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Hereditary neuropathy or pain disorder v8.1 SLC52A3 Ida Ertmanska commented on gene: SLC52A3: Comment on mode of inheritance: There are more than 3 unrelated patients with both monoallelic and biallelic variants in SLC52A3 and Brown-Vialetto-Van Laere syndrome. Both modes of inheritance result in the same phenotype of hearing loss and ponto-bulbar palsy / bilateral vestibular neuropathy. Hence, the mode of inheritance for Hereditary neuropathy or pain disorder should be updated from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal.
Hereditary neuropathy or pain disorder v7.45 APOPT1 Alexander Rossor gene: APOPT1 was added
gene: APOPT1 was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: APOPT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: APOPT1 were set to 25175347; 38098475
Phenotypes for gene: APOPT1 were set to 25175347; 38098475Encephalopathic episodes; loss of developmental milestones; seizures; spasticity; cavitating leukodystrophy
Penetrance for gene: APOPT1 were set to Complete
Review for gene: APOPT1 was set to GREEN
Added comment: Sources: Expert list
Hereditary neuropathy or pain disorder v7.45 MT-TV Alexander Rossor gene: MT-TV was added
gene: MT-TV was added to Hereditary neuropathy or pain disorder. Sources: Other
Mode of inheritance for gene gene: MT-TV was set to MITOCHONDRIAL
Publications for gene: MT-TV were set to 32715519: 39468830: 38371303
Phenotypes for gene: MT-TV were set to peripheral neuropathy; spasticity
Mode of pathogenicity for gene: MT-TV 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-TV was set to GREEN
Added comment: Described in 3 unrelated families with neuropathy and spasticity
Sources: Other
Hereditary neuropathy or pain disorder v7.45 FAT3 Alexander Rossor gene: FAT3 was added
gene: FAT3 was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: FAT3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FAT3 were set to PMID: 41937739
Phenotypes for gene: FAT3 were set to axonal sensory and motor peripheral neuropathy; cranial neuropathy; scoliosis; respiratory failure; pseudoobstruction
Review for gene: FAT3 was set to GREEN
Added comment: 3 unrelated individuals
Sources: Expert list
Hereditary neuropathy or pain disorder v7.44 NDC1 Ida Ertmanska Phenotypes for gene: NDC1 were changed from demyelinating neuropathy; alacrima; achalasia to Neurodevelopmental disorder with achalasia, polyneuropathy, and alacrima, OMIM:621328; neurodevelopmental disorder with achalasia, polyneuropathy, and alacrima, MONDO:0979875
Hereditary neuropathy or pain disorder v7.43 SOD1 Ida Ertmanska changed review comment from: Comment on list classification: There are more than 3 unrelated patients reported in literature with heterozygous SOD1 variants and hereditary neuropathy (motor and/ or sensory), often diagnosed as CMT disease. Sensory neuropathy may precede classical motor symptoms of ALS. Hence, SOD1 should be promoted to Green at the next GMS update.; to: Comment on list classification: There are more than 3 unrelated patients reported in literature with heterozygous SOD1 variants and hereditary neuropathy (motor and/ or sensory), often diagnosed as CMT disease. Sensory neuropathy may precede classical motor symptoms of ALS. Hence, SOD1 should be promoted to Green on Hereditary neuropathy or pain disorder at the next GMS update.
Hereditary neuropathy or pain disorder v7.42 SOD1 Ida Ertmanska gene: SOD1 was added
gene: SOD1 was added to Hereditary neuropathy or pain disorder. Sources: Literature
Q1_26_promote_green tags were added to gene: SOD1.
Mode of inheritance for gene: SOD1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SOD1 were set to 22475618; 36316849; 39932579
Phenotypes for gene: SOD1 were set to Charcot-Marie-Tooth disease, MONDO:0015626; Amyotrophic lateral sclerosis 1, OMIM:105400
Review for gene: SOD1 was set to GREEN
Added comment: PMID: 39932579 Ando et al., 2025
17 Japanese patients with 10 different missense SOD1 variants and peripheral neuropathy with avg onset at 47 years. Electrophysiology predominantly indicated a length-dependent, motor-dominant axonal neuropathy. Distal muscle weakness was noted in 9/13 patients, asymmetric muscle weakness and atrophy in 10/14, mild sensory disturbances observed in 8 patients, with some showing hyperreflexia and abnormal reflexes.

