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Hereditary neuropathy or pain disorder v7.36 SPTAN1 Arina Puzriakova Phenotypes for gene: SPTAN1 were changed from Developmental and epileptic encephalopathy 5, OMIM:613477; developmental and epileptic encephalopathy, 5, MONDO:0013277 to Neuronopathy, distal hereditary motor, autosomal dominant 11, OMIM:620528; Spastic paraplegia 91, autosomal dominant, with or without cerebellar ataxia, OMIM:620538
Hereditary neuropathy or pain disorder v7.32 SPG7 Ida Ertmanska changed review comment from: Many homozygous and compound heterozygous cases reported in large spastic paraplegia cohorts, with variable symptom severity and age of onset (childhood to late adulthood).
Recurrent SPG7 variants:
SPG7: c.1529C>T, p.Ala510Val has MAF = 0.007265 in gnomAD v4.1.0 (European population), with 44 total homozygotes reported;
SPG7: c.1454_1462del, p.Arg485_Glu487del - highest frequency in gnomAD v4.1.0 = 0.0006758 (Finnish population), no homozygotes;
SPG7: c.233T>A, p.Leu78Ter - MAF = 0.002778 (South Asian population), 5 homozygotes reported.
SPG7: c.1045G>A, p.Gly349Ser -MAF = 0.002041 (European), 3 homozygotes in gnomAD.

