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| Adult onset neurodegenerative disorder v8.3 | SPTLC1 |
Ida Ertmanska changed review comment from: As reviewed by James Polke, there are at least 11 unrelated cases with juvenile ALS with monoallelic SPTLC1 variants: PMID: 34059824 Mohassel et al., 2021 11 patients from seven independent families with 4 different SPTLC1 variants, with juvenile ALS (age of onset 3-16 years). Affected individuals presented with abnormal gait, toe walking, lower extremities spasticity, respiratory insufficiency, and progressive weakness. EMG signal amplitude and duration were elevated in 9/11 patients tested; compound muscle action potential in motor NCS was low in all 11 patients. Variants were either de novo (Families 1-6) or inherited in an autosomal dominant manner (Family 7), not present in gnomAD v4: Reported variants: c.58G>T, p.A20S; c.68A>T p.Y23F; c.115_117delCTT p.L39del; c.118_123delTTCTCT p.F40_S41del. PMID: 34459874 Johnson et al., 2021 Identified pathogenic SPTLC1 variants in 4 unrelated patients with juvenile ALS (age of onset: 4-15 years). Variants identified: p.Ala20Ser, p.Ser331Tyr, p.Leu39del - Method: WES; confirmed de novo in 3 / 4 individuals. Functional evidence: Evidence for pathogenicity of variants: PMID: 35900868 Lone et al., 2022. Authors tested HSAN1 variants C133W and S331F, and juvenile ALS variants Y23F, L39del, F40S41del. Study showed that pathogenic SPTLC1-ALS alleles disrupt the normal regulation of SPT, leading to increased synthesis of sphingolipids and potentially damaging motor neuronse. Results indicate a separate disease mechanism: variants in SPTLC1 may cause HSAN1 or juvenile ALS, depending on the variant. Mouse model: PMID: 40027730 Pant et al. 2025 (preprint) - novel mouse model with a CRISPR/Cas9-mediated deletion of exon 2 in Sptlc1. Heterozygous mice did not develop motor defects or ALS-like neuropathology, but homozygous mutants died prematurely. SPTLC1 is associated with AD Amyotrophic lateral sclerosis 27, juvenile, OMIM:620285 and AD Neuropathy, hereditary sensory and autonomic, type IA OMIM:162400 (accessed 10th Oct 2025). Based on the available evidence, SPTLC1 fits into the scope of this panel and should be rated Green for Adult onset neurodegenerative disorder.; to: As reviewed by James Polke, SPTLC1 variants are associated with juvenile-onset amyotrophic lateral sclerosis. There are at least 11 unrelated cases with juvenile ALS with monoallelic SPTLC1 variants: PMID: 34059824 Mohassel et al., 2021 11 patients from seven independent families with 4 different SPTLC1 variants, with juvenile ALS (age of onset 3-16 years). Affected individuals presented with abnormal gait, toe walking, lower extremities spasticity, respiratory insufficiency, and progressive weakness. EMG signal amplitude and duration were elevated in 9/11 patients tested; compound muscle action potential in motor NCS was low in all 11 patients. Variants were either de novo (Families 1-6) or inherited in an autosomal dominant manner (Family 7), none of them present in gnomAD v4. Reported variants: c.58G>T, p.A20S; c.68A>T p.Y23F; c.115_117delCTT p.L39del; c.118_123delTTCTCT p.F40_S41del. PMID: 34459874 Johnson et al., 2021 Identified pathogenic SPTLC1 variants in 4 unrelated patients with juvenile ALS (age of onset: 4-15 years). Variants identified: p.Ala20Ser (2 patients), p.Ser331Tyr, p.Leu39del - Method: WES; confirmed de novo in 3 / 4 individuals. Functional evidence: Evidence for pathogenicity of variants: PMID: 35900868 Lone et al., 2022. Authors tested HSAN1 variants C133W and S331F, and juvenile ALS variants Y23F, L39del, F40S41del. Study showed that pathogenic SPTLC1 ALS-related alleles disrupt the normal regulation of SPT, leading to increased synthesis of sphingolipids and potentially damaging motor neurons. ALS causing variants tend to cluster in the N-terminal transmembrane domain (TMD); variants in the cytosolic domain are largely associated with HSAN1. Mouse model: PMID: 40027730 Pant et al. 2025 (preprint) - novel mouse model with a CRISPR/Cas9-mediated deletion of exon 2 in Sptlc1. Heterozygous mice did not develop motor defects or ALS-like neuropathology, but homozygous mutants died prematurely. SPTLC1 is associated with AD Amyotrophic lateral sclerosis 27, juvenile, OMIM:620285 and AD Neuropathy, hereditary sensory and autonomic, type IA OMIM:162400 (accessed 10th Oct 2025). |
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| Adult onset neurodegenerative disorder v8.3 | SPTLC1 |
Ida Ertmanska changed review comment from: As reviewed by James Polke, there are at least 11 unrelated cases with juvenile ALS with monoallelic SPTLC1 variants: PMID: 34059824 Mohassel et al., 2021 11 patients from seven independent families with 4 different SPTLC1 variants, with juvenile ALS (age of onset 3-16 years). Affected individuals presented with abnormal gait, toe walking, lower extremities spasticity, respiratory insufficiency, and progressive weakness. EMG signal amplitude and duration were elevated in 9/11 patients tested; compound muscle action potential in motor NCS was low in all 11 patients. Variants were either de novo (Families 1-6) or inherited in an autosomal dominant manner (Family 7), not present in gnomAD v4: Reported variants: c.58G>T, p.A20S; c.68A>T p.Y23F; c.115_117delCTT p.L39del; c.118_123delTTCTCT p.F40_S41del. PMID: 34459874 Johnson et al., 2021 Identified pathogenic SPTLC1 variants in 4 unrelated patients with juvenile ALS (age of onset: 4-15 years). Variants identified: p.Ala20Ser, p.Ser331Tyr, p.Leu39del - Method: WES; confirmed de novo in 3 / 4 individuals. Functional evidence: Evidence for pathogenicity of variants: PMID: 35900868 Lone et al., 2022. Authors tested HSAN1 variants C133W and S331F, and juvenile ALS variants Y23F, L39del, F40S41del. Study showed that pathogenic SPTLC1-ALS alleles disrupt the normal regulation of SPT, leading to increased synthesis of sphingolipids and potentially damaging motor neuronse. Results indicate a separate disease mechanism: variants in SPTLC1 may cause HSAN1 or juvenile ALS, depending on the variant. Mouse model: PMID: 40027730 Pant et al. 2025 (preprint) - novel mouse model with a CRISPR/Cas9-mediated deletion of exon 2 in Sptlc1. Heterozygous mice did not develop motor defects or ALS-like neuropathology, but homozygous mutants died prematurely. SPTLC1 is associated with AD Amyotrophic lateral sclerosis 27, juvenile, OMIM:620285 and AD Neuropathy, hereditary sensory and autonomic, type IA OMIM:162400. Based on the available evidence, SPTLC1 fits into the scope of this panel and should be rated Green for Adult onset neurodegenerative disorder.; to: As reviewed by James Polke, there are at least 11 unrelated cases with juvenile ALS with monoallelic SPTLC1 variants: PMID: 34059824 Mohassel et al., 2021 11 patients from seven independent families with 4 different SPTLC1 variants, with juvenile ALS (age of onset 3-16 years). Affected individuals presented with abnormal gait, toe walking, lower extremities spasticity, respiratory insufficiency, and progressive weakness. EMG signal amplitude and duration were elevated in 9/11 patients tested; compound muscle action potential in motor NCS was low in all 11 patients. Variants were either de novo (Families 1-6) or inherited in an autosomal dominant manner (Family 7), not present in gnomAD v4: Reported variants: c.58G>T, p.A20S; c.68A>T p.Y23F; c.115_117delCTT p.L39del; c.118_123delTTCTCT p.F40_S41del. PMID: 34459874 Johnson et al., 2021 Identified pathogenic SPTLC1 variants in 4 unrelated patients with juvenile ALS (age of onset: 4-15 years). Variants identified: p.Ala20Ser, p.Ser331Tyr, p.Leu39del - Method: WES; confirmed de novo in 3 / 4 individuals. Functional evidence: Evidence for pathogenicity of variants: PMID: 35900868 Lone et al., 2022. Authors tested HSAN1 variants C133W and S331F, and juvenile ALS variants Y23F, L39del, F40S41del. Study showed that pathogenic SPTLC1-ALS alleles disrupt the normal regulation of SPT, leading to increased synthesis of sphingolipids and potentially damaging motor neuronse. Results indicate a separate disease mechanism: variants in SPTLC1 may cause HSAN1 or juvenile ALS, depending on the variant. Mouse model: PMID: 40027730 Pant et al. 2025 (preprint) - novel mouse model with a CRISPR/Cas9-mediated deletion of exon 2 in Sptlc1. Heterozygous mice did not develop motor defects or ALS-like neuropathology, but homozygous mutants died prematurely. SPTLC1 is associated with AD Amyotrophic lateral sclerosis 27, juvenile, OMIM:620285 and AD Neuropathy, hereditary sensory and autonomic, type IA OMIM:162400 (accessed 10th Oct 2025). Based on the available evidence, SPTLC1 fits into the scope of this panel and should be rated Green for Adult onset neurodegenerative disorder. |
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| Adult onset neurodegenerative disorder v3.53 | MAG | Arina Puzriakova Tag watchlist was removed from gene: MAG. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Adult onset neurodegenerative disorder v3.53 | MAG | Arina Puzriakova Publications for gene: MAG were set to 24482476; 26179919 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Adult onset neurodegenerative disorder v3.52 | MAG | Arina Puzriakova Phenotypes for gene: MAG were changed from Spastic paraplegia 75, autosomal recessive, 616680 to Spastic paraplegia 75, autosomal recessive, OMIM:616680 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Adult onset neurodegenerative disorder v2.57 | CHCHD2 | Ivone Leong Publications for gene: CHCHD2 were set to Funayama, M., Ohe, K., Amo, T., Furuya, N., Yamaguchi, J., Saiki, S., Li, Y., Ogaki, K., Ando, M., Yoshino, H., Tomiyama, H., Nishioka, K., and 12 others. CHCHD2 mutations in autosomal dominant late-onset Parkinson's disease: a genome-wide linkage and sequencing study. Lancet Neurol. 14: 274-282, 2015; 25662902; 26067114; 26705026; 26067110 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Adult onset neurodegenerative disorder v1.106 | MAG | Louise Daugