave as Red on the R78 panel, but promote to Green on larger panel for WGS; to: Gene rated Red : From feedback from Genomics England Clinical team (Anna de Burca). Congenital myasthenia gene; currently Green on Congenital myaesthenic syndrome Panel so recommend leave as Red on the R78 panel, but promote to Green on larger panel for WGS
Hereditary neuropathy or pain disorder v0.37 SYT2 Louise Daugherty commented on gene: SYT2: Gene rated Red : From feedback from Genomics England Clinical team (Anna de Burca). Congenital myasthenia gene; currently Red on congenital myasthenic syndrome panel but Oxford have given Green review for that panel so suggest promote on the congenital myasthenic syndrome panel, leave as Red on the R78 panel, but promote to Green on larger panel for WGS
Hereditary neuropathy or pain disorder v0.37 PRNP Louise Daugherty changed review comment from: Gene rated red : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart) Extension of panel scope but limited evidence / Broader phenotype: good evidence for ataxia/oculomotor apraxia, less for more severe phenotype. AlexRossor felt that there was sufficient evidence that this can cause a neuropathy but that this would be an unusual presentation – suggest that AR provide additional evidence for a Green rating on the WGS panel but make Red for the R78 panel; to: Gene rated red : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart) Extension of panel scope but limited evidence / Broader phenotype: good evidence for ataxia/oculomotor apraxia, less for more severe phenotype. Alex Rossor felt that there was sufficient evidence that this can cause a neuropathy but that this would be an unusual presentation – suggest that Alex Rossor provide additional evidence for a Green rating on the WGS panel but make Red for the R78 panel
Hereditary neuropathy or pain disorder v0.37 SETX Louise Daugherty changed review comment from: Gene rated Green : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Re-evaluation of evidence - demotion / James Polke Red review but no comment?? Pretty rare for this to present as a dominant juvenile ALS phenotype but three different mutations reported. Probably reasonable to keep as green but presumably in ALS panel; to: Gene rated Green : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Re-evaluation of evidence - demotion / James Polke Red review but no comment?? Pretty rare for this to present as a dominant juvenile ALS phenotype but three different mutations reported. Probably reasonable to keep as green but presumably in ALS panel. SETX had been reviewed by James Polke as Red but he had not left a comment, since he was not on the call, agreed that this gene be left as Green unless James provides an explanation for his Red review
Hereditary neuropathy or pain disorder v0.37 SETX Louise Daugherty changed review comment from: Gene rated Green : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Re-evaluation of evidence - demotion / James Polke Red review but no comment?? Pretty rare for this to present as a dominant juvenile ALS phenotype but three different mutations reported. Probably reasonable to keep as green but presumably in ALS panel; to: Gene rated Green : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Re-evaluation of evidence - demotion / James Polke Red review but no comment?? Pretty rare for this to present as a dominant juvenile ALS phenotype but three different mutations reported. Probably reasonable to keep as green but presumably in ALS panel
Hereditary neuropathy or pain disorder v0.37 PRNP Louise Daugherty changed review comment from: Gene rated red : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart) Extension of panel scope but limited evidence / Broader phenotype: good evidence for ataxia/oculomotor apraxia, less for more severe phenotype; to: Gene rated red : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart) Extension of panel scope but limited evidence / Broader phenotype: good evidence for ataxia/oculomotor apraxia, less for more severe phenotype. AlexRossor felt that there was sufficient evidence that this can cause a neuropathy but that this would be an unusual presentation – suggest that AR provide additional evidence for a Green rating on the WGS panel but make Red for the R78 panel
Hereditary neuropathy or pain disorder v0.37 PRNP Louise Daugherty changed review comment from: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
AlexRossor felt that there was sufficient evidence that this can cause a neuropathy but that this would be an unusual presentation – suggest that AR provide additional evidence for a Green rating on the WGS panel but make Red for the R78 panel; to: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.37 SLC5A7 Louise Daugherty edited their review of gene: SLC5A7: Added comment: Gene rated Green : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). New evidence/re-evaluation of evidence - promotion to Green? / Limited evidence? See Natalie review but AR says multiple families; Changed rating: GREEN
Hereditary neuropathy or pain disorder v0.37 SETX Louise Daugherty edited their review of gene: SETX: Added comment: Gene rated Green : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Re-evaluation of evidence - demotion / James Polke Red review but no comment?? Pretty rare for this to present as a dominant juvenile ALS phenotype but three different mutations reported. Probably reasonable to keep as green but presumably in ALS panel; Changed rating: GREEN