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

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

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


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

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

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

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

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

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

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

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

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

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

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

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

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

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


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

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

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

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

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

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

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

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

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

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

SPG7 is associated with Spastic paraplegia 7, autosomal recessive, OMIM:607259 (accessed 8th Jan 2026). Entry for Spastic paraplegia 7 in GeneReviews (https://www.ncbi.nlm.nih.gov/books/NBK1107/) mentions that the possibility of autosomal dominant inheritance remains controversial. SPG7 link to SPG7-related spastic paraplegia (biallelic_autosomal) is classified as definitive on the Gene2Phenotype Eye disorders panel.
Hereditary neuropathy or pain disorder v7.32 SPG7 Ida Ertmanska edited their review of gene: SPG7: Changed publications to: 22964162, 23065789, 24727571, 26506339, 31068484, 31854126, 32548275, 33598982, 33774748, 34405107, 39978794; Changed phenotypes to: Spastic paraplegia 7, autosomal recessive, OMIM:607259, hereditary spastic paraplegia 7, MONDO:0011803
Hereditary neuropathy or pain disorder v7.32 SPG7 Ida Ertmanska commented on gene: SPG7: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126), as well as possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Heterozygous carriers of SPG7 variants in recessive pedigrees are usually unaffected. Based on available evidence, the mode of inheritance for SPG7 should be changed to BIALLELIC, autosomal or pseudoautosomal.
Hereditary neuropathy or pain disorder v6.164 SPAST Sarah Leigh Added comment: Comment on publications: PMID: 39731306 was identified by the Genomics England Applied Machine Learning (ML) team in a Biocuration-ML project for identifying new gene-disease associations using Natural Language Processing (NLP) and Generative AI techniques.
Hereditary neuropathy or pain disorder v6.164 SPAST Sarah Leigh Publications for gene: SPAST were set to 28572275
Hereditary neuropathy or pain disorder v6.163 SPAST Sarah Leigh Tag Q1_25_ MOI tag was added to gene: SPAST.
Hereditary neuropathy or pain disorder v6.163 SPAST Sarah Leigh edited their review of gene: SPAST: Added comment: Numerous heterozygous SPAST variants have been associated with Spastic paraplegia 4, autosomal dominant (OMIM:182601). PMID: 39731306 reports five homozygous SPAST variants in nine individuals from six families with spastic paraplegia and neurodegeneration. Amongst the homozygous children, all had lower limb spasticity, 5/6 had upper limb spasticity and 3/6 had severe intellectual disability. Evidence of consanguinity was evident in five of the families and the parents of the homozygous children were heterozygous for the SPAST variant found in the child, these carrier parents were asymptomatic in all but one the families studied.; Changed mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v6.148 SPAST Sarah Leigh Tag Q3_24_promote_green was removed from gene: SPAST.
Tag Q3_24_NHS_review was removed from gene: SPAST.
Hereditary neuropathy or pain disorder v6.148 SPAST Sarah Leigh reviewed gene: SPAST: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Hereditary neuropathy or pain disorder v6.147 SPAST Sarah Leigh Source Expert Review Green was added to SPAST.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Hereditary neuropathy or pain disorder v6.131 SPAST Arina Puzriakova Classified gene: SPAST as Amber List (moderate evidence)
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 v6.131 SPAST Arina Puzriakova Gene: spast has been classified as Amber List (Moderate Evidence).
Hereditary neuropathy or pain disorder v6.127 SPAST Arina Puzriakova Tag Q3_24_promote_green tag was added to gene: SPAST.
Tag Q3_24_NHS_review tag was added to gene: SPAST.
Hereditary neuropathy or pain disorder v6.111 SOX10 Achchuthan Shanmugasundram Phenotypes for gene: SOX10 were changed from Waardenburg syndrome, type 2E, with or without neurologic involvement, 611584; Waardenburg syndrome, type 4C, 613266; PCWH syndrome, 609136; Hypopigmentation of the hair and skin, sensory hearing loss, demyelinating neuropathy, dysmyelinating leukodystrophy, developmental delay, spasticity, ataxia, Hirschsprung disease to PCWH syndrome, OMIM:609136
Hereditary neuropathy or pain disorder v6.82 ZFYVE26 Arina Puzriakova Phenotypes for gene: ZFYVE26 were changed from Hereditary Neuropathies; Onset second decade, spastic paraplegia, intellectual disability and cognitive decline, thin corpus callosum, mild cerebellar eye signs, axonal sensory-motor neuropathy, parkinsonism and dystonia, pseudobulbar involvement and pigmentry maculopathy; Spastic paraplegia 15, autosomal recessive, 270700 to Spastic paraplegia 15, autosomal recessive, OMIM:270700
Hereditary neuropathy or pain disorder v6.64 DSTYK Sarah Leigh Phenotypes for gene: DSTYK were changed from Spastic paraplegia 23, autosomal recessive, OMIM:270750; hereditary spastic paraplegia 23, MONDO:0010046 to Spastic paraplegia 23, autosomal recessive, OMIM:270750; hereditary spastic paraplegia 23, MONDO:0010046
Hereditary neuropathy or pain disorder v6.62 DSTYK Sarah Leigh edited their review of gene: DSTYK: Added comment: Two DSTYK variants (as compound heterozygotes) have been associated with Spastic paraplegia 23, autosomal recessive (OMIM:270750) in 3 unrelated families of Middle Eastern origin. This combination of variants in the reported families was revealed to be founder effect by haplotype analysis (PMID: 28157540).; Changed rating: AMBER; Changed publications to: 28157540; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v6.62 DSTYK Sarah Leigh Added comment: Comment on phenotypes: Childhood onset spastic paraplegia, prominent skin pigment abnormalities (vitiligo, hyperpigmentation, diffuse lentigines), premature greying of hair, sensory predominant axonal neuropathy (mild).
Hereditary neuropathy or pain disorder v6.62 DSTYK Sarah Leigh Phenotypes for gene: DSTYK were changed from Childhood onset spastic paraplegia, prominent skin pigment abnormalities (vitiligo, hyperpigmentation, diffuse lentigines), premature greying of hair, sensory predominant axonal neuropathy (mild).; Spastic paraplegia 23, 270750 to Spastic paraplegia 23, autosomal recessive, OMIM:270750; hereditary spastic paraplegia 23, MONDO:0010046
Hereditary neuropathy or pain disorder v6.43 DARS2 Sarah Leigh Added comment: Comment on phenotypes: Slowly progressive spasticity, ataxia and dorsal column dysfunction, sensory-motor axonal neuropathy, characteristic MRI findings
Hereditary neuropathy or pain disorder v6.43 DARS2 Sarah Leigh Phenotypes for gene: DARS2 were changed from Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation, 611105; Slowly progressive spasticity, ataxia and dorsal column dysfunction, sensory-motor axonal neuropathy, characteristic MRI findings to Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation, OMIM:611105; leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome MONDO:0012622
Hereditary neuropathy or pain disorder v6.41 CYP2U1 Sarah Leigh Phenotypes for gene: CYP2U1 were changed from spastic paraplegia; cognitive impairment; subvlincial peripheral neuropathy to Spastic paraplegia 56, autosomal recessive, OMIM:615030; hereditary spastic paraplegia 56, MONDO:0014015
