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| Hereditary neuropathy or pain disorder v8.32 | ATXN1_CAG |
Eleanor Williams changed review comment from: Review of the mode of inheritance for this STR to check for any reported biallelic cases: 4 publications report biallelic repeat expansions in individuals with Spinocerebellar ataxia 1 (SCA1) PMID: 39289638 Baille et al 2024 23 yo male of Tamil origin with severe ataxia with alleles with 61 and 37 CAG repeats both uninterrupted. Onset at age 15. No other family members sequenced. Father had tremors but died at age 40 of unrelated cause. Mother and 2 siblings unaffected. PMID: 25344417 Kumaran et al 2014 Studied 100 individuals from 15 families from a small village in southern India, all lived there for at least 20 years awith a high level of consanguineous marriage. 16 individuals from 6 families with clinical symptoms of ataxia. CAT interruption of the CAG repeats was assessed. A normal range of repeats (24 to 35) was seen in 63 individuals and expansions ranging from 41-51 were observed in 37 individuals (16 symptomatic and 21 pre-symptomatic). Homozygous states of repeat expansions were seen in 2 individuals with genotypes of 41/49 (O8) and 45/46 (O20). O20 (20 years old) is pre-symptomatic and O8 (43 year old) symptomatic for SCA1 . O19 (43 years old) with repeat size 28/47 shows symptoms as severe as O8, indicating that homozygosity does not contribute to disease severity. PMID: 36618024 Sharma et al 2022 Study of 4604 individuals with ataxia from India. 4.8% diagnosed with SCA1. 19 biallelic cases with SCA were identified, 2 cases with SCA1 and repeat expansions in ATXN1 (48/48 and 54/43 repeats). Interruption of the repeats was not determined. Also found two individuals which showed coexistence of expanded alleles in SCA1 (ATXN1) (CAG‐30/40, 29/42) and SCA2(ATXN2) (CAG‐23/45, 23/41) PMID: 8619528 Goldtarb et al., 1996 Siberian kindred of 1484 individuals! 225 were affected by Spinocerebellar ataxia 1 and 78 were examined. Gene is called SCA1 in this publication. 3 individuals were identified with expanded repeats on both alleles; 1 asymptomatic and 2 symptomatic. Not clear if interruption analysis was done on these specific individuals. Asymptomatic - 54 and 45 repeats (age unknown), Symptomatic individual 1 - 56 and 48 repeats, age of onset 22 yo. Symptomatic individual 2 - 50 and 44 repeats. age of onset 32 yo. They state that phenotypic expression of SCA1 in 2 symptomatic homozygotes corresponded to the number of CAG repeats in the larger but not in the smaller of their mutated alleles, indicating that the larger allele controls the phenotype. They did not find evidence for additive effect in these SCA1 patients. Although there are 8 cases reported with biallelic repeat expansions the evidence is not clear cut: - 2 are pre-symptomatic (45/46 repeats (age 20, Kumaran et al 2014 020), 54/45 repeats (age unknown, Goldtarb et al., 1996) - 4 symptomatic but only 1 repeat expansion beyond the pathogenic threshold of 45 and the other in the indeterminate range - Baille et al 2024 (lower repeat expansion 37) and Kumaran et al 2014, 08 (lower repeat expansion of 41) - interruptions determined in both, plus Goltarb et al 1996 (lower repeat expansion of 44, and Sharma et al 2022 (lower repeat expansion of 43) - interruptions not determined). - 2 symptomatic with repeats over 45 but interruption of the repeats was not determined (1 cases from Sharma et al 2022 and 1 case from Goldtarb et al., 1996) Therefore, propose waiting for further evidence before considering changing the mode of inheritance to both mono and biallelic.; to: Review of the mode of inheritance for this STR to check for any reported biallelic cases: 4 publications report biallelic repeat expansions in individuals with Spinocerebellar ataxia 1 (SCA1) PMID: 39289638 Baille et al 2024 23 yo male of Tamil origin with severe ataxia with alleles with 61 and 37 CAG repeats both uninterrupted. Onset at age 15. No other family members sequenced. Father had tremors but died at age 40 of unrelated cause. Mother and 2 siblings unaffected. PMID: 25344417 Kumaran et al 2014 Studied 100 individuals from 15 families from a small village in southern India, all lived there for at least 20 years and there is a high level of consanguineous marriage. 