Hereditary neuropathy or pain disorder v0.37 SBF1 Louise Daugherty edited their review of gene: SBF1: Added comment: Gene rated Green : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). New evidence/re-evaluation of evidence - promotion to Green / New evidence: 1 more family - promote to Green; Changed rating: GREEN
Hereditary neuropathy or pain disorder v0.37 PRNP Louise Daugherty commented on gene: PRNP: Gene rated red : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart) Extension of panel scope but limited evidence / Broader phenotype: good evidence for ataxia/oculomotor apraxia, less for more severe phenotype
Hereditary neuropathy or pain disorder v0.37 PMP2 Louise Daugherty edited their review of gene: PMP2: Added comment: Gene rated Green : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). New evidence/re-evaluation of evidence - promotion to Green / New evidence - green; Changed rating: GREEN
Hereditary neuropathy or pain disorder v0.37 NEFH Louise Daugherty commented on gene: NEFH: Gene rated Green : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). New evidence/re-evaluation of evidence - promotion to Green? / New CMT gene, 2 families & functional evidence in OMIM
Hereditary neuropathy or pain disorder v0.36 MCM3AP Louise Daugherty edited their review of gene: MCM3AP: Added comment: Gene rated Green : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart) New evidence/re-evaluation of evidence - promotion to Green/ New evidence - PMID:28633435; Changed rating: GREEN
Hereditary neuropathy or pain disorder v0.36 GNB4 Louise Daugherty commented on gene: GNB4: Gene rated Green : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). New evidence/re-evaluation of evidence - promotion to Green / CMT - new evidence Agree promote to Green
Hereditary neuropathy or pain disorder v0.36 DST Louise Daugherty commented on gene: DST: Gene rated Green : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart) . New evidence/re-evaluation of evidence - promotion to Green / New evidence - upgrade to Green? New evidence promote to Green
Hereditary neuropathy or pain disorder v0.36 DRP2 Louise Daugherty commented on gene: DRP2: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). New evidence/re-evaluation of evidence - promotion to Green? 2 cases but functional studies don't show features of neuropathy - Amber? More evidence needed
Hereditary neuropathy or pain disorder v0.36 DNAJB2 Louise Daugherty commented on gene: DNAJB2: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart)/ Green for larger panel only as main phenotype is distal SMA; AR to provide further references
Hereditary neuropathy or pain disorder v0.36 DCTN1 Louise Daugherty edited their review of gene: DCTN1: Added comment: Gene rated Green : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart) . New evidence/re-evaluation of evidence - promotion to Green / New evidence - upgrade to Green; Changed rating: GREEN
Hereditary neuropathy or pain disorder v0.36 DCTN1 Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.35 ATP1A1 Louise Daugherty edited their review of gene: ATP1A1: Added comment: Gene rated Green : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). New evidence/re-evaluation of evidence - promotion to Green / New gene - 7 unrelated families (2018) Agree promote to Green; Changed rating: GREEN
Hereditary neuropathy or pain disorder v0.35 ARHGEF10 Louise Daugherty commented on gene: ARHGEF10: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Re-evaluation of evidence - demotion / One published family plus functional evidence (NB. Bristol review although Green acknowledges limited evidence) - demote
Hereditary neuropathy or pain disorder v0.35 ATL3 Louise Daugherty commented on gene: ATL3: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Re-evaluation of evidence - demotion / Limited evidence highlighted by Natalie - same variant in 2 families and other variant didn't segregate - downgrade to Amber? Agree downgrade due to lack of evidence
Hereditary neuropathy or pain disorder v0.35 CNTNAP1 Louise Daugherty commented on gene: CNTNAP1: 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 - congenital hypomyelinating neuropathy, arthrogryposis, severe dev delay
Hereditary neuropathy or pain disorder v0.35 CNTNAP1 Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.34 CD59 Louise Daugherty commented on gene: CD59: 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: haemolytic anaemia, strokes and relapsing immune-mediated demyelinating neuropathy
Hereditary neuropathy or pain disorder v0.34 CD59 Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.33 C12orf65 Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.32 BCKDHB Louise Daugherty commented on gene: BCKDHB: 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 - Maple syrup urine disease
Hereditary neuropathy or pain disorder v0.32 BCKDHB Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.31 BAG3 Louise Daugherty commented on gene: BAG3: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - myopathy with neuropathy / Broader phenotype - not reviewed by Alex in this round but previously reviewed as Green; myofibrillar myopathy, sufficient evidence for neuropathy?