PMID: 36316849 Luo et al., 2022
Case report: 50yo female patient with hereditary motor and sensory neuropathy (CMT diagnosis). Presented with weakness of lower extremities. Heterozygous SOD1 c.140A>G, p(.His47Arg) was detected. Father with similar disease progression starting at age 50, not genotyped (deceased).

PMID: 22475618 Østern et al., 2012
Large Norwegian pedigree with hereditary neuropathy (diagnosis of CMT type 2), segregating with SOD1 c.140A>G, p.His47Arg variant.

PMID: 37610446 Bombaci et al., 2023 - literature review of ALS cases
Many authors reported an overlap of both sensory and motor symptoms in ALS patients. 20/29 ALS patients from case reports had sensory symptoms - common in spinal onset ALS. If sensory neuropathy precedes ALS there is usually a delay in ALS diagnosis.

SOD1 is linked to AD, AR Amyotrophic lateral sclerosis 1, OMIM:105400 & AR Spastic tetraplegia and axial hypotonia, progressive, OMIM:618598 (OMIM accessed 12th Mar 2026).
Sources: Literature
Hereditary neuropathy or pain disorder v7.39 CHRNA3 Ida Ertmanska Added comment: Comment on list classification: There are more than 3 individuals reported in literature with an autonomic nervous system disorder and biallelic CHRNA3 variants. Individuals presented with severe orthostatic hypotension, nonreactive pupils, constipation, and bladder dysfunction. Hence, CHRNA3 should be promoted to Green at the next update.
Hereditary neuropathy or pain disorder v7.38 CHRNA3 Ida Ertmanska Phenotypes for gene: CHRNA3 were changed from Familial Autonomic Ganglionopathy to Bladder dysfunction, autonomic, with impaired pupillary reflex and secondary CAKUT, OMIM:191800; autonomic nervous system disorder, MONDO:0001292
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 v7.32 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 v7.29 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 v7.25 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 v7.20 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: 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 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 v7.18 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 v7.8 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 v7.5 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 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 v6.167 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 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 v6.163 DHX9 Achchuthan Shanmugasundram Phenotypes for gene: DHX9 were changed from Adult-onset axonal neuropathy; Charcot-Marie-Tooth disease, MONDO:0015626 to Intellectual developmental disorder, autosomal dominant 75, OMIM:620988
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 v6.144 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 v6.142 PIGG Achchuthan Shanmugasundram Phenotypes for gene: PIGG were changed from HMN to Neurodevelopmental disorder with or without hypotonia, seizures, and cerebellar atrophy, OMIM:616917; childhood-onset motor neuropathy
Hereditary neuropathy or pain disorder v6.141 PIGG Achchuthan Shanmugasundram reviewed gene: PIGG: Rating: GREEN; Mode of pathogenicity: None; Publications: 39444079; Phenotypes: Neurodevelopmental disorder with or without hypotonia, seizures, and cerebellar atrophy, OMIM:616917, childhood-onset motor neuropathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v6.136 MAPK8IP3 Eleanor Williams Phenotypes for gene: MAPK8IP3 were changed from developmental delay; motor axonal neuropathy to Neurodevelopmental disorder with or without variable brain abnormalities, OMIM:618443; neurodevelopmental disorder with or without variable brain abnormalities, NEDBA, MONDO:0032755
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 v6.130 OPA3 Eleanor Williams Phenotypes for gene: OPA3 were changed from Infantile optic atrophy, additionally, extra pyramidal disorder (chorea), ataxia, cognitive defects, axonal sensory neuropathy, autonomic neuropathy, pseudo-obstruction; Optic atrophy 3 with cataract, 165300; 3-methylglutaconic aciduria, type III, 258501 to Optic atrophy 3 with cataract, OMIM:165300; optic atrophy 3, MONDO:0008133
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 v6.54 NFASC Achchuthan Shanmugasundram Phenotypes for gene: NFASC were changed from Developmental delay; peripheral neuropathy to Neurodevelopmental disorder with central and peripheral motor dysfunction, OMIM:618356