16 individuals from 6 families with clinical symptoms of ataxia. CAT interruption of the CAG repeats was assessed. A normal range of repeats (24 to 35) was seen in 63 individuals and expansions ranging from 41-51 were observed in 37 individuals (16 symptomatic and 21 pre-symptomatic). Homozygous states of repeat expansions were seen in 2 individuals with genotypes of 41/49 (O8) and 45/46 (O20). O20 (20 years old) is pre-symptomatic and O8 (43 year old) symptomatic for SCA1 . O19 (43 years old) with repeat size 28/47 shows symptoms as severe as O8, indicating that homozygosity does not contribute to disease severity. PMID: 36618024 Sharma et al 2022 Study of 4604 individuals with ataxia from India. 4.8% diagnosed with SCA1. 19 biallelic cases with SCA were identified, 2 cases with SCA1 and repeat expansions in ATXN1 (48/48 and 54/43 repeats). Interruption of the repeats was not determined. Also found two individuals which showed coexistence of expanded alleles in SCA1 (ATXN1) (CAG‐30/40, 29/42) and SCA2(ATXN2) (CAG‐23/45, 23/41) PMID: 8619528 Goldtarb et al., 1996 Siberian kindred of 1484 individuals! 225 were affected by Spinocerebellar ataxia 1 and 78 were examined. Gene is called SCA1 in this publication. 3 individuals were identified with expanded repeats on both alleles; 1 asymptomatic and 2 symptomatic. Not clear if interruption analysis was done on these specific individuals. Asymptomatic - 54 and 45 repeats (age unknown), Symptomatic individual 1 - 56 and 48 repeats, age of onset 22 yo. Symptomatic individual 2 - 50 and 44 repeats. age of onset 32 yo. They state that phenotypic expression of SCA1 in 2 symptomatic homozygotes corresponded to the number of CAG repeats in the larger but not in the smaller of their mutated alleles, indicating that the larger allele controls the phenotype. They did not find evidence for additive effect in these SCA1 patients. Although there are 8 cases reported with biallelic repeat expansions the evidence is not clear cut: - 2 are pre-symptomatic (45/46 repeats (age 20, Kumaran et al 2014 020), 54/45 repeats (age unknown, Goldtarb et al., 1996) - 4 symptomatic but only 1 repeat expansion beyond the pathogenic threshold of 45 and the other in the indeterminate range - Baille et al 2024 (lower repeat expansion 37) and Kumaran et al 2014, 08 (lower repeat expansion of 41) - interruptions determined in both, plus Goltarb et al 1996 (lower repeat expansion of 44, and Sharma et al 2022 (lower repeat expansion of 43) - interruptions not determined). - 2 symptomatic with repeats over 45 but interruption of the repeats was not determined (1 cases from Sharma et al 2022 and 1 case from Goldtarb et al., 1996) Therefore, propose waiting for further evidence before considering changing the mode of inheritance to both mono and biallelic. |
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| 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. |
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| Hereditary neuropathy or pain disorder v6.166 | RFC1_AAGGG | Sarah Leigh edited their review of STR: RFC1_AAGGG: Added comment: Pathogenicity at the RFC1_AAGGG repeat locus can result from the biallelic replacement of the benign AAAAG repeat with a variable number of AAGGG repeats (PMID: 30926972; 32040566). Furthermore, biallelic expansions of (AAAAG)exp/(AAAGG)exp, (AAAAG)exp/(AAGGG)exp or (AAAGG)exp/(AAGGG)exp were not pathogenic, therefore, it is the biallelic expansions of AAGGG that is pathogenic (PMID: 30926972). An additional pathogenic biallelic expansion :RFC1_ACAGG, was seen in was seen in two Asia-Pacific CANVAS families and a Japanese case (PMID: 33103729, 35355059).; Changed publications to: 30926972, 35883251, 36250766, 36289003, 36524104, 36478048, 32040566, 33103729, 35355059 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v6.148 | XPA |
Sarah Leigh Tag Q3_24_promote_green was removed from gene: XPA. Tag Q3_24_NHS_review was removed from gene: XPA. |
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| Hereditary neuropathy or pain disorder v6.148 | XPA | Sarah Leigh reviewed gene: XPA: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v6.147 | XPA |
Sarah Leigh Source Expert Review Green was added to XPA. Rating Changed from Amber List (moderate evidence) to Green List (high evidence) |
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| 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 |
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| 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 |
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| 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 |
