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| Hereditary neuropathy or pain disorder v7.32 | SPG7 | Ida Ertmanska commented on gene: SPG7: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia / spinocerebellar ataxia have biallelic SPG7 variants. While several monoallelic cases have been described to date, the dominant inheritance was likely erroneously assigned due to technical study limitations (e.g., deep intronic SPG7 variant detectable only by WGS - PMID: 31854126), as well as possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Heterozygous carriers of SPG7 variants in recessive pedigrees are usually unaffected. Based on available evidence, the mode of inheritance for SPG7 should be changed to BIALLELIC, autosomal or pseudoautosomal. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v7.24 | PNPT1 |
Achchuthan Shanmugasundram edited their review of gene: PNPT1: Added comment: There are additional cases reported recently: PMID:39899068 (2025) reported a 1-year-8-month-old female proband of Brazilian descent with Spinocerebellar Ataxia 25 that presented with progressive ataxia, cerebellar atrophy, and sensory neuropathy. She was identified with a novel heterozygous truncating variant in PNPT1 (c.2068del), which she inherited from her father. Although the father was previously reported as asymptomatic, he was affected with axonal and demyelinating polyneuropathy but not ataxia upon detailed examination. PMID:39924761 (2025) reported two unrelated families, where all individuals presented with sensory ataxic neuropathy (SAN), while some individuals developed cerebellar signs. Analysis of WGS variant data through the 100,000 Genomes Project identified two different heterozygous variants in these families. Family 1 underwent a 'quad' study and the previously reported c.2014‐3C>G variant segregated in all affected family members and was absent in all unaffected family members. Sanger sequencing confirmed segregation in two other individuals. c.2014‐3C>G is the same variant that was found in the 3-generation Australian family reported by PMID:35411967, where unaffected family members harboured the variant. A novel nonsense variant (c.2143C>T/ p.Arg715Ter) was found in both affected members of Family 2.; Changed publications to: 14705117, 35411967, 37935417, 39899068, 39924761 |
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| Hereditary neuropathy or pain disorder v7.20 | CPOX |
Ida Ertmanska changed review comment from: HCP patients may present with acute neurovisceral attacks, characterised by severe abdominal pain and neuropsychiatric symptoms - often provoked by drugs, alcohol, or endocrine factors. Diagnosis of HCP is established based on increased faecal coproporphyrin III:I ratio when VP has been excluded by the plasma fluorescence scan wavelength (PMID: 11309681 Lamoril et al., 2001; 38940544 Aarsand et al., 2022). Acute episodes can progress to include seizures, peripheral motor neuropathy and posterior reversible encephalopathy syndrome if left untreated (PMID: 35584894 Schulenburg-Brand et al., 2022) PMID: 11074238 Kuhnel et al., 2000 53 patients with HCP. Phenotype: abdominal pain (89% of the cohort), neurologic (33%), psychiatric (28%), cardiovascular (25%), and skin symptoms (14%). PMID: 21103937 Hasanoglu 2011 Male infant from a Turkish consanguineous family presented with the Harderoporphyria phenotype: neonatal hyperbilirubinemia, hemolytic anemia, hepatosplenomegaly, and skin lesions when exposed to UV light. Heterozygous for c.980A>G (p.His327Arg) The patient died at 5 months old due to an apparent acute neurologic porphyric attack. Structural studies predicted that p.H327R interacts with residue W399 in the CPOX active site. CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 21st Oct 2025).; to: HCP patients may present with acute neurovisceral attacks, characterised by severe abdominal pain and neuropsychiatric symptoms - often provoked by drugs, alcohol, or endocrine factors. Diagnosis of HCP is established based on increased faecal coproporphyrin III:I ratio when VP has been excluded by the plasma fluorescence scan wavelength (PMID: 11309681 Lamoril et al., 2001; 38940544 Aarsand et al., 2022). Acute episodes can progress to include seizures, peripheral motor neuropathy and posterior reversible encephalopathy syndrome if left untreated (PMID: 35584894 Schulenburg-Brand et al., 2022) PMID: 8008008 Barohn et al. 1994 A 23-year-old man with no genetic diagnosis. Presented with epilepsy and a past history of abdominal pain. Electrophysiologic studies demonstrated a peripheral neuropathy with features of axonal degeneration and demyelination. PMID: 11074238 Kuhnel et al., 2000 53 patients with HCP. Phenotype: abdominal pain (89% of the cohort), neurologic (33%), psychiatric (28%), cardiovascular (25%), and skin symptoms (14%). PMID: 21103937 Hasanoglu 2011 Male infant from a Turkish consanguineous family presented with the Harderoporphyria phenotype: neonatal hyperbilirubinemia, hemolytic anemia, hepatosplenomegaly, and skin lesions when exposed to UV light. Heterozygous for c.980A>G (p.His327Arg) The patient died at 5 months old due to an apparent acute neurologic porphyric attack. Structural studies predicted that p.H327R interacts with residue W399 in the CPOX active site. PMID: 24353603 Chen et al., 2013 46yo Chinese woman with a biochemical diagnosis of HCP. Phenotype: acute abdominal pain and progressive bilateral weakness and pain in the limbs. She also experienced significant muscle atrophy and decreased strength. Nerve conduction potential study revealed motor-sensory polyneuropathy. Successfully treated with hemin. PMID: 24156084 Jiménez-Jiménez et al., 2013 44-year-old patient presenting clinically with acute ataxia who was diagnosed with HCP. Heterozygous for p.Q306X. PMID: 35228944 Upchurch et al., 2025 26-year-old female with HCP who presented with acute ascending flaccid paralysis and respiratory failure after COVID-19 infection and was initially misdiagnosed and treated for Guillain-Barré syndrome. Patient developed progressively worsening abdominal pain; symmetric, distal-predominant, and ascending weakness developed four weeks later, associated with severe headaches and complex visual hallucinosis. Electrodiagnostic testing: profound axonal sensorimotor peripheral polyneuropathy affecting all extremities. No abnormalities on brain MRI. Successfully treated with hemin. Heterozygous for c.1070G>A (p.Cys357Tyr) - rare in gnomAD v4, Revel score = 0.9. Seq method: unknown. CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 21st Oct 2025). |