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 v6.37 NFASC Achchuthan Shanmugasundram reviewed gene: NFASC: Rating: GREEN; Mode of pathogenicity: None; Publications: 30850329, 31501903; Phenotypes: Neurodevelopmental disorder with central and peripheral motor dysfunction, OMIM:618356; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
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 v6.10 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 v6.10 NOP56_GGCCTG Arina Puzriakova STR: NOP56_GGCCTG was added
STR: NOP56_GGCCTG was added to Hereditary neuropathy or pain disorder. Sources: NHS GMS,Expert Review Amber,Expert Review
STR tags were added to STR: NOP56_GGCCTG.
Mode of inheritance for STR: NOP56_GGCCTG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for STR: NOP56_GGCCTG were set to Spinocerebellar ataxia 36, OMIM:614153
Hereditary neuropathy or pain disorder v5.104 MAPK8IP3 Eleanor Williams reviewed gene: MAPK8IP3: Rating: AMBER; Mode of pathogenicity: None; Publications: 37462082, 30945334, 30612693; Phenotypes: Neurodevelopmental disorder with or without variable brain abnormalities, OMIM:618443, neurodevelopmental disorder with or without variable brain abnormalities, NEDBA, MONDO:0032755; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Hereditary neuropathy or pain disorder v5.104 HPDL Eleanor Williams Phenotypes for gene: HPDL were changed from developmental delay; spastic paraplegia; peripheral neuropathy to Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities, OMIM:619026; Spastic paraplegia 83, autosomal recessive, OMIM:619027; neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities, MONDO:0033613; spastic paraplegia 83, autosomal recessive, MONDO:0033614
Hereditary neuropathy or pain disorder v5.102 HPDL Eleanor Williams reviewed gene: HPDL: Rating: GREEN; Mode of pathogenicity: None; Publications: 32707086; Phenotypes: Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities, OMIM:619026, Spastic paraplegia 83, autosomal recessive, OMIM:619027, neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities, MONDO:0033613, spastic paraplegia 83, autosomal recessive, MONDO:0033614; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
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 v5.76 NUDT2 Achchuthan Shanmugasundram Phenotypes for gene: NUDT2 were changed from Sensorimotor polyneuropathy; Muscular hypotonia; Intellectual disability; no OMIM number to Intellectual developmental disorder with or without peripheral neuropathy, OMIM:619844
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 v5.73 NARS Achchuthan Shanmugasundram Phenotypes for gene: NARS were changed from developmental delay; seizures; peripheral neuropathy to Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, autosomal recessive, OMIM:619091; Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, autosomal dominant, OMIM:619092
Hereditary neuropathy or pain disorder v5.71 NARS Achchuthan Shanmugasundram reviewed gene: NARS: Rating: GREEN; Mode of pathogenicity: None; Publications: 32738225, 32788587; Phenotypes: Neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, autosomal recessive, OMIM:619091, Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, autosomal dominant, OMIM:619092; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
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 v5.66 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 v5.23 ATXN1_CAG Sarah Leigh STR: ATXN1_CAG was added
STR: ATXN1_CAG was added to Hereditary neuropathy or pain disorder. Sources: Expert Review Green,NHS GMS
STR tags were added to STR: ATXN1_CAG.
Mode of inheritance for STR: ATXN1_CAG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for STR: ATXN1_CAG were set to Spinocerebellar ataxia 1, OMIM:164400
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 v5.21 FGF14_GAA Sarah Leigh STR: FGF14_GAA was added
STR: FGF14_GAA was added to Hereditary neuropathy or pain disorder. Sources: Expert Review Amber
watchlist tags were added to STR: FGF14_GAA.
Mode of inheritance for STR: FGF14_GAA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for STR: FGF14_GAA were set to 36516086; 36493768; 37267898
Phenotypes for STR: FGF14_GAA were set to Spinocerebellar ataxia 27B, late-onset, OMIM: 620174
Penetrance for STR: FGF14_GAA were set to Complete
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 v5.20 FMR1_CGG Sarah Leigh STR: FMR1_CGG was added
STR: FMR1_CGG was added to Hereditary neuropathy or pain disorder. Sources: NHS GMS,Expert Review Amber,Expert Review
STR tags were added to STR: FMR1_CGG.
Mode of inheritance for STR: FMR1_CGG 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 STR: FMR1_CGG were set to 26212380
Phenotypes for STR: FMR1_CGG were set to Fragile X syndrome, OMIM:300624; Fragile X tremor/ataxia syndrome, OMIM:300623
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 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 UCHL1 Alexander Rossor gene: UCHL1 was added
gene: UCHL1 was added to Hereditary neuropathy or pain disorder. Sources: Expert list
Mode of inheritance for gene: UCHL1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: UCHL1 were set to 35986737
Phenotypes for gene: UCHL1 were set to spasticity; ataxia; peripheral neuropathy
Penetrance for gene: UCHL1 were set to Complete
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 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 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 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 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 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 v5.4 LRP12 Sarah Leigh gene: LRP12 was added
gene: LRP12 was added to Hereditary neuropathy or pain disorder. Sources: Literature
Mode of inheritance for gene: LRP12 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: LRP12 were set to 39013564
Phenotypes for gene: LRP12 were set to Motor axonal neuropathy
Hereditary neuropathy or pain disorder v5.3 MYO9B Sarah Leigh gene: MYO9B was added
gene: MYO9B was added to Hereditary neuropathy or pain disorder. Sources: Literature
Mode of inheritance for gene: MYO9B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MYO9B were set to 36260368
Phenotypes for gene: MYO9B were set to CMT2
Penetrance for gene: MYO9B were set to Complete
Hereditary neuropathy or pain disorder v5.2 NDC1 Sarah Leigh gene: NDC1 was added
gene: NDC1 was added to Hereditary neuropathy or pain disorder. Sources: Literature
Mode of inheritance for gene: NDC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDC1 were set to 39003500
Phenotypes for gene: NDC1 were set to demyelinating neuropathy; alacrima; achalasia
Penetrance for gene: NDC1 were set to Complete
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 v4.11 PMM2 Sarah Leigh reviewed gene: PMM2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Congenital disorder of glycosylation, type Ia, OMIM:212065; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v4.11 PEX7 Sarah Leigh reviewed gene: PEX7: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Peroxisome biogenesis disorder 9B, OMIM:14879; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v4.11 PEX10 Sarah Leigh reviewed gene: PEX10: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Peroxisome biogenesis disorder 6A (Zellweger), OMIM:614870, Peroxisome biogenesis disorder 6B, OMIM:614871; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v4.8 SPTBN4 Arina Puzriakova Phenotypes for gene: SPTBN4 were changed from Neurodevelopmental disorder with hypotonia, neuropathy, and deafness, 617519 to Neurodevelopmental disorder with hypotonia, neuropathy, and deafness, OMIM:617519
Hereditary neuropathy or pain disorder v4.7 NEMF Arina Puzriakova Phenotypes for gene: NEMF were changed from Hypotonia; Axonal neuropathy; Ataxia; Abnormal brain imaging; Global developmental delay; Intellectual disability; Kyphosis; Scoliosis; Tremor; Respiratory distress to Intellectual developmental disorder with speech delay and axonal peripheral neuropathy, OMIM:619099
Hereditary neuropathy or pain disorder v3.88 RTN2 Achchuthan Shanmugasundram gene: RTN2 was added
gene: RTN2 was added to Hereditary neuropathy or pain disorder. Sources: Literature
Mode of inheritance for gene: RTN2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RTN2 were set to 38527963
Phenotypes for gene: RTN2 were set to distal hereditary motor neuropathy, MONDO:0018894
Review for gene: RTN2 was set to GREEN
Added comment: PMID:38527963 reported the identification of seven novel or ultra-rare homozygous loss-of-function RTN2 variants in 14 individuals from seven unrelated families with distal hereditary motor neuropathy.

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

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

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

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

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

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

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

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

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