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| Hereditary neuropathy or pain disorder v6.131 | SPAST | Arina Puzriakova Added comment: Comment on list classification: Axonal peripheral polyneuropathy was reported in at least 8 individuals with SPAST-related HSP (PMID:28572275) and has been recommended for this panel by Alex Rossor (UCL). The scope of this panel has now been expanded to include complex forms of neuropathy and therefore this gene can be promoted to Green at the next GMS panel update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v6.127 | PRNP | Arina Puzriakova Added comment: Comment on list classification: Neuropathy (predominantly sensory and autonomic) has been reported in at least 7 unrelated families with PRNP-related prion disease, which can present as an early and/or isolated feature. The scope of this panel has now been expanded to include complex forms of neuropathy and therefore this gene can be promoted to Green at the next GMS panel update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v6.120 | TUBB3 | Arina Puzriakova Added comment: Comment on list classification: Peripheral neuropathy has been reported >3 unrelated cases with CFEOM3A and one family with multiple mutant carriers had isolated peripheral neuropathy (PMID: 20074521). The scope of this panel has now been expanded to complex forms of neuropathy and therefore this gene can be promoted to Green at the next GMS panel update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v6.116 | TWNK |
Arina Puzriakova Added comment: Comment on list classification: TWNK is associated with multiple phenotypes that feature peripheral neuropathy (Mitochondrial DNA depletion syndrome 7 (hepatocerebral type), OMIM:271245 (AR); Perrault syndrome 5, OMIM:616138 (AR); Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 3, OMIM:609286 (AD)) - sufficient cases with dominant and recessive forms of disease to support the association. The scope of this panel has now been expanded to complex forms of neuropathy and therefore this gene can be promoted to Green at the next GMS panel update. |
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| Hereditary neuropathy or pain disorder v6.115 | XPA |
Arina Puzriakova Tag Q3_24_promote_green tag was added to gene: XPA. Tag Q3_24_NHS_review tag was added to gene: XPA. |
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| Hereditary neuropathy or pain disorder v6.115 | XPA | Arina Puzriakova Publications for gene: XPA were set to 2168777 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v6.114 | XPA | Arina Puzriakova Classified gene: XPA as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v6.114 | XPA | Arina Puzriakova Added comment: Comment on list classification: Peripheral neuropathy is a reported feature in at least 8 unrelated families with xeroderma pigmentosum. The scope of this panel has now been expanded to complex forms of neuropathy and therefore this gene can be promoted to Green at the next GMS panel update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v6.114 | XPA | Arina Puzriakova Gene: xpa has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v6.99 | XPA | Arina Puzriakova Phenotypes for gene: XPA were changed from Photosensitivity and increased risk of cutaneous malignancy, global developmental delay, deafness, sensory-motor axonal peripheral neuropathy; Xeroderma pigmentosum, group A, 278700 to Xeroderma pigmentosum, group A, OMIM:278700; Sensory-motor axonal peripheral neuropathy | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v6.80 | ZFYVE26 | Arina Puzriakova Added comment: Comment on list classification: Peripheral neuropathy is a reported feature in at least 5 unrelated families with SPG15. The scope of this panel has now been expanded to complex forms of neuropathy and therefore this gene can be promoted to Green at the next GMS panel update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v6.51 | AP1S1 | Arina Puzriakova Added comment: Comment on list classification: Neuropathy in adulthood is a feature of MEDNIK syndrome. >3 unrelated cases have been reported. The scope of this panel has now been expanded to complex forms of neuropathy and therefore this gene can be promoted to Green at the next GMS panel update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v6.14 | NDUFS6 |
Eleanor Williams changed review comment from: Associated with Mitochondrial complex I deficiency, nuclear type 9, OMIM: 618232 (AR) Biallelic loss of function variants are associated with severe CI deficiency and Leigh syndrome in previous reports (PubMed: 19259137 and PubMed: 15372108). There is now phenotypic expansion with 4 families reported with a less severe phenotype. 3 families share a common variant. PMID: 38459834 - Camila Armirola-Ricaurte et al 2024. Describe 5 patients from 3 unrelated families from Spain, Turkey and Greece. They share a homozygous NDUFS6 NM_004553.6:c.309+5G>A variant found be exome sequencing and an axonal Charcot-Marie-Tooth (CMT) neuropathy. Age of onset ranged from 1 to 10 years. In all cases the unaffected parents were heterozygous for the variant. The variant is predicted to affect splicing and in family 1 was shown to cause the expression of aberrantly spliced transcripts and negligible levels of the canonical transcript. Haplotype analysis showed that the variant lies on a shared haplotype of 0.74MB on chromosome 5 and estimate the most recent common ancestor with the haplotype would have lived 740 years ago PMID: 38549004 – Ferreira et al 2024 – screened nearly 11,000 patients with peripheral neuropathy for variants in known mitochondrial disease genes. 1 male was found with a homozygous variant c.320_323delCAAA, p.Thr107LysfsTer40 in NDUFS6.; to: Associated with Mitochondrial complex I deficiency, nuclear type 9, OMIM: 618232 (AR) Biallelic loss of function variants are associated with severe CI deficiency and Leigh syndrome in previous reports (PubMed: 19259137 Spiegal et al 2009 and PubMed: 15372108 Kirby et al 2004, PMID: 30948790 - Rouzier et al 2019, PMID: 22474353 Ke et al 2012). There is now phenotypic expansion with 5 families reported with a less severe phenotype. 4 families share a common variant. PMID: 38459834 - Armirola-Ricaurte et al 2024. Describe 5 patients from 3 unrelated families from Spain, Turkey and Greece. They share a homozygous NDUFS6 NM_004553.6:c.309+5G>A variant found be exome sequencing and an axonal Charcot-Marie-Tooth (CMT) neuropathy. Age of onset ranged from 1 to 10 years. In all cases the unaffected parents were heterozygous for the variant. The variant is predicted to affect splicing and in family 1 was shown to cause the expression of aberrantly spliced transcripts and negligible levels of the canonical transcript. Haplotype analysis showed that the variant lies on a shared haplotype of 0.74MB on chromosome 5 and estimate the most recent common ancestor with the haplotype would have lived 740 years ago PMID: 38549004 – Ferreira et al 2024 – screened nearly 11,000 patients with peripheral neuropathy for variants in known mitochondrial disease genes. 1 male was found with a homozygous variant c.320_323delCAAA, p.Thr107LysfsTer40 in NDUFS6. PMID: 38217609 - Gangfuß et al 2024 - identified a homozygous variant (c.309 + 5 G > A) in NDUFS6 in one male patient aged 10 with axonal neuropathy accompanied by loss of small fibers in skin biopsy. The patient also showed optic atrophy and borderline intellectual disability. |
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| Hereditary neuropathy or pain disorder v6.14 | NDUFS6 |
Eleanor Williams changed review comment from: Associated with Mitochondrial complex I deficiency, nuclear type 9, OMIM: 618232 (AR) Biallelic loss of function variants are associated with severe CI deficiency and Leigh syndrome. 4 families reported although 3 share a common variant. PMID: 38459834 - Camila Armirola-Ricaurte et al 2024. Describe 5 patients from 3 unrelated families from Spain, Turkey and Greece. They share a homozygous NDUFS6 NM_004553.6:c.309+5G>A variant found be exome sequencing and an axonal Charcot-Marie-Tooth (CMT) neuropathy. Age of onset ranged from 1 to 10 years. In all cases the unaffected parents were heterozygous for the variant. The variant is predicted to affect splicing and in family 1 was shown to cause the expression of aberrantly spliced transcripts and negligible levels of the canonical transcript. Haplotype analysis showed that the variant lies on a shared haplotype of 0.74MB on chromosome 5 and estimate the most recent common ancestor with the haplotype would have lived 740 years ago PMID: 38549004 – Ferreira et al 2024 – screened nearly 11,000 patients with peripheral neuropathy for variants in known mitochondrial disease genes. 1 male was found with a homozygous variant c.320_323delCAAA, p.Thr107LysfsTer40 in NDUFS6.; to: Associated with Mitochondrial complex I deficiency, nuclear type 9, OMIM: 618232 (AR) Biallelic loss of function variants are associated with severe CI deficiency and Leigh syndrome in previous reports (PubMed: 19259137 and PubMed: 15372108). There is now phenotypic expansion with 4 families reported with a less severe phenotype. 