Hereditary neuropathy or pain disorder v6.33 CAPN1 Sarah Leigh Phenotypes for gene: CAPN1 were changed from spasticity; pes cavus; peripheral neuropathy to autosomal recessive spastic paraplegia type 76, MONDO:0014827; Spastic paraplegia 76, autosomal recessive, OMIM:616907
Hereditary neuropathy or pain disorder v6.32 ATP13A2 Sarah Leigh Phenotypes for gene: ATP13A2 were changed from spastic paraplegia; cognitive impairment; peripheral neuropathy to Spastic paraplegia 78, autosomal recessive, OMIM:617225; Kufor-Rakeb syndrome, OMIM:606693; Kufor-Rakeb syndrome, MONDO:0011706; autosomal recessive spastic paraplegia type 78, MONDO:0014975
Hereditary neuropathy or pain disorder v6.20 CAPN1 Sarah Leigh reviewed gene: CAPN1: Rating: GREEN; Mode of pathogenicity: ; Publications: 23741357, 27153400; Phenotypes: autosomal recessive spastic paraplegia type 76, MONDO:0014827, Spastic paraplegia 76, autosomal recessive, OMIM:616907; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v6.20 ATP13A2 Sarah Leigh reviewed gene: ATP13A2: Rating: GREEN; Mode of pathogenicity: ; Publications: 28137957, 27217339, 22296644; Phenotypes: Spastic paraplegia 78, autosomal recessive, OMIM:617225, Kufor-Rakeb syndrome, OMIM:606693, Kufor-Rakeb syndrome, MONDO:0011706, autosomal recessive spastic paraplegia type 78, MONDO:0014975; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v6.20 ARL6IP1 Sarah Leigh reviewed gene: ARL6IP1: Rating: GREEN; Mode of pathogenicity: ; Publications: 28471035, 31272422, 33188530, 30237576, 24482476, 30980493; Phenotypes: Spastic paraplegia 61, autosomal recessive, OMIM:615685, hereditary spastic paraplegia 61, MONDO:0014304; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v6.20 AP5Z1 Sarah Leigh reviewed gene: AP5Z1: Rating: GREEN; Mode of pathogenicity: ; Publications: 20613862: 24833714; Phenotypes: Spastic paraplegia 48, autosomal recessive, OMIM:613647; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
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 v5.100 FA2H Eleanor Williams Phenotypes for gene: FA2H were changed from SPG35, Childhood onset spasticity, cognitive decline and leukodystrophy. Mild sensory axonal neuropathy on NCS. Epilepsy, dysphagia, dysarthria and dystonia also observed; Spastic paraplegia 35, autosomal recessive, 612319 to Spastic paraplegia 35, autosomal recessive, OMIM:612319; hereditary spastic paraplegia 35, MONDO:0012866
Hereditary neuropathy or pain disorder v5.97 FA2H Eleanor Williams edited their review of gene: FA2H: Changed phenotypes to: Spastic paraplegia 35, autosomal recessive, OMIM:612319, hereditary spastic paraplegia 35, MONDO:0012866
Hereditary neuropathy or pain disorder v5.97 FA2H Eleanor Williams reviewed gene: FA2H: Rating: ; Mode of pathogenicity: None; Publications: 22146942, 31135052; Phenotypes: Spastic paraplegia 35, autosomal recessive, OMIM:612319; Mode of inheritance: None
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 v5.85 TRMT5 Arina Puzriakova Phenotypes for gene: TRMT5 were changed from develomental delay; spasticity; peripheral neuropathy to Peripheral neuropathy with variable spasticity, exercise intolerance, and developmental delay, OMIM:616539
Hereditary neuropathy or pain disorder v5.83 UCHL1 Arina Puzriakova Added comment: Comment on list classification: Sensorimotor neuropathy has been reported in both Spastic paraplegia 79A, autosomal dominant, OMIM:620221 and Spastic paraplegia 79B, autosomal recessive, OMIM:615491. Sufficient unrelated cases for both MOIs to promote to Green at the next GMS panel update.
Hereditary neuropathy or pain disorder v5.82 UCHL1 Arina Puzriakova Phenotypes for gene: UCHL1 were changed from spasticity; ataxia; peripheral neuropathy to Spastic paraplegia 79B, autosomal recessive, OMIM:615491; Spastic paraplegia 79A, autosomal dominant, OMIM:620221
Hereditary neuropathy or pain disorder v5.79 VPS13D Arina Puzriakova Phenotypes for gene: VPS13D were changed from ataxia; spasticity; peripheral neuropathy to Spinocerebellar ataxia, autosomal recessive 4, OMIM:607317
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 v5.64 AP5Z1 Sarah Leigh Phenotypes for gene: AP5Z1 were changed from spasticity; ataxia; retinopathy; neuropathy; parkinsonism to Spastic paraplegia 48, autosomal recessive, OMIM:613647; hereditary spastic paraplegia 48, MONDO:0013342
Hereditary neuropathy or pain disorder v5.56 ALDH18A1 Sarah Leigh Phenotypes for gene: ALDH18A1 were changed from spastic paraplegia; cognitive impairment; motor neuronopathy to Spastic paraplegia 9A, autosomal dominant, OMIM:601162; hereditary spastic paraplegia 9A, MONDO:0011006; Spastic paraplegia 9B, autosomal recessive, OMIM:616586; autosomal recessive complex spastic paraplegia type 9B, MONDO:0014702
Hereditary neuropathy or pain disorder v5.54 AFG3L2 Sarah Leigh Phenotypes for gene: AFG3L2 were changed from Optic atrophy 12,OMIM; 618977; Spastic ataxia 5, autosomal recessive, OMIM:614487 to Spastic ataxia 5, autosomal recessive, OMIM:614487
Hereditary neuropathy or pain disorder v5.53 AFG3L2 Sarah Leigh Phenotypes for gene: AFG3L2 were changed from spasticity, peripheral neuropathy, ptosis, oculomotor apraxia; dystonia; cerebellar atrophy; progressive myoclonic epilepsy to Optic atrophy 12,OMIM; 618977; Spastic ataxia 5, autosomal recessive, OMIM:614487
Hereditary neuropathy or pain disorder v5.19 SPAST Alexander Rossor commented on gene: SPAST: 23% have peripheralneuropathy and should therefore be inlcuded in R78 as this now includes complex phenotypes
Hereditary neuropathy or pain disorder v5.19 DSTYK Alexander Rossor reviewed gene: DSTYK: Rating: AMBER; Mode of pathogenicity: None; Publications: 28157540; Phenotypes: spastic paraplegia, peripheral neuropathy, grey hair; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v5.19 DARS2 Alexander Rossor edited their review of gene: DARS2: Added comment: Multiple additional unrelated individuals with variants in DARS2 and peripheral neuropathy - should now be green; Changed publications to: 28334938: 38790244: 22677571: 38549004; Changed phenotypes to: Slowly progressive spasticity, ataxia and dorsal column dysfunction, sensory-motor axonal neuropathy, characteristic MRI findings
Hereditary neuropathy or pain disorder v5.19 C12orf65 Alexander Rossor edited their review of gene: C12orf65: Added comment: PN in multiple affected individuals from different families; Changed rating: GREEN; Changed publications to: 24080142: 23188110: 6303658: 24424123: 24198383; Changed phenotypes to: optic atrophy, spasticity, peripheral neuropathy; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v5.19 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 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 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 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 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 ARL6IP1 Alexander Rossor reviewed gene: ARL6IP1: Rating: ; Mode of pathogenicity: None; Publications: 28471035: 24482476: 31272422; Phenotypes: Spastic paraplegia, neuropathy; Mode of inheritance: None
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 v5.16 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 v4.11 SACS Sarah Leigh reviewed gene: SACS: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic ataxia, Charlevoix-Saguenay type, OMIM:270550; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v4.11 PNPLA6 Sarah Leigh reviewed gene: PNPLA6: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Oliver-McFarlane syndrome, OMIM:275400, Spastic paraplegia 39, autosomal recessive, OMIM:612020, Boucher-Neuhauser syndrome, OMIM:215470; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v4.11 PLP1 Sarah Leigh reviewed gene: PLP1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic paraplegia 2, X-linked, OMIM:312920, Pelizaeus-Merzbacher disease, OMIM:312080; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Hereditary neuropathy or pain disorder v4.11 GBA2 Sarah Leigh reviewed gene: GBA2: Rating: GREEN; Mode of pathogenicity: ; Publications: 24252062, 23332917, 23332916; Phenotypes: Spastic paraplegia 46, autosomal recessive, OMIM:614409; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v4.11 B4GALNT1 Sarah Leigh reviewed gene: B4GALNT1: Rating: GREEN; Mode of pathogenicity: ; Publications: 23746551; Phenotypes: Spastic paraplegia 26, autosomal recessive, OMIM:609195; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v3.89 RTN2 Achchuthan Shanmugasundram changed review comment from: PMID:38527963 reported the identification of seven novel or ultra-rare homozygous loss-of-function RTN2 variants in 14 individuals from seven unrelated families with distal hereditary motor neuropathy.

All affected individuals exhibited weakness in the distal upper and lower limbs, lower limb spasticity, hyperreflexia, with an onset in the first decade of life. Nerve conduction studies revealed axonal motor neuropathy with neurogenic changes in the electromyography.

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

Biallelic variants in RTN2 gene have not yet been associated with any phenotypes in OMIM or Gene2Phenotype, while monoallelic variants have been associated with spastic paraplegia (MIM #604805) in OMIM.
Sources: Literature; to: PMID:38527963 reported the identification of seven novel or ultra-rare homozygous loss-of-function RTN2 variants in 14 individuals from seven unrelated families with distal hereditary motor neuropathy.

All affected individuals exhibited weakness in the distal upper and lower limbs, lower limb spasticity, hyperreflexia, with an onset in the first decade of life. Nerve conduction studies revealed axonal motor neuropathy with neurogenic changes in the electromyography.

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

Biallelic variants in RTN2 gene have not yet been associated with any phenotypes in OMIM or Gene2Phenotype, while monoallelic variants have been associated with spastic paraplegia (MIM #604805) in OMIM.
Sources: Literature
Hereditary neuropathy or pain disorder v3.89 RTN2 Achchuthan Shanmugasundram changed review comment from: PMID:38527963 reported the identification of seven novel or ultra-rare homozygous loss-of-function RTN2 variants in 14 individuals from seven unrelated families with distal hereditary motor neuropathy.

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

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

Biallelic variants in RTN2 gene have not yet been associated with any phenotypes in OMIM or Gene2Phenotype, while monoallelic variants have been associated with spastic paraplegia (MIM #604805) in OMIM.
Sources: Literature; to: PMID:38527963 reported the identification of seven novel or ultra-rare homozygous loss-of-function RTN2 variants in 14 individuals from seven unrelated families with distal hereditary motor neuropathy.

All affected individuals exhibited weakness in the distal upper and lower limbs, lower limb spasticity, hyperreflexia, with an onset in the first decade of life. Nerve conduction studies revealed axonal motor neuropathy with neurogenic changes in the electromyography.