Hereditary neuropathy or pain disorder v0.31 BAG3 Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.30 B4GALNT1 Louise Daugherty commented on gene: B4GALNT1: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - HSP with neuropathy / Broader phenotype: HSP gene but can be associated with neuropathy.
Hereditary neuropathy or pain disorder v0.30 B4GALNT1 Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.29 ATM Louise Daugherty commented on gene: ATM: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - ataxia with neuropathy / Broader phenotype - biallelic only (cancer risk)
Hereditary neuropathy or pain disorder v0.29 ATM Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.28 ARSA Louise Daugherty commented on gene: ARSA: Gene rated as Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - syndrome with non-neurological features / Metachromatic leukodystrophy - broader phenotype
Hereditary neuropathy or pain disorder v0.28 ARSA Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.27 APTX Louise Daugherty commented on gene: APTX: Gene remains rated as Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - ataxia with neuropathy / Broader phenotype: Ataxia with oculomotor apraxia
Hereditary neuropathy or pain disorder v0.27 APTX Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.25 APOA1 Louise Daugherty commented on gene: APOA1: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.25 APOA1 Louise Daugherty changed review comment from: Gene remains rated as Red : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart).. Extension of panel scope - minor feature. Amyloidosis - most cases visceral amyloidosis but 1 family with neurological phenotype- rate Red.
R78 was going to be broadened to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP. Subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for this panel to be restricted to genes that are associated with isolated neuropathy.; to: Gene remains rated as Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart).. Extension of panel scope - minor feature. Amyloidosis - most cases visceral amyloidosis but 1 family with neurological phenotype- rate Red.
Hereditary neuropathy or pain disorder v0.24 AP1S1 Louise Daugherty commented on gene: AP1S1: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.24 AP1S1 Louise Daugherty changed review comment from: Gene remains rated as Red : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope but limited evidence / Congenital onset, Mental retardation, Enteropathy (severe congenital diarrhoea), Deafness, sensory-motor Neuropathy with intermediate conduction velocities, Ichthyosis, Keratoderma - OMIM 4 families from Quebec with same splice site mutation - rated Red
R78 was going to be broadened to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP. Subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for this panel to be restricted to genes that are associated with isolated neuropathy.; to: Gene remains rated as Amber: From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope but limited evidence / Congenital onset, Mental retardation, Enteropathy (severe congenital diarrhoea), Deafness, sensory-motor Neuropathy with intermediate conduction velocities, Ichthyosis, Keratoderma - OMIM 4 families from Quebec with same splice site mutation
Hereditary neuropathy or pain disorder v0.24 AGXT Louise Daugherty changed review comment from: Gene remains rated as Red : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - minor feature / Gene well established to cause PH1 Primary Hyperoxaluria (green). 2 reports of neuropathy - enough cases?- rated Red
R78 was going to be broadened to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP. Subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for this panel to be restricted to genes that are associated with isolated neuropathy.; to: Gene remains rated Amber: From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - minor feature / Gene well established to cause PH1 Primary Hyperoxaluria (green). 2 reports of neuropathy - enough cases?
Hereditary neuropathy or pain disorder v0.24 AGXT Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.21 AGTPBP1 Louise Daugherty commented on gene: AGTPBP1: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.21 AGTPBP1 Louise Daugherty changed review comment from: Gene remains rated as Red : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart).Extension of panel scope - syndrome with non-neurological features / Early onset cerebellar atrophy, developmental delay, and feeding and respiratory difficulties, severe motor neuronopathy - complex phenotype - overlap with ID - rated Red.
R78 was going to be broadened to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP. Subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for this panel to be restricted to genes that are associated with isolated neuropathy.; to: 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 / Early onset cerebellar atrophy, developmental delay, and feeding and respiratory difficulties, severe motor neuronopathy - complex phenotype - overlap with ID
Hereditary neuropathy or pain disorder v0.21 ABCA1 Louise Daugherty commented on gene: ABCA1: The gene has changed ratings as the panel to be used for R78 was going to be broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/
Hereditary neuropathy or pain disorder v0.21 ABCA1 Louise Daugherty changed review comment from: Comment on list classification: Amber gene: Feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - syndrome with non-neurological features/ Peripheral neuropathy with low HDL.
The gene has changed ratings as the panel to be used for R78 was going to be broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/

; to: Comment on list classification: Amber gene: Feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - syndrome with non-neurological features/ Peripheral neuropathy with low HDL.
Hereditary neuropathy or pain disorder v0.21 ABHD12 Louise Daugherty changed review comment from: Gene remains rated as Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - syndrome with non-neurological features / Polyneuropathy with SNCV (slow nerve conduction velocity?), sensorineuronal hearing loss, retinitis pigmentosa, spastic paraplegia, ataxia - rated Red.
; to: 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 / Polyneuropathy with SNCV (slow nerve conduction velocity?), sensorineuronal hearing loss, retinitis pigmentosa, spastic paraplegia, ataxia
Hereditary neuropathy or pain disorder v0.21 ABHD12 Louise Daugherty commented on gene: ABHD12: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.21 ABHD12 Louise Daugherty changed review comment from: Gene remains rated as Red : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - syndrome with non-neurological features / Polyneuropathy with SNCV (slow nerve conduction velocity?), sensorineuronal hearing loss, retinitis pigmentosa, spastic paraplegia, ataxia - rated Red.
R78 was going to be broadened to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP. Subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for this panel to be restricted to genes that are associated with isolated neuropathy.; to: Gene remains rated as Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - syndrome with non-neurological features / Polyneuropathy with SNCV (slow nerve conduction velocity?), sensorineuronal hearing loss, retinitis pigmentosa, spastic paraplegia, ataxia - rated Red.
Hereditary neuropathy or pain disorder v0.21 WARS Louise Daugherty commented on gene: WARS: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.21 VRK1 Louise Daugherty commented on gene: VRK1: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.21 TRIM2 Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.20 SYT2 Louise Daugherty commented on gene: SYT2: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.20 SLC5A7 Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.19 SETX Louise Daugherty commented on gene: SETX: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.19 SBF1 Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.17 PRNP Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
AlexRossor felt that there was sufficient evidence that this can cause a neuropathy but that this would be an unusual presentation – suggest that AR provide additional evidence for a Green rating on the WGS panel but make Red for the R78 panel
Hereditary neuropathy or pain disorder v0.16 PMP2 Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.15 NEFH Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.14 MCM3AP Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.13 GNB4 Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.12 DST Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.11 DRP2 Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.10 DNAJB2 Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.9 ATP1A1 Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.8 ATL3 Louise Daugherty Added comment: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.7 ARHGEF10 Louise Daugherty changed review comment from: Comment on list classification: The gene has changed ratings as the panel to be used for R78 was going to be broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.; to: Comment on list classification: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.7 ARHGEF10 Louise Daugherty Added comment: Comment on list classification: The gene has changed ratings as the panel to be used for R78 was going to be broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.6 ABCA1 Louise Daugherty changed review comment from: Comment on list classification: Amber gene: Feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - syndrome with non-neurological features/ Peripheral neuropathy with low HDL.
The gene has changed ratings as the panel to be used for R78 was going to be broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents

; to: Comment on list classification: Amber gene: Feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - syndrome with non-neurological features/ Peripheral neuropathy with low HDL.
The gene has changed ratings as the panel to be used for R78 was going to be broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/
Hereditary neuropathy or pain disorder v0.6 ABCA1 Louise Daugherty changed review comment from: Comment on list classification: Amber gene: Feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - syndrome with non-neurological features/ Peripheral neuropathy with low HDL
The gene has changed ratings as the panel that was going to be used for R78 was going to be broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents

; to: Comment on list classification: Amber gene: Feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - syndrome with non-neurological features/ Peripheral neuropathy with low HDL.
The gene has changed ratings as the panel to be used for R78 was going to be broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents
Hereditary neuropathy or pain disorder v0.5 ABCA1 Louise Daugherty changed review comment from: Comment on list classification: Changed from Red to Green: Feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - syndrome with non-neurological features/ Peripheral neuropathy with low HDL - rated Green.
R78 was going to be broadened to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP. Subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for this panel to be restricted to genes that are associated with isolated neuropathy.; to: Comment on list classification: Amber gene: Feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - syndrome with non-neurological features/ Peripheral neuropathy with low HDL
The gene has changed ratings as the panel that was going to be used for R78 was going to be broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents
Hereditary neuropathy or pain disorder v0.5 ABCA1 Louise Daugherty Deleted their comment
Hereditary neuropathy or pain disorder v0.1 TRPV4 Ellen McDonagh gene: TRPV4 was added
gene: TRPV4 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS,Illumina TruGenome Clinical Sequencing Services,London North GLH,Expert list,Emory Genetics Laboratory,UKGTN,Expert Review Green,South West GLH,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: TRPV4 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: TRPV4 were set to 20037586
Phenotypes for gene: TRPV4 were set to Hereditary motor and sensory neuropathy, type IIc, 606071
Mode of pathogenicity for gene: TRPV4 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Hereditary neuropathy or pain disorder v0.1 SPTLC2 Ellen McDonagh gene: SPTLC2 was added
gene: SPTLC2 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS,Illumina TruGenome Clinical Sequencing Services,London North GLH,Expert list,Emory Genetics Laboratory,UKGTN,Expert Review Green,South West GLH,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: SPTLC2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SPTLC2 were set to 20920666
Phenotypes for gene: SPTLC2 were set to Hereditary Sensory and Autonomic Neuropathy, Type IC; Neuropathy, hereditary sensory and autonomic, type IC, 613640
Mode of pathogenicity for gene: SPTLC2 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Hereditary neuropathy or pain disorder v0.1 SIGMAR1 Ellen McDonagh gene: SIGMAR1 was added
gene: SIGMAR1 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS,London North GLH,Expert Review,Expert Review Green
Mode of inheritance for gene: SIGMAR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SIGMAR1 were set to PMID: 26088964 is a commentary on PMID: 25678561 raising a lack of evidence for SIGMARI to be pathogenic, and that previous reports of patients with SIGMARI variants were also shown to harbour C9orf72 expansions. PMID: 26088963 - in reply, authors state that there is in vitro and in vivo evidence, and expression evidence, and that a case reported did not have the C9orf72 expansion; PubMed: 21842496 - E102Q variant identified in a Saudi Arabian family to be associated with amyotrophic lateral sclerosis 16, juvenile; PMID: 26078401 - c.151+1G>T variant in SIGMARI resulted in a 60 bp deletion in the transcript, and segrated with the distal hereditary motor neuropathy in a Chinese family.; PMID: 26205306 one family report for association with Amyotrophic lateral sclerosis and c.672*31A>G (rs4879809) - the C9ORF72 repeat region in intron 1, previously implicated in a related phenotype, was excluded through linkage, and further confirmation of exclusion was obtained by amplifying intron 1 of C9ORF72 with multiple primers in affected individuals and controls
Hereditary neuropathy or pain disorder v0.1 MME Ellen McDonagh gene: MME was added
gene: MME was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS,London North GLH,Other,Expert Review Green
Mode of inheritance for gene: MME was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MME were set to 26991897; 27588448
Phenotypes for gene: MME were set to Charcot-Marie-Tooth disease, axonal, type 2T, 617017