3 families share a common variant. PMID: 38459834 - Camila Armirola-Ricaurte et al 2024. Describe 5 patients from 3 unrelated families from Spain, Turkey and Greece. They share a homozygous NDUFS6 NM_004553.6:c.309+5G>A variant found be exome sequencing and an axonal Charcot-Marie-Tooth (CMT) neuropathy. Age of onset ranged from 1 to 10 years. In all cases the unaffected parents were heterozygous for the variant. The variant is predicted to affect splicing and in family 1 was shown to cause the expression of aberrantly spliced transcripts and negligible levels of the canonical transcript. Haplotype analysis showed that the variant lies on a shared haplotype of 0.74MB on chromosome 5 and estimate the most recent common ancestor with the haplotype would have lived 740 years ago PMID: 38549004 – Ferreira et al 2024 – screened nearly 11,000 patients with peripheral neuropathy for variants in known mitochondrial disease genes. 1 male was found with a homozygous variant c.320_323delCAAA, p.Thr107LysfsTer40 in NDUFS6. |
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| 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). |
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| Hereditary neuropathy or pain disorder v6.9 | NOP56 | Arina Puzriakova Added comment: Comment on list classification: Added to this panel by Alexander Rossor (UCL Institute of Neurology). Good evidence but mechanism of disease is repeat expansions (GGCCTG)n rather than SNVs and so rating the gene entity as Red. Added STR entity instead. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v6.8 | NOP56 |
Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: NOP56. Tag currently-ngs-unreportable tag was added to gene: NOP56. |
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| Hereditary neuropathy or pain disorder v5.19 | XPA | Alexander Rossor edited their review of gene: XPA: Added comment: PN seems otbe mostly associated with XPA- Aditional paper attached. Now that R78 inlcudes complex phenotypes should be included; Changed publications to: 2168777: 34627174 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v5.8 | LRP12 |
Sarah Leigh changed review comment from: A trinucleotide expansion LRP12_CGG variant has been reported in numerous unrelated Japanese individuals with either Amyotrophic lateral sclerosis 28, OMIM:620452 or Oculopharyngodistal myopathy 1, OMIM:164310 (PMID:39013564; 37339631; 31332380). This STR has not been approved or verified by Genomics England Clinical Team or Rare Disease Analyst, it can not be added to PanelApp at present.; to: A trinucleotide expansion LRP12_CGG variant has been reported in numerous unrelated Japanese individuals with either Amyotrophic lateral sclerosis 28, OMIM:620452 or Oculopharyngodistal myopathy 1, OMIM:164310 (PMID:39013564; 37339631; 31332380). This STR has not been approved or verified by Genomics England Clinical Team or Rare Disease Analyst, therefore, it can not be added to PanelApp at present. |
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| Hereditary neuropathy or pain disorder v5.8 | LRP12 |
Sarah Leigh changed review comment from: A trinucleotide expansion LRP12_CGG variant has been reported in numerous unrelated Japanese individuals with either Amyotrophic lateral sclerosis 28, OMIM:620452 or Oculopharyngodistal myopathy 1, OMIM:164310 (PMID:39013564; 37339631; 31332380). ; to: A trinucleotide expansion LRP12_CGG variant has been reported in numerous unrelated Japanese individuals with either Amyotrophic lateral sclerosis 28, OMIM:620452 or Oculopharyngodistal myopathy 1, OMIM:164310 (PMID:39013564; 37339631; 31332380). This STR has not been approved or verified by Genomics England Clinical Team or Rare Disease Analyst, it can not be added to PanelApp at present. |
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| Hereditary neuropathy or pain disorder v5.8 | LRP12 | Sarah Leigh changed review comment from: A trinucleotide expansion LRP12_CGG variant has been reported in numerous unrelated Japanese individuals with either Amyotrophic lateral sclerosis 28, OMIM:620452 or Oculopharyngodistal myopathy 1, OMIM:164310 (PMID:39013564; 37339631; 31332380).; to: A trinucleotide expansion LRP12_CGG variant has been reported in numerous unrelated Japanese individuals with either Amyotrophic lateral sclerosis 28, OMIM:620452 or Oculopharyngodistal myopathy 1, OMIM:164310 (PMID:39013564; 37339631; 31332380). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v3.91 | GAN |