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| Hereditary neuropathy or pain disorder v7.20 | CPOX |
Ida Ertmanska changed review comment from: HCP patients may present with acute neurovisceral attacks, characterised by severe abdominal pain and neuropsychiatric symptoms - often provoked by drugs, alcohol, or endocrine factors. Diagnosis of HCP is established based on increased faecal coproporphyrin III:I ratio when VP has been excluded by the plasma fluorescence scan wavelength (PMID: 11309681 Lamoril et al., 2001; 38940544 Aarsand et al., 2022). Acute episodes can progress to include seizures, peripheral motor neuropathy and posterior reversible encephalopathy syndrome if left untreated (PMID: 35584894 Schulenburg-Brand et al., 2022) PMID: 11074238 Kuhnel et al., 2000 53 patients with HCP. Phenotype: abdominal pain (89% of the cohort), neurologic (33%), psychiatric (28%), cardiovascular (25%), and skin symptoms (14%). CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 21st Oct 2025).; to: HCP patients may present with acute neurovisceral attacks, characterised by severe abdominal pain and neuropsychiatric symptoms - often provoked by drugs, alcohol, or endocrine factors. Diagnosis of HCP is established based on increased faecal coproporphyrin III:I ratio when VP has been excluded by the plasma fluorescence scan wavelength (PMID: 11309681 Lamoril et al., 2001; 38940544 Aarsand et al., 2022). Acute episodes can progress to include seizures, peripheral motor neuropathy and posterior reversible encephalopathy syndrome if left untreated (PMID: 35584894 Schulenburg-Brand et al., 2022) PMID: 11074238 Kuhnel et al., 2000 53 patients with HCP. Phenotype: abdominal pain (89% of the cohort), neurologic (33%), psychiatric (28%), cardiovascular (25%), and skin symptoms (14%). PMID: 21103937 Hasanoglu 2011 Male infant from a Turkish consanguineous family presented with the Harderoporphyria phenotype: neonatal hyperbilirubinemia, hemolytic anemia, hepatosplenomegaly, and skin lesions when exposed to UV light. Heterozygous for c.980A>G (p.His327Arg) The patient died at 5 months old due to an apparent acute neurologic porphyric attack. Structural studies predicted that p.H327R interacts with residue W399 in the CPOX active site. CPOX is associated with Coproporphyria 121300 (AR and AD) and Harderoporphyria 618892 (AR) in OMIM (accessed 21st Oct 2025). |
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| Hereditary neuropathy or pain disorder v7.8 | CPOX |
Sharon Whatley changed review comment from: Relevant metabolic investigation: Urine porphobilinogen PMID: 38940544 Aarsand reports that the acute porphyrias are a group of rare inborn errors of metabolism caused by abnormal functioning of haem biosynthesis enzymes and are associated with acute neurovisceral attacks characterized by severe abdominal pain and neuropsychiatric symptoms that may require highly specialized intensive care. The acute porphyrias, acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria (HCP), usually become symptomatic in early adulthood. PMID: 11309681 Lamoril reports that HCP is the least common of the autosomal dominant, acute hepatic porphyrias. It results from pathogenic variants in the CPOX gene that encodes the mitochondrial enzyme, coproporphyrinogen oxidase. PMID: 38940544 Aarsand and 23605133 Whatley report that HCP is an autosomal dominant disorder with an estimated prevalence of HCP in the UK as 1–2 in a million with a rough estimate of the clinical penetrance of 0.4%. Due to this low penetrance, genetic testing alone may be misleading and cause misdiagnosis. IPNET advises that biochemical testing is used to diagnose active HCP as the penetrance is so low. PMID: 35584894 Schulenburg-Brand reviews the neuropathy that may occur in the acute porphyrias. Weakness and altered sensation are typically mild in an acute attack and improve as the pain resolves. In a small number of cases, severe, progressive peripheral neuropathy develops. Neuropathy can worsen, even after the acute pain resolves, with a Guillain-Barré like picture. Proximal muscle weakness occurs in the upper limbs and can progress to involve the legs and cause respiratory failure. Cranial nerves can be involved, with the facial, vagus and hypoglossal nerves most often affected, causing swallowing difficulties. Sensory neuropathy is less common, but can cause numbness over the torso and thighs, sometimes with severe pain. Cases gradually resolve with respiratory support, and some patients may need prolonged mechanical ventilation. After recovery, some degree of peripheral neuropathy can persist, with foot drop and wrist drop being fairly typical. Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the CPOX gene, due to its low clinical penetrance (~0.4%).; to: Relevant metabolic investigation: Urine porphobilinogen PMID: 38940544 Aarsand reports that the acute porphyrias are a group of rare inborn errors of metabolism caused by abnormal functioning of haem biosynthesis enzymes and are associated with acute neurovisceral attacks characterized by severe abdominal pain and neuropsychiatric symptoms that may require highly specialized intensive care. The acute porphyrias, acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria (HCP), usually become symptomatic in early adulthood. PMID: 11309681 Lamoril reports that HCP is the least common of the autosomal dominant, acute hepatic porphyrias. It results from pathogenic variants in the CPOX gene that encodes the mitochondrial enzyme, coproporphyrinogen oxidase. PMID: 38940544 Aarsand and 23605133 Whatley report that HCP is an autosomal dominant disorder with an estimated prevalence of HCP in the UK as 1–2 in a million with a rough estimate of the clinical penetrance of 0.4%. Due to this low penetrance, genetic testing alone may be misleading and cause misdiagnosis. IPNET advises that biochemical testing is used to diagnose active HCP as the penetrance is so low. PMID: 35584894 Schulenburg-Brand reviews the neuropathy that may occur in the acute porphyrias. Weakness and altered sensation are typically mild in an acute attack and improve as the pain resolves. In a small number of cases, severe, progressive peripheral neuropathy develops. Neuropathy can worsen, even after the acute pain resolves, with a Guillain-Barré like picture. Proximal muscle weakness occurs in the upper limbs and can progress to involve the legs and cause respiratory failure. Cranial nerves can be involved, with the facial, vagus and hypoglossal nerves most often affected, causing swallowing difficulties. Sensory neuropathy is less common, but can cause numbness over the torso and thighs, sometimes with severe pain. Cases gradually resolve with respiratory support, and some patients may need prolonged mechanical ventilation. After recovery, some degree of peripheral neuropathy can persist, with foot drop and wrist drop being fairly typical. Careful consideration should be given to the reporting of a single pathogenic variant as an incidental finding in the CPOX gene, due to its low clinical penetrance (~0.4%). |
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| Hereditary neuropathy or pain disorder v6.127 | OPA3 |
Eleanor Williams changed review comment from: Associated with 3-methylglutaconic aciduria, type III, OMIM:258501 (AR) and Optic atrophy 3 with cataract, OMIM:165300 (AD). PMID:28050599 - Bourne et al 2017 - 1 case - woman with cataracts, optic atrophy, lipodystrophy/lipoatrophy, and peripheral neuropathy. Exome sequencing identified a OPA3 c.235C > G p.(Leu79Val) variant that was confirmed to be de novo. The variant is not reported in gnomAD. PMID: 31119193 - Horga et al 2019 - describe 2 families and one sporadic case with a syndromic form of OPA3-related autosomal dominant optic atrophy and cataract in which patients also show peripheral neuropathy. Heterozyous variants in OPA3 were identified c.23T>C (p.Met8Thr), c.313C>G (p.Gln105Glu) and c.313C>G (p.Gln105Glu) in each of the 3 families. In In 4 patients, the peripheral neuropathy was a major cause of disability or was severe enough to motivate the referral to specialists. PMID:21036400 - Yu-Wai-Man et al 2011 - no patients with OPA3 variants reported, only OPA1 variants.; to: Associated with 3-methylglutaconic aciduria, type III, OMIM:258501 (AR) and Optic atrophy 3 with cataract, OMIM:165300 (AD). PMID:28050599 - Bourne et al 2017 - 1 case - woman with cataracts, optic atrophy, lipodystrophy/lipoatrophy, and peripheral neuropathy. Exome sequencing identified a OPA3 c.235C > G p.(Leu79Val) variant that was confirmed to be de novo. The variant is not reported in gnomAD. PMID: 31119193 - Horga et al 2019 - describe 2 families and one sporadic case with a syndromic form of OPA3-related autosomal dominant optic atrophy and cataract in which patients also show peripheral neuropathy. Heterozyous variants in OPA3 were identified c.23T>C (p.Met8Thr), c.313C>G (p.Gln105Glu) and c.313C>G (p.Gln105Glu) in each of the 3 families. In 4 patients, the peripheral neuropathy was a major cause of disability or was severe enough to motivate the referral to specialists. PMID:21036400 - Yu-Wai-Man et al 2011 - no patients with OPA3 variants reported, only OPA1 variants. |
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| Hereditary neuropathy or pain disorder v6.123 | POLG | Achchuthan Shanmugasundram Phenotypes for gene: POLG were changed from sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO); Mitochondrial DNA depletion syndrome 4A (Alpers type); Cardiomyopathy; Progressive external ophthalmoplegia, autosomal recessive 1; Mitochondrial recessive ataxia syndrome (includes SANDO and SCAE); Progressive external ophthalmoplegia, autosomal dominant 1; Mitochondrial DNA depletion syndrome 4B (MNGIE type) to Mitochondrial DNA depletion syndrome 4B (MNGIE type), OMIM:613662; Mitochondrial recessive ataxia syndrome (includes SANDO and SCAE), OMIM:607459; Progressive external ophthalmoplegia, autosomal dominant 1, OMIM:157640; Progressive external ophthalmoplegia, autosomal recessive 1, OMIM:258450 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v6.118 | POLG | Achchuthan Shanmugasundram edited their review of gene: POLG: Changed publications to: 12975295, 25281868, 33791913, 36703500, 38975049; Changed phenotypes to: Mitochondrial DNA depletion syndrome 4B (MNGIE type), OMIM:613662, Mitochondrial recessive ataxia syndrome (includes SANDO and SCAE), OMIM:607459, Progressive external ophthalmoplegia, autosomal dominant 1, OMIM:157640, Progressive external ophthalmoplegia, autosomal recessive 1, OMIM:258450 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v6.118 | POLG | Achchuthan Shanmugasundram edited their review of gene: POLG: Changed publications to: 25281868, 33791913, 36703500, 38975049; Changed phenotypes to: Mitochondrial DNA depletion syndrome 4B (MNGIE type), OMIM:613662, Mitochondrial recessive ataxia syndrome (includes SANDO and SCAE), OMIM:607459' | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v6.95 | HADHB | Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Alexander Rossor, mitochondrial trifunctional protein deficiency 2 (MIM #620300) includes peripheral neuropathy as one of the clinical manifestations. There are more than three unrelated cases reported with neuropathy in literature. Hence, this gene can be promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v6.90 | HADHA | Achchuthan Shanmugasundram changed review comment from: Comment on list classification: As reviewed by by Alexander Rossor, mitochondrial trifunctional protein deficiency 1 (MIM #609015) includes peripheral neuropathy as one of the clinical manifestations. There are at least three unrelated cases reported with neuropathy in literature. Hence, this gene can be promoted to green rating in the next GMS update.; to: Comment on list classification: As reviewed by Alexander Rossor, mitochondrial trifunctional protein deficiency 1 (MIM #609015) includes peripheral neuropathy as one of the clinical manifestations. There are at least three unrelated cases reported with neuropathy in literature. Hence, this gene can be promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v6.89 | FAH | Sarah Leigh Phenotypes for gene: FAH were changed from Infantile or adolescent onset liver disease, renal tubular dysfunction and hypophosphatemic rickets. Acute episodes of neuropathy similar to AIP; Tyrosinemia, type I, 276700 to Tyrosinemia, type I, OMIM:276700 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v6.88 | HADHA | Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by by Alexander Rossor, mitochondrial trifunctional protein deficiency 1 (MIM #609015) includes peripheral neuropathy as one of the clinical manifestations. There are at least three unrelated cases reported with neuropathy in literature. Hence, this gene can be promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v6.19 | PLA2G16 |
Eleanor Williams changed review comment from: Associated with Lipodystrophy, familial partial, type 9 620683 (AR) in OMIM where Demyelinating sensorimotor neuropathy is listed as a clinical feature. PMID: 37919452 - Schuermans et al 2023 - 7 patients from 4 unrelated families with 3 different homozygous variants (c.16-4823_118+167del p.(Pro6ValfsTer15), c.286dupG p.(Ala96GlyfsTer16) and c.339C>A p.(Cys113Ter). All patients had generalized or partial Lipoatrophy, insulin resistance and Liver steatosis, and 6/7 showed Dyslipidemia/hypertriglyceridemia. Demyelinating peripheral neuropathy was seen in 5/7 patients from all 4 families. Function studies with PLAAT3 inactivation in human adipose stem cells provides evidence for PLAAT3 in PPARγ-mediated adipogenesis.; to: Associated with Lipodystrophy, familial partial, type 9 620683 (AR) in OMIM where Demyelinating sensorimotor neuropathy is listed as a clinical feature. PMID: 37919452 - Schuermans et al 2023 - 7 patients from 4 unrelated families with 3 different homozygous variants (c.16-4823_118+167del p.(Pro6ValfsTer15), c.286dupG p.(Ala96GlyfsTer16) and c.339C>A p.(Cys113Ter). All patients had generalized or partial lipoatrophy, insulin resistance and Liver steatosis, and 6/7 showed Dyslipidemia/hypertriglyceridemia. Demyelinating peripheral neuropathy was seen in 5/7 patients from all 4 families. Psychomotor retardation/intellectual disability was observed in 3/7 patients but the severity is not recorded. Age of onset of symptoms was 19 years, 8 years, 9 months, 4 years, 4 years (not available for 2 patients). Function studies with PLAAT3 inactivation in human adipose stem cells provides evidence for PLAAT3 in PPARγ-mediated adipogenesis. |
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| Hereditary neuropathy or pain disorder v6.19 | PLA2G16 | Eleanor Williams Added comment: Comment on list classification: Promoting to amber with recommendation for green rating following GMS review. 4 cases with 3 different variants in PLAAT3 and a consistent phenotype that includes peripheral neuropathy. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v6.17 | PLA2G16 |
Eleanor Williams edited their review of gene: PLA2G16: Added comment: Associated with Lipodystrophy, familial partial, type 9 620683 (AR) in OMIM where Demyelinating sensorimotor neuropathy is listed as a clinical feature. PMID: 37919452 - Schuermans et al 2023 - 7 patients from 4 unrelated families with 3 different homozygous variants (c.16-4823_118+167del p.(Pro6ValfsTer15), c.286dupG p.(Ala96GlyfsTer16) and c.339C>A p.(Cys113Ter). All patients had generalized or partial Lipoatrophy, insulin resistance and Liver steatosis, and 6/7 showed Dyslipidemia/hypertriglyceridemia. Demyelinating peripheral neuropathy was seen in 5/7 patients from all 4 families. Function studies with PLAAT3 inactivation in human adipose stem cells provides evidence for PLAAT3 in PPARγ-mediated adipogenesis.; Changed phenotypes to: Associated with Lipodystrophy, familial partial, type 9, OMIM:620683, lipodystrophy, familial partial, type 9, MONDO:0958034 |
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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 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 v5.81 | UQCRC1 |
Arina Puzriakova Added comment: Comment on list classification: Rating Amber based on current evidence - three unrelated individuals with Parkinson's disease and heterozygous variants identified by one group (PMID: 33141179) but results have failed to be replicated in large European and Chinese cohorts (PMIDs: 33779694; 33248804). This matches the latest classification on other GMS panels. Furthermore, polyneuropathy was only confirmed in 1/3 families. Knock-in mice with the affected family variant did exhibit significant reductions in distal CMAP amplitudes compared to WT littermates at 12 months (but not 9 months), as well as a slightly reduced conduction velocity but preserved distal motor latency. Peripheral nerve fibre morphology showed decrease in the diameter of myelinated nerve fibres. |
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| Hereditary neuropathy or pain disorder v5.74 | NARS | Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the promotion of this gene top green rating on the next GMS update. The MOI can be set as 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal" as there are at least three cases reported with both modes of inheritance. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v5.69 | FDXR |
Arina Puzriakova Added comment: Comment on list classification: New gene added to this panel by Alexander Rossor (UCL Institute of Neurology). There is sufficient evidence to promote this gene to Green at the next GMS panel update. Review by Masnada et al (2023) of 44 individuals from 35 families reported in literature with FDXR variants revealed sensorimotor peripheral polyneuropathy in more than 20% of patients. In most cases peripheral neuropathy manifests in late stages of disease but presentation since clinical onset has also been described. Other common features include optic neuropathy (93.2%) and acoustic neuropathy (50%). |
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| 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. |
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| 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. |