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

Biallelic variants in RTN2 gene have not yet been associated with any phenotypes in OMIM or Gene2Phenotype, while monoallelic variants have been associated with spastic paraplegia (MIM #604805) in OMIM.
Sources: Literature
Hereditary neuropathy or pain disorder v3.88 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 v3.84 SPG7 Sarah Leigh changed review comment from: SPG7 variants have been associated with Spastic paraplegia 7, autosomal recessive (OMIM:607259) and have a definitive association with the same condition on the Eye panel at Gen2Phen. Various phenotypic features are apparent in cases of OMIM:607259. Peripheral neuropathy has been reported in at least three cases (PMID: 35096021, in the review on this panel by Williams Kirsty), and optical neuropathy has been reported in many more cases (as mentioned in PMID:35243150).; to: SPG7 variants have been associated with Spastic paraplegia 7, autosomal recessive (OMIM:607259) and have a definitive association with the same condition on the Eye panel at Gen2Phen. Various phenotypic features are apparent in cases of OMIM:607259. Peripheral neuropathy has been reported in at least three cases (PMID: 35096021, in the review on this panel by Kirsty Williams), and optical neuropathy has been reported in many more cases (as mentioned in PMID:35243150).
Hereditary neuropathy or pain disorder v3.83 SPG7 Sarah Leigh edited their review of gene: SPG7: Added comment: SPG7 variants have been associated with Spastic paraplegia 7, autosomal recessive (OMIM:607259) and have a definitive association with the same condition on the Eye panel at Gen2Phen. Various phenotypic features are apparent in cases of OMIM:607259. Peripheral neuropathy has been reported in at least three cases (PMID: 35096021, in the review on this panel by Williams Kirsty), and optical neuropathy has been reported in many more cases (as mentioned in PMID:35243150).; Changed rating: GREEN; Changed publications to: 30098094, 35637455, 35096021, 35243150, 22964162
Hereditary neuropathy or pain disorder v3.83 GALC Alexander Rossor edited their review of gene: GALC: Added comment: Can present with peripheral neuropathy and should be included in R78 panel; Changed publications to: 26840509; Changed phenotypes to: Krabbe. Spastic paraplegia, developmental delay, optic atrophy, adult onset has spastic paraplegia and sensory-motor axonal neuropathy with slow or normal conduction velocities, MRI shows leukodystrophy
Hereditary neuropathy or pain disorder v3.74 PCYT2 Achchuthan Shanmugasundram changed review comment from: PMID:35243002 reported two brothers with a novel homozygous missense variant in the first catalytic domain of PCYT2 (c.88T>G/ p.Cys30Gly). Although these two patients shared several phenotypic features with previously reported patients with syndromic spastic paraplegia including short stature, spastic tetraparesis, cerebellar ataxia, epilepsy, and cognitive decline, these were the first patients reported with axonal polyneuropathy.; to: PMID:35243002 reported two brothers with a novel homozygous missense variant in the first catalytic domain of PCYT2 (c.88T>G/ p.Cys30Gly). Although these two patients shared several phenotypic features with previously reported patients with syndromic spastic paraplegia including short stature, spastic tetraparesis, cerebellar ataxia, epilepsy, and cognitive decline, axonal polyneuropathy reported in these two brothers were not reported in any previous cases.
Hereditary neuropathy or pain disorder v3.74 PCYT2 Achchuthan Shanmugasundram Phenotypes for gene: PCYT2 were changed from to Spastic paraplegia 82, autosomal recessive, OMIM:618770; axonal neuropathy, MONDO:0004183
Hereditary neuropathy or pain disorder v3.71 PCYT2 Achchuthan Shanmugasundram reviewed gene: PCYT2: Rating: RED; Mode of pathogenicity: None; Publications: 35243002; Phenotypes: Spastic paraplegia 82, autosomal recessive, OMIM:618770, axonal neuropathy, MONDO:0004183; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v3.9 SPG7 Sarah Leigh changed review comment from: Associated with relevant phenotype in OMIM and as definitive Gen2Phen gene. Numerous biallelic SPG7 variants have been reported (PMIDs: 9635427; 16534102; 17646629; 18200586, 20186691; 22571692) and at least five monoallelic SPG7 variants have been associated with Spastic paraplegia 7, autosomal recessive, OMIM:607259 (PMIDs: 18200586; 22571692). For this reason, the mode of inheritance for this gene should be BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form) autosomal or pseudoautosomal; to: Associated with OMIM:607259 and as definitive Gen2Phen gene for the same condition. Numerous biallelic SPG7 variants have been reported (PMIDs: 9635427; 16534102; 17646629; 18200586, 20186691; 22571692) and at least five monoallelic SPG7 variants have been associated with Spastic paraplegia 7, autosomal recessive, OMIM:607259 (PMIDs: 18200586; 22571692). For this reason, the mode of inheritance for this gene should be BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form) autosomal or pseudoautosomal
Hereditary neuropathy or pain disorder v3.7 SPG7 Sarah Leigh Phenotypes for gene: SPG7 were changed from Hereditary Neuropathies; Spastic paraplegia, optic atrophy, ataxia and sensory-motor axonal neuropathy in some patients to Spastic paraplegia 7, autosomal recessive, OMIM:607259; hereditary spastic paraplegia 7, MONDO:0011803
Hereditary neuropathy or pain disorder v2.28 SPAST Sarah Leigh Phenotypes for gene: SPAST were changed from Hereditary Neuropathies; Spastic paraplegia 4, autosomal dominant; Spasticity to Spastic paraplegia 4, autosomal dominant, OMIM:182601; hereditary spastic paraplegia 4, MONDO:0008438
Hereditary neuropathy or pain disorder v2.21 MAG Arina Puzriakova Entity copied from Hereditary spastic paraplegia - childhood onset v3.18
Hereditary neuropathy or pain disorder v2.21 MAG Arina Puzriakova gene: MAG was added
gene: MAG was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS,Expert Review Amber,Literature,Yorkshire and North East GLH,London North GLH
Q1_23_promote_green tags were added to gene: MAG.
Mode of inheritance for gene: MAG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MAG were set to 24482476; 26179919; 31402626; 32629324; 32340215
Phenotypes for gene: MAG were set to Spastic paraplegia 75, autosomal recessive, OMIM:616680
Hereditary neuropathy or pain disorder v2.5 SLC25A46 Achchuthan Shanmugasundram Phenotypes for gene: SLC25A46 were changed from Neuropathy, hereditary motor and sensory, type VIB, 616505; Optic atrophy and progressive visual loss in the 1st decade, then spasticity, cerebellar ataxia, sensory-motor axonal neuropathy to Neuropathy, hereditary motor and sensory, type VIB, MIM# 616505; Pontocerebellar hypoplasia, type 1E, MIM# 619303, MONDO:0030260
Hereditary neuropathy or pain disorder v1.99 SETX Sarah Leigh Added comment: Comment on publications: PMID: 25025039 - a likely pathogenic variant in SETX reported in a sporadic case with CMT2 and spasticity. Found with a REEP1 variant, and the authors assume digenic pathogenicity.;PMID:25802885 - Identifiy one previously reported variant and three novel variants in 4 families. Report the variants found in CMT patients are likely nonpathogenic due to bioinformatics analysis. Report SETX c.7640T>C is a nonpathogenic rare variant
Hereditary neuropathy or pain disorder v1.99 SETX Sarah Leigh Publications for gene: SETX were set to PMID: 25025039 - a likely pathogenic variant in SETX reported in a sporadic case with CMT2 and spasticity. Found with a REEP1 variant, and the authors assume digenic pathogenicity.; PMID:25802885 - Identifiy one previously reported variant and three novel variants in 4 families. Report the variants found in CMT patients are likely nonpathogenic due to bioinformatics analysis. Report SETX c.7640T>C is a nonpathogenic rare variant
Hereditary neuropathy or pain disorder v1.54 GALC Arina Puzriakova Phenotypes for gene: GALC were changed from Krabbe. Spastic paraplegia, developmental delay, optic atrophy; Krabbe disease, 245200; adult onset has spastic paraplegia and sensory-motor axonal neuropathy with slow or normal conduction velocities, MRI shows leukodystrophy to Krabbe disease, OMIM:245200
Hereditary neuropathy or pain disorder v1.53 C12orf65 Arina Puzriakova Phenotypes for gene: C12orf65 were changed from to Combined oxidative phosphorylation deficiency 7, OMIM:613559; Spastic paraplegia 55, autosomal recessive, OMIM:615035
Hereditary neuropathy or pain disorder v1.50 TFG Arina Puzriakova Phenotypes for gene: TFG were changed from Hereditary motor and sensory neuropathy, Okinawa type; Chondrosarcoma, extraskeletal myxoid, 612237; Hereditary motor and sensory neuropathy, proximal type, 604484 to Hereditary motor and sensory neuropathy, Okinawa type, OMIM:604484; Spastic paraplegia 57, autosomal recessive, OMIM:615658
Hereditary neuropathy or pain disorder v1.36 KIF1A Arina Puzriakova Phenotypes for gene: KIF1A were changed from Hereditary Sensory and Autonomic Neuropathy, Type II; Neuropathy, hereditary sensory, type IIC, 614213 to Neuropathy, hereditary sensory, type IIC, OMIM:614213; Spastic paraplegia 30, autosomal dominant, OMIM:610357; Spastic paraplegia 30, autosomal recessive, OMIM:610357; NESCAV syndrome, OMIM:614255
Hereditary neuropathy or pain disorder v1.31 BSCL2 Arina Puzriakova Phenotypes for gene: BSCL2 were changed from Lipodystrophy, congenital generalized, type 2 269700; Neuropathy, distal hereditary motor, type VA 600794; Encephalopathy, progressive, with or without lipodystrophy, 615924; Silver spastic paraplegia syndrome 270685 to Neuropathy, distal hereditary motor, type VC, OMIM:619112
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 v1.23 POLR3B Zornitza Stark gene: POLR3B was added
gene: POLR3B was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature
Mode of inheritance for gene: POLR3B was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: POLR3B were set to 33417887
Phenotypes for gene: POLR3B were set to Ataxia, spasticity, and demyelinating neuropathy
Review for gene: POLR3B was set to GREEN
Added comment: Note biallelic variants cause a leukodystrophy.