Arina Puzriakova Added comment: Comment on list classification: This gene should be promoted to Green at the next GMS panel update as the scope of this panel has now been expanded to include complex cases of neuropathy. Biallelic variants in the GAN gene cause giant axonal neuropathy. This childhood onset polyneuropathy results in progressive neurodegeneration of both the peripheral and central nervous systems. More than 10 unrelated cases have been reported in the literature which is sufficient for making this gene Green (PMIDs: 18595793; 19231187; 20949505; 27852232; 36866531) |
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| Hereditary neuropathy or pain disorder v3.83 | FXN | Alexander Rossor edited their review of gene: FXN: Added comment: FA can present with a sensory neuropathy and should be included in the R78 panel. A missense may prompt testing for an expansion in the other allele.; Changed publications to: 20339857 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v1.68 | RFC1 | Eleanor Williams commented on gene: RFC1: Copied this gene from the Hereditary ataxia - adult onset panel so that it is noted that the STR associated with this gene is relevant to the panel, NOT SNV/indels or deletions covering this gene. In PMID: 33969391 - Curro et al 2021 - they found that 43 patients (34%) with sensory neuropathy had biallelic AAGGG repeat expansions in RFC1and in none with sensory-motor neuropathy. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v1.65 | FXN | Arina Puzriakova Added comment: Comment on mode of inheritance: Updated MOI to 'Biallelic' as monoallelic variants have not been associated with disease. Patients either harbour a homozygous expansion or are compound heterozygous for an expansion and a point mutation. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v1.64 | FXN | Arina Puzriakova Tag nucleotide-repeat-expansion tag was added to gene: FXN. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v0.86 | XPA | Louise Daugherty commented on gene: XPA: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart): Extension of panel scope - syndrome with non-neurological features / Broader phenotype: XP/de Sanctis-Cacchione syndrome - does only this form of XP have neurological features? | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v0.84 | XPA | Louise Daugherty commented on gene: XPA: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v0.83 | XPA |
Louise Daugherty Source Expert Review Amber was added to XPA. Rating Changed from Red List (low evidence) to Amber List (moderate evidence) |
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| Hereditary neuropathy or pain disorder v0.1 | XPA |
Ellen McDonagh gene: XPA was added gene: XPA was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS,London North GLH Mode of inheritance for gene: XPA was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: XPA were set to 2168777 Phenotypes for gene: XPA were set to Photosensitivity and increased risk of cutaneous malignancy, global developmental delay, deafness, sensory-motor axonal peripheral neuropathy; Xeroderma pigmentosum, group A, 278700 |
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| Hereditary neuropathy or pain disorder v0.1 | SIGMAR1 |
Ellen McDonagh gene: SIGMAR1 was added gene: SIGMAR1 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS,London North GLH,Expert Review,Expert Review Green Mode of inheritance for gene: SIGMAR1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SIGMAR1 were set to PMID: 26088964 is a commentary on PMID: 25678561 raising a lack of evidence for SIGMARI to be pathogenic, and that previous reports of patients with SIGMARI variants were also shown to harbour C9orf72 expansions. PMID: 26088963 - in reply, authors state that there is in vitro and in vivo evidence, and expression evidence, and that a case reported did not have the C9orf72 expansion; PubMed: 21842496 - E102Q variant identified in a Saudi Arabian family to be associated with amyotrophic lateral sclerosis 16, juvenile; PMID: 26078401 - c.151+1G>T variant in SIGMARI resulted in a 60 bp deletion in the transcript, and segrated with the distal hereditary motor neuropathy in a Chinese family.; PMID: 26205306 one family report for association with Amyotrophic lateral sclerosis and c.672*31A>G (rs4879809) - the C9ORF72 repeat region in intron 1, previously implicated in a related phenotype, was excluded through linkage, and further confirmation of exclusion was obtained by amplifying intron 1 of C9ORF72 with multiple primers in affected individuals and controls |
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