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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 v5.19 | TUBB3 | Alexander Rossor edited their review of gene: TUBB3: Added comment: multiple affected individuals - unrelated - should be includedin R78 now that includes complex phenotypes; Changed publications to: 34652576 : 25482575; Changed phenotypes to: ptosis, ophthalmoplegia, exotropia, facial weakness, facial dysmorphisms, and, in most cases, distal congenital joint contractures, and subsequently develop intellectual disabilities, gait disorders with proximal joint contractures, Kallmann syndrome (hypogonadotropic hypogonadism and anosmia), and a progressive peripheral neuropathy during the first decade of life | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v5.19 | TTPA | Alexander Rossor edited their review of gene: TTPA: Added comment: Eripheral neuropathy well established part of this complex phenotype. Now that R78 inlcudes complex phenotypes this gene should be included; Changed publications to: 24369383 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v5.19 | SPAST | Alexander Rossor commented on gene: SPAST: 23% have peripheralneuropathy and should therefore be inlcuded in R78 as this now includes complex phenotypes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v5.19 | POLG | Alexander Rossor edited their review of gene: POLG: Added comment: Now R78 includes complex phenotypes this needs to be included as PN well established in POLG disease; Changed publications to: 36703500 : 33791913: 25281868: 38975049; Changed phenotypes to: peripheral neuropathy, CPEO | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v5.19 | PHYH | Alexander Rossor edited their review of gene: PHYH: Added comment: Refsums disease is a well established (historical) cause of peripheral neuropathy. It is treatable and has to be included in the R78 panel now that it includes complex phenotypes; Changed publications to: 9326940; Changed phenotypes to: Refsums diseasd; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v5.19 | HADHB | Alexander Rossor edited their review of gene: HADHB: Added comment: PN well established part of phenotype. Multiple affected families. Now R78 includes complex phenotypes should be included; Changed publications to: 3744096: 28685493: 31521624: 24664533: 28649548: 35235001 : 37388542; Changed phenotypes to: rhabdomyloysis, hypoparathyroidism, peripheral neuropathy | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v5.19 | HADHA | Alexander Rossor edited their review of gene: HADHA: Added comment: trifucnctional protein deificeincy, inlcudes peripheral neuropathy. NOw R78 includes complex phenotypes should be included; Changed publications to: 23868323: 28132977: 32897397; Changed phenotypes to: rhabdomyloysis, peripheral neuropathy | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v5.19 | FLVCR1 | Alexander Rossor edited their review of gene: FLVCR1: Added comment: Multiple additional reports of association with neuropathy. Now R78 includes complex phenotypes should be included; Changed publications to: 21070897: 38405817: 32822874: 28766925: 37469134: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v5.19 | FAM126A | Alexander Rossor edited their review of gene: FAM126A: Added comment: Multiple unrelated patients with peripheralneuropathy. Now that R78 includes complex phneotypes needs to be included; Changed publications to: 16951682: 23998934: 21911699: 33531944: 22749724: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v5.19 | ETFDH | Alexander Rossor edited their review of gene: ETFDH: Added comment: multiple families with neuropathy as part of syndrome, Now R78 includes complex phenotypes should be included; Changed publications to: 32608139: 26821934: 0587156 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v5.19 | ERCC8 | Alexander Rossor edited their review of gene: ERCC8: Added comment: now that R78 includes complex phenotypes sould be included; Changed publications to: 25453614 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v5.19 | ERCC6 | Alexander Rossor edited their review of gene: ERCC6: Added comment: now that R78 includes complex pheotypes should be included; Changed publications to: 25453614 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v5.19 | COA7 | Alexander Rossor edited their review of gene: COA7: Added comment: Multiple additional cases now reported with peripheral neuropathy - should be green and on panle now that R78 includes complex phenotypes; Changed publications to: 29718187: 37264311: 35603692: 27683825 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v5.19 | CNTNAP1 | Alexander Rossor edited their review of gene: CNTNAP1: Added comment: Multiple affected individuals. Now that R78 panel includes complex phenotypes should be green and on panel; Changed publications to: 28374019: 29511323: 27668699: 27782105:; Changed phenotypes to: arthrogryposis, developmental dleay, peripheral neuropathy; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v5.19 | CD59 | Alexander Rossor edited their review of gene: CD59: Added comment: No wthat the R78 panel includes complex phenotypees with peripheral neuropathy this should now be included in the R78 panel; Changed publications to: 23149847, 24382084 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v4.11 | SPTBN4 | Sarah Leigh edited their review of gene: SPTBN4: Added comment: At least six SPTBN4 variants have been associated with OMIM:617519, which includes axonal and demyelinating peripheral neuropathy as one of the clinical features. Six SPTBN4 variants have been reported by PMID: 28540413;29861105 in five unrelated cases of OMIM:617519.; Changed rating: GREEN; Changed publications to: 28540413, 29861105; Changed phenotypes to: Neurodevelopmental disorder with hypotonia, neuropathy, and deafness, OMIM:617519; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v4.6 | PPOX | Arina Puzriakova Phenotypes for gene: PPOX were changed from Porphyria variegata, 176200; Skin photosensitivity. Acute episodes similar to AIP to Porphyria variegata, OMIM:176200; Sensory neuropathy, HP:0000763 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v3.83 | XK | Alexander Rossor commented on gene: XK: Should be included in R78 as now inlcudes many other complex phenotype genes that can present with neuropathy | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v3.83 | SURF1 | Alexander Rossor edited their review of gene: SURF1: Added comment: Should be included as R78 now includes complex phenotype genes; Changed