New MOI and new phenotype reported in PMID: 33417887: Six unrelated individuals with de novo missense variants and ataxia, spasticity, variable intellectual disability and epilepsy, and predominantly demyelinating sensory motor peripheral neuropathy.
Protein modeling and proteomic analysis shows variants caused aberrant association of individual enzyme subunits rather than affecting overall enzyme assembly or stability.
Sources: Literature
Hereditary neuropathy or pain disorder v0.86 SPAST Louise Daugherty commented on gene: SPAST: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart): Extension of panel scope - HSP with neuropathy / Broader phenotype (HSP)
Hereditary neuropathy or pain disorder v0.86 SLC25A46 Louise Daugherty commented on gene: SLC25A46: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart): Extension of panel scope - syndrome with non-neurological features / Broader phenotype: Optic atrophy and progressive visual loss in the 1st decade, then spasticity, cerebellar ataxia, sensory-motor axonal neuropathy
Hereditary neuropathy or pain disorder v0.86 POLR3A Louise Daugherty commented on gene: POLR3A: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart): Extension of panel scope - ataxia with neuropathy / Broader phenotype: spastic ataxia with abnormal nerve conduction in 8/14 cases
Hereditary neuropathy or pain disorder v0.86 PLP1 Louise Daugherty commented on gene: PLP1: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart): Extension of panel scope - minor feature / Broader phenotype: Pelizaeus-Merbacher/Spastic paraplegia 2 - is neuropathy a feature?
Hereditary neuropathy or pain disorder v0.84 SPAST Louise Daugherty commented on gene: SPAST: This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.
Hereditary neuropathy or pain disorder v0.83 SPAST Louise Daugherty Source Expert Review Amber was added to SPAST.
Rating Changed from Green List (high evidence) to Amber List (moderate evidence)
Hereditary neuropathy or pain disorder v0.21 ABHD12 Louise Daugherty changed review comment from: Gene remains rated as Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - syndrome with non-neurological features / Polyneuropathy with SNCV (slow nerve conduction velocity?), sensorineuronal hearing loss, retinitis pigmentosa, spastic paraplegia, ataxia - rated Red.
; to: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - syndrome with non-neurological features / Polyneuropathy with SNCV (slow nerve conduction velocity?), sensorineuronal hearing loss, retinitis pigmentosa, spastic paraplegia, ataxia
Hereditary neuropathy or pain disorder v0.21 ABHD12 Louise Daugherty changed review comment from: Gene remains rated as Red : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - syndrome with non-neurological features / Polyneuropathy with SNCV (slow nerve conduction velocity?), sensorineuronal hearing loss, retinitis pigmentosa, spastic paraplegia, ataxia - rated Red.
R78 was going to be broadened to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP. Subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for this panel to be restricted to genes that are associated with isolated neuropathy.; to: Gene remains rated as Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - syndrome with non-neurological features / Polyneuropathy with SNCV (slow nerve conduction velocity?), sensorineuronal hearing loss, retinitis pigmentosa, spastic paraplegia, ataxia - rated Red.
Hereditary neuropathy or pain disorder v0.1 ZFYVE26 Ellen McDonagh gene: ZFYVE26 was added
gene: ZFYVE26 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Emory Genetics Laboratory,South West GLH,London North GLH,NHS GMS
Mode of inheritance for gene: ZFYVE26 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: ZFYVE26 were set to Hereditary Neuropathies; Onset second decade, spastic paraplegia, intellectual disability and cognitive decline, thin corpus callosum, mild cerebellar eye signs, axonal sensory-motor neuropathy, parkinsonism and dystonia, pseudobulbar involvement and pigmentry maculopathy; Spastic paraplegia 15, autosomal recessive, 270700
Hereditary neuropathy or pain disorder v0.1 SPG7 Ellen McDonagh gene: SPG7 was added
gene: SPG7 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Emory Genetics Laboratory,South West GLH,London North GLH,NHS GMS
Mode of inheritance for gene: SPG7 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SPG7 were set to Hereditary Neuropathies; Spastic paraplegia, optic atrophy, ataxia and sensory-motor axonal neuropathy in some patients
Hereditary neuropathy or pain disorder v0.1 SOX10 Ellen McDonagh gene: SOX10 was added
gene: SOX10 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS,London North GLH,Expert list,UKGTN,South West GLH
Mode of inheritance for gene: SOX10 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SOX10 were set to 21898658
Phenotypes for gene: SOX10 were set to Waardenburg syndrome, type 2E, with or without neurologic involvement, 611584; Waardenburg syndrome, type 4C, 613266; PCWH syndrome, 609136; Hypopigmentation of the hair and skin, sensory hearing loss, demyelinating neuropathy, dysmyelinating leukodystrophy, developmental delay, spasticity, ataxia, Hirschsprung disease
Hereditary neuropathy or pain disorder v0.1 SLC25A46 Ellen McDonagh gene: SLC25A46 was added
gene: SLC25A46 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS,London North GLH
Mode of inheritance for gene: SLC25A46 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC25A46 were set to 26168012
Phenotypes for gene: SLC25A46 were set to Neuropathy, hereditary motor and sensory, type VIB, 616505; Optic atrophy and progressive visual loss in the 1st decade, then spasticity, cerebellar ataxia, sensory-motor axonal neuropathy
Hereditary neuropathy or pain disorder v0.1 SELENOI Ellen McDonagh gene: SELENOI was added
gene: SELENOI was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS,London North GLH
Mode of inheritance for gene: SELENOI was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SELENOI were set to Infantile onset, global developmental delay, spasticity, periventricular white mater signal change on MRI, peripheral neuropathy with SNCV. Seizures and bifid uvula in some affected individuals
Hereditary neuropathy or pain disorder v0.1 POLR3A Ellen McDonagh gene: POLR3A was added
gene: POLR3A was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS,London North GLH
Mode of inheritance for gene: POLR3A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLR3A were set to 28459997
Phenotypes for gene: POLR3A were set to Bilateral hyperintensities on MRI from the superior cerebellar peduncle to the dentate nucleus / midbrain; Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism, 607694; Adolescent onset progressive spastic ataxia, tremor, involvement of central sensory tracts, dental complications
Hereditary neuropathy or pain disorder v0.1 PNPLA6 Ellen McDonagh gene: PNPLA6 was added
gene: PNPLA6 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Emory Genetics Laboratory,South West GLH,London North GLH,NHS GMS
Mode of inheritance for gene: PNPLA6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PNPLA6 were set to 24355708
Phenotypes for gene: PNPLA6 were set to Hereditary Neuropathies; Childhood onset of slowly progressive spastic paraplegia; progressive distal motor neuropathy beginning in early through late adolescence
Hereditary neuropathy or pain disorder v0.1 NIPA1 Ellen McDonagh gene: NIPA1 was added
gene: NIPA1 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Emory Genetics Laboratory,South West GLH,NHS GMS
Mode of inheritance for gene: NIPA1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: NIPA1 were set to 14508710; 15711826; 21419568; 22302102; 15643603
Phenotypes for gene: NIPA1 were set to Hereditary Neuropathies; Spastic paraplegia 6, autosomal dominant
Hereditary neuropathy or pain disorder v0.1 KLC2 Ellen McDonagh gene: KLC2 was added
gene: KLC2 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS,London North GLH
Mode of inheritance for gene: KLC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KLC2 were set to 26385635
Phenotypes for gene: KLC2 were set to SPOAN, Early onset spastic paraplegia, congenital optic atrophy, and axonal sensory-motor neuropathy; Spastic paraplegia, optic atrophy, and neuropathy, 609541
Hereditary neuropathy or pain disorder v0.1 KCNA2 Ellen McDonagh gene: KCNA2 was added
gene: KCNA2 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS,London North GLH
Mode of inheritance for gene: KCNA2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KCNA2 were set to 27543892
Phenotypes for gene: KCNA2 were set to Epileptic encephalopathy, early infantile, 32, 616366; Childhood onset spasticity, intellectual disability, ataxia, seizures, sensory and motor SNCV in one family
Hereditary neuropathy or pain disorder v0.1 GJC2 Ellen McDonagh gene: GJC2 was added
gene: GJC2 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS,London North GLH
Mode of inheritance for gene: GJC2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: GJC2 were set to Leukodystrophy, hypomyelinating, 2, 608804; Infantile-onset Pelizaeus-Merzbacher disease-like phenotype slowly evolving into a form of complicated hereditary spastic paraplegia with mental retardation, dysarthria, optic atrophy andperipheral neuropathyin adulthood. Leukodystrophy; Spastic paraplegia 44, autosomal recessive, 613206
Hereditary neuropathy or pain disorder v0.1 GBA2 Ellen McDonagh gene: GBA2 was added
gene: GBA2 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS,London North GLH
Mode of inheritance for gene: GBA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GBA2 were set to 23332916
Phenotypes for gene: GBA2 were set to SPG46, Spastic paraplegia, cognitive decline, thin corpus callosum, ataxia, cataracts, bulbar dysfunction, axonal sensory-motor neuropathy; Spastic paraplegia 46, autosomal recessive, 614409
Hereditary neuropathy or pain disorder v0.1 GALC Ellen McDonagh gene: GALC was added
gene: GALC was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS,London North GLH
Mode of inheritance for gene: GALC was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: GALC were set to Krabbe. Spastic paraplegia, developmental delay, optic atrophy; Krabbe disease, 245200; adult onset has spastic paraplegia and sensory-motor axonal neuropathy with slow or normal conduction velocities, MRI shows leukodystrophy
Hereditary neuropathy or pain disorder v0.1 FA2H Ellen McDonagh gene: FA2H was added
gene: FA2H was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS,London North GLH
Mode of inheritance for gene: FA2H was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FA2H were set to 22146942
Phenotypes for gene: FA2H were set to SPG35, Childhood onset spasticity, cognitive decline and leukodystrophy. Mild sensory axonal neuropathy on NCS. Epilepsy, dysphagia, dysarthria and dystonia also observed; Spastic paraplegia 35, autosomal recessive, 612319
Hereditary neuropathy or pain disorder v0.1 DSTYK Ellen McDonagh gene: DSTYK was added
gene: DSTYK was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS,London North GLH
Mode of inheritance for gene: DSTYK was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: DSTYK were set to Childhood onset spastic paraplegia, prominent skin pigment abnormalities (vitiligo, hyperpigmentation, diffuse lentigines), premature greying of hair, sensory predominant axonal neuropathy (mild).; Spastic paraplegia 23, 270750
Hereditary neuropathy or pain disorder v0.1 DEGS1 Ellen McDonagh gene: DEGS1 was added
gene: DEGS1 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS,London North GLH
Mode of inheritance for gene: DEGS1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DEGS1 were set to 30620337; 30620338
Phenotypes for gene: DEGS1 were set to Demyelinating neuropathy. Motor developmental delay, spasticity, cerebellar atrophy and microcephaly, hypomyelination on MRI, scoliosis, neurogenic bladder, enteral nutrition; Leukodystrophy, hypomyelinating, 18, 618404