publications to: 27475922, 12026244, 24027061 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v3.83 | SLC25A19 | Alexander Rossor edited their review of gene: SLC25A19: Added comment: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46; Changed phenotypes to: Acute encephalopathic episodes and paralysis following febrile illness with almost complete recovery. Absent sensory-motor action potential during illness. Bilateral striatal necrosis on MRI. Additional chronic progressive axonal neuropathy | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v3.83 | SCARB2 | Alexander Rossor edited their review of gene: SCARB2: Added comment: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46; Changed publications to: 21670406, 19597094 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v3.83 | SACS | Alexander Rossor edited their review of gene: SACS: Added comment: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46; Changed publications to: 30460542 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v3.83 | POLR3A | Alexander Rossor commented on gene: POLR3A: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v3.83 | PNPLA6 | Alexander Rossor commented on gene: PNPLA6: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v3.83 | PMM2 | Alexander Rossor edited their review of gene: PMM2: Added comment: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46; Changed phenotypes to: Neonatal onset, leukodystrophy, abnormal serum glycoproteins, mental retardation, hypotonia, ataxia, retinitis pigmentosa, seizures, slowly progressive neuropathy with SNCV, severe infections, hepatic insufficiency and cardiomyopathy. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v3.83 | PLP1 | Alexander Rossor edited their review of gene: PLP1: Added comment: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46; Changed publications to: 12601703 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v3.83 | PEX10 | Alexander Rossor edited their review of gene: PEX10: Added comment: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46; Changed publications to: 27230853, 20695019 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v3.83 | PDYN | Alexander Rossor commented on gene: PDYN: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v3.83 | NAGA | Alexander Rossor commented on gene: NAGA: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v3.83 | MTTP | Alexander Rossor commented on gene: MTTP: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v3.83 | MMACHC | Alexander Rossor edited their review of gene: MMACHC: Added comment: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46; Changed phenotypes to: Onset infancy to adulthood, thrombotic thrombocytopenia with encephalopathy, myelopathy, renal and pulmonary complications (can be life threatening), retinitis pigmentosa, axonal motor neuropathy. Treated with high dose vitamin B12. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v3.83 | LYST | Alexander Rossor commented on gene: LYST: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v3.83 | IARS2 | Alexander Rossor edited their review of gene: IARS2: Added comment: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46; Changed publications to: 25130867, 28328135, 30041933, 30419932 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v3.83 | GBA2 | Alexander Rossor commented on gene: GBA2: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v3.83 | BCKDHB | Alexander Rossor edited their review of gene: BCKDHB: Added comment: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46; Changed publications to: 18855118, 11180212; Changed phenotypes to: Maple Syrup Urine Disease, Metabolic encephalopathy, elevated branched chain amino acids in urine, acute axonal neuropathy | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v3.83 | B4GALNT1 | Alexander Rossor commented on gene: B4GALNT1: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v3.83 | APOA1 | Alexander Rossor commented on gene: APOA1: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v3.83 | AP1S1 | Alexander Rossor commented on gene: AP1S1: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v3.83 | AGXT | Alexander Rossor edited their review of gene: AGXT: Added comment: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46; Changed publications to: 4701948, 25363903 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v3.83 | AGTPBP1 | Alexander Rossor commented on gene: AGTPBP1: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v3.83 | ABHD12 | Alexander Rossor edited their review of gene: ABHD12: Added comment: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46; Changed publications to: 29571850, 20797687 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v3.83 | GAN | Alexander Rossor commented on gene: GAN: should be included in R78 panel as panel now includes complex phenotypes e.g. ACOX1, HEXA, HEXB, MCM3AP, MORC2, PIGB, POLR3B, SLC25A46 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v3.6 | TDP1 |
Achchuthan Shanmugasundram changed review comment from: As reviewed by Ian Berry (Leeds Genetics Laboratory), there are now three unrelated families reported in literature with Spinocerebellar ataxia with axonal neuropathy-1 (SCAN1) and identified with homozygous variant in TDP1 gene. However, all three families are of Arab descent (one family from Saudi Arabia and two families from Oman) and they presented with the same homozygous variant (p.His493Arg). This gene has been associated with phenotypes in OMIM (MIM #607250), but not in Gene2Phenotype.; to: As reviewed by Ian Berry (Leeds Genetics Laboratory), there are now three unrelated families reported in literature with Spinocerebellar ataxia with axonal neuropathy-1 (SCAN1) and identified with homozygous variant in TDP1 gene. However, all three families are of Arab descent (one family from Saudi Arabia and two families from Oman) and they presented with the same homozygous variant (p.His493Arg). There are a number of functional studies characterising the function of H493R variant in vitro (PMIDs:15920477, 17948061 & 31723605). This gene has been associated with phenotypes in OMIM (MIM #607250), but not in Gene2Phenotype. |
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| Hereditary neuropathy or pain disorder v3.6 | TDP1 | Achchuthan Shanmugasundram Added comment: Comment on list classification: This gene can now be promoted to AMBER as there are three unrelated cases. The "founder-effect" tag has been added as they are all of Middle Eastern descent and harboured the same homozygous variant. Hence, it cannot be promoted to green rating. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v2.9 | TECPR2 | Mafalda Gomes changed review comment from: Neuser et al. (2021) report 17 unrelated cases with a biallelic pathogenic variants in TECPR2. The study also includes 11 previously reported patients. The core manifestations in these individuals are global developmental delay/intellectual disability, muscular hypotonia, ataxia, hyporeflexia, respiratory infections, and central/nocturnal hypopnea. Peripheral neuropathy was present in two-thirds of all individuals. The majority of the pathogenic variants identified are truncating variants; however, missense variants were also found, predominantly located in the N-terminal and C-terminal regions. The TECPR2 gene is implicated in the autophagy pathway, which is critical to the development and function of the central nervous system. Loss?of?function variants in several genes of the autophagy pathway lead to both neurodevelopmental and neurodegenerative diseases. In summary, this gene should be promoted to GREEN in this panel, with autosomal recessive mode of inheritance.; to: Neuser et al. (2021) report 17 unrelated cases with a biallelic pathogenic variants in TECPR2. The study also includes 11 previously reported patients. The core manifestations in these individuals are global developmental delay/intellectual disability, muscular hypotonia, ataxia, hyporeflexia, respiratory infections, and central/nocturnal hypopnea. Peripheral neuropathy was present in two-thirds of all individuals. The majority of the pathogenic variants identified are truncating variants; however, missense variants were also found, predominantly located in the N-terminal and C-terminal regions. The TECPR2 gene is implicated in the autophagy pathway, which is critical to the development and function of the central nervous system. Loss of function variants in several genes of the autophagy pathway lead to both neurodevelopmental and neurodegenerative diseases. In summary, this gene should be promoted to GREEN in this panel, with autosomal recessive mode of inheritance. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v1.73 | HEXB | Arina Puzriakova Added comment: Comment on list classification: Neuropathy has been described in Sandhoff disease, particularly in adult-onset cases where this can be an initial finding and other symptoms may be more mild. Sufficient unrelated cases of neuropathy due to variants in this gene have been reported in literature (>3). Overall HEXB should be promoted to Green at the next GMS panel update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v1.70 | HEXA | Arina Puzriakova Added comment: Comment on list classification: Neuronopathy and peripheral neuropathy have been described in Tay-Sachs disease, particularly in adult-onset cases where this can be an initial finding and other symptoms may be more mild. Sufficient unrelated cases of neuropathy due to variants in this gene have been reported in literature (>3). Overall HEXA should be promoted to Green at the next GMS panel update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v1.14 | NUDT2 | Arina Puzriakova commented on gene: NUDT2: Comment on tags: added 'founder-effect' tag - although authors state that they do not believe p.Ala63GlnfsTer3 to be a founder variant (one family of Mexican descent while the other of Cajun descent), this was not confirmed by haplotype analysis. Also added 'watchlist' tag in anticipation of further publications/clinical evidence to support association with this phenotype. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v1.11 | NEMF | Arina Puzriakova Added comment: Comment on mode of inheritance: Set MOI to 'Biallelic' as only 1 case with a monoallelic variant described at present. The 'watchlist' tag has been added while further evidence is gathered to establish whether or not there is a wider association with monoallelic variants and disease. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v1.5 | EMILIN1 |
Zornitza Stark gene: EMILIN1 was added gene: EMILIN1 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Literature Mode of inheritance for gene: EMILIN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: EMILIN1 were set to 31978608; 26462740 Phenotypes for gene: EMILIN1 were set to Peripheral neuropathy; aortic aneurysm Review for gene: EMILIN1 was set to AMBER Added comment: Missense mutations identified in two families. First family, proband presented with ascending and descending aortic aneurysms, bilateral lower leg and foot sensorimotor peripheral neuropathy, arthropathy, and increased skin elasticity. Variant segregated with disease in the affected proband, mother, and son. Second family, father and three affected children showed amyotrophy and weakness of the distal lower limbs, dating back to early childhood. Some functional studies performed in patient fibroblasts and zebrafish, however these were not conclusive as the two missense mutations are at different locations within the protein. Sources: Literature |
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| Hereditary neuropathy or pain disorder v0.53 | FAH | Louise Daugherty commented on gene: FAH: Gene rated Amber : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Extension of panel scope - syndrome with non-neurological features / Broader phenotype: Tyrosinemia, acute episodes of neuropathy similar to AIP | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v0.37 | SETX | Louise Daugherty changed review comment from: Gene rated Green : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Re-evaluation of evidence - demotion / James Polke Red review but no comment?? Pretty rare for this to present as a dominant juvenile ALS phenotype but three different mutations reported. Probably reasonable to keep as green but presumably in ALS panel; to: Gene rated Green : From feedback from Genomics England Clinical team (Anna de Burca and Meriel McEntagart). Re-evaluation of evidence - demotion / James Polke Red review but no comment?? Pretty rare for this to present as a dominant juvenile ALS phenotype but three different mutations reported. Probably reasonable to keep as green but presumably in ALS panel. SETX had been reviewed by James Polke as Red but he had not left a comment, since he was not on the call, agreed that this gene be left as Green unless James provides an explanation for his Red review | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hereditary neuropathy or pain disorder v0.1 | SLC25A19 |
Ellen McDonagh gene: SLC25A19 was added gene: SLC25A19 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS,London North GLH Mode of inheritance for gene: SLC25A19 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC25A19 were set to 19798730 Phenotypes for gene: SLC25A19 were set to Acute encephalopathic episodes and paralysis following febrile illness with almost complete recovery. Absent sensory-motor action potential during illness. Bilateral striatal necrosis on MRI. Additional chronic progressive axonal neuropathy; Thiamine metabolism dysfunction syndrome 4 (progressive polyneuropathy type), 613710 |
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| Hereditary neuropathy or pain disorder v0.1 | SCYL1 |
Ellen McDonagh gene: SCYL1 was added gene: SCYL1 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS,London North GLH Mode of inheritance for gene: SCYL1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SCYL1 were set to 26581903 Phenotypes for gene: SCYL1 were set to Spinocerebellar ataxia, autosomal recessive 21, 616719; Early onset ataxia (<1 yr) with recurrent episodes of liver failure, sensory-motor axonal neuropathy, cerebellar atrophy |
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| Hereditary neuropathy or pain disorder v0.1 | PPOX |
Ellen McDonagh gene: PPOX was added gene: PPOX was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS,London North GLH Mode of inheritance for gene: PPOX was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: PPOX were set to Porphyria variegata, 176200; Skin photosensitivity. Acute episodes similar to AIP |
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| Hereditary neuropathy or pain disorder v0.1 | PEX10 |
Ellen McDonagh gene: PEX10 was added gene: PEX10 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS,London North GLH Mode of inheritance for gene: PEX10 was set to Publications for gene: PEX10 were set to 27230853; 20695019 Phenotypes for gene: PEX10 were set to Peroxisome biogenesis disorder 6A (Zellweger), 614870; Failure to thrive, facial dismorphism, agenesis of the corpus callosum, death in first year of life, axonal motor neuropathy, progressive ataxia and sensory-motor axonal neuropathy in adulthood described; Peroxisome biogenesis disorder 6B, 614871 |
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| Hereditary neuropathy or pain disorder v0.1 | NAGA |
Ellen McDonagh gene: NAGA was added gene: NAGA was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS,London North GLH Mode of inheritance for gene: NAGA was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NAGA were set to 15136691 Phenotypes for gene: NAGA were set to Kanzaki disease, 609242; Kanzaki disease. Adult onset diffuse angiokeratoma, sensory-neural hearing loss, recurrent episodes of vertigo, sensory-motor axonal neuropathy. Periventricular white matter abnormalities on MRI |
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| Hereditary neuropathy or pain disorder v0.1 | MT-TL1 |
Ellen McDonagh gene: MT-TL1 was added gene: MT-TL1 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS,London North GLH Mode of inheritance for gene gene: MT-TL1 was set to MITOCHONDRIAL Phenotypes for gene: MT-TL1 were set to Myopathy, deafness, ophthalmoplegia, diabetes, stroke like episodes, predominantly sensory axonal neuropathy |
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| Hereditary neuropathy or pain disorder v0.1 | FAH |
Ellen McDonagh gene: FAH was added gene: FAH was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS,London North GLH Mode of inheritance for gene: FAH was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: FAH were set to Infantile or adolescent onset liver disease, renal tubular dysfunction and hypophosphatemic rickets. Acute episodes of neuropathy similar to AIP; Tyrosinemia, type I, 276700 |
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| Hereditary neuropathy or pain disorder v0.1 | DES |
Ellen McDonagh gene: DES was added gene: DES was added to Hereditary neuropathy NOT PMP22 copy number. Sources: Emory Genetics Laboratory,South West GLH,NHS GMS Mode of inheritance for gene: DES was set to Phenotypes for gene: DES were set to Cardiomyopathy |
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| Hereditary neuropathy or pain disorder v0.1 | CYP27A1 |
Ellen McDonagh gene: CYP27A1 was added gene: CYP27A1 was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS,London North GLH Mode of inheritance for gene: CYP27A1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CYP27A1 were set to 22878431 Phenotypes for gene: CYP27A1 were set to SNCV described in a minority of patients; Adolescent-onset progressive ataxia, myelopathy and dementia, cataracts, low cholesterol, atherosclerosis, xanthomas, soft palate myoclonus, intractable infantile-onset diarrhoea, cerebral white matter lesions on MRI, sensory to motor axonal neuropathy; Cerebrotendinous xanthomatosis, 213700 |
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| Hereditary neuropathy or pain disorder v0.1 | POLG |
Ellen McDonagh gene: POLG was added gene: POLG was added to Hereditary neuropathy NOT PMP22 copy number. Sources: NHS GMS,London North GLH,Expert list,Emory Genetics Laboratory,Expert Review Green Mode of inheritance for gene: POLG was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Phenotypes for gene: POLG were set to sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO); Mitochondrial DNA depletion syndrome 4A (Alpers type); Cardiomyopathy; Progressive external ophthalmoplegia, autosomal recessive 1; Mitochondrial recessive ataxia syndrome (includes SANDO and SCAE); Progressive external ophthalmoplegia, autosomal dominant 1; Mitochondrial DNA depletion syndrome 4B (MNGIE type) |
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