Hereditary neuropathy or pain disorder v0.1 DARS2 Ellen McDonagh gene: DARS2 was added
gene: DARS2 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS,London North GLH
Mode of inheritance for gene: DARS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DARS2 were set to 28334938
Phenotypes for gene: DARS2 were set to Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation, 611105; Slowly progressive spasticity, ataxia and dorsal column dysfunction, sensory-motor axonal neuropathy, characteristic MRI findings
Hereditary neuropathy or pain disorder v0.1 CCT5 Ellen McDonagh gene: CCT5 was added
gene: CCT5 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS,Illumina TruGenome Clinical Sequencing Services,London North GLH,Expert list,UKGTN,Expert Review Red,South West GLH,Radboud University Medical Center, Nijmegen
Mode of inheritance for gene: CCT5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCT5 were set to 16399879
Phenotypes for gene: CCT5 were set to Sensory Neuropathy with Spastic Paraplegia; Neuropathy, hereditary sensory, with spastic paraplegia, 256840
Hereditary neuropathy or pain disorder v0.1 C19orf12 Ellen McDonagh gene: C19orf12 was added
gene: C19orf12 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS,London North GLH
Mode of inheritance for gene: C19orf12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C19orf12 were set to 23857908; 20039086
Phenotypes for gene: C19orf12 were set to SPG43, Childhood onset spastic paraplegia and sensory-motor axonal neuropathy, NBIA with optic atrophy, extrapyramidal signs; Spastic paraplegia 43, autosomal recessive, 615043; Neurodegeneration with brain iron accumulation 4, 614298
Hereditary neuropathy or pain disorder v0.1 B4GALNT1 Ellen McDonagh gene: B4GALNT1 was added
gene: B4GALNT1 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS,London North GLH
Mode of inheritance for gene: B4GALNT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: B4GALNT1 were set to 23746551
Phenotypes for gene: B4GALNT1 were set to Spastic paraplegia, intellectual disability, ataxia, dystonia, axonal sensory-motor neuropathy; Spastic paraplegia 26, autosomal recessive, 609195; SPG26
Hereditary neuropathy or pain disorder v0.1 ARL6IP1 Ellen McDonagh gene: ARL6IP1 was added
gene: ARL6IP1 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS,London North GLH
Mode of inheritance for gene: ARL6IP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ARL6IP1 were set to 24482476
Phenotypes for gene: ARL6IP1 were set to Spastic paraplegia 61, autosomal recessive, 615685; Childhood onset spastic paraplegia with mutilating, sensory to motor axonal neuropathy
Hereditary neuropathy or pain disorder v0.1 ABHD12 Ellen McDonagh gene: ABHD12 was added
gene: ABHD12 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS,London North GLH
Mode of inheritance for gene: ABHD12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ABHD12 were set to 20797687; 29571850
Phenotypes for gene: ABHD12 were set to Neurodegeneration, childhood-onset, with cerebellar atrophy,612674; Onset 2nd decade, neuropathy with SNCV, sensory neuronal hearing loss, retinitis pigmentosa, spastic paraplegia, ataxia
Hereditary neuropathy or pain disorder v0.1 SPAST Ellen McDonagh gene: SPAST was added
gene: SPAST was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS,London North GLH,Emory Genetics Laboratory,UKGTN,Expert Review Green
Mode of inheritance for gene: SPAST was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SPAST were set to 28572275
Phenotypes for gene: SPAST were set to Hereditary Neuropathies; Spastic paraplegia 4, autosomal dominant; Spasticity
Hereditary neuropathy or pain disorder v0.1 SETX Ellen McDonagh gene: SETX was added
gene: SETX was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS,London North GLH,Expert Review Green,Expert list
Mode of inheritance for gene: SETX was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SETX were set to PMID: 25025039 - a likely pathogenic variant in SETX reported in a sporadic case with CMT2 and spasticity. Found with a REEP1 variant, and the authors assume digenic pathogenicity.; PMID:25802885 - Identifiy one previously reported variant and three novel variants in 4 families. Report the variants found in CMT patients are likely nonpathogenic due to bioinformatics analysis. Report SETX c.7640T>C is a nonpathogenic rare variant
Hereditary neuropathy or pain disorder v0.1 REEP1 Ellen McDonagh gene: REEP1 was added
gene: REEP1 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS,London North GLH,Expert list,Emory Genetics Laboratory,Expert Review Green,South West GLH
Mode of inheritance for gene: REEP1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: REEP1 were set to 19034539; 22703882
Phenotypes for gene: REEP1 were set to Spastic paraplegia 31, autosomal dominant 610250; ?Neuronopathy, distal hereditary motor, type VB, 614751; Cardiomyopathy
Hereditary neuropathy or pain disorder v0.1 KIF5A Ellen McDonagh gene: KIF5A was added
gene: KIF5A was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Emory Genetics Laboratory,London North GLH,Expert Review Green,NHS GMS
Mode of inheritance for gene: KIF5A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for gene: KIF5A were set to Hereditary Neuropathies; Spastic paraplegia 10, autosomal dominant
Hereditary neuropathy or pain disorder v0.1 BSCL2 Ellen McDonagh gene: BSCL2 was added
gene: BSCL2 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS,London North GLH,Expert list,Emory Genetics Laboratory,UKGTN,Expert Review Green,South West GLH
Mode of inheritance for gene: BSCL2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: BSCL2 were set to 26392352
Phenotypes for gene: BSCL2 were set to Lipodystrophy, congenital generalized, type 2 269700; Neuropathy, distal hereditary motor, type VA 600794; Encephalopathy, progressive, with or without lipodystrophy, 615924; Silver spastic paraplegia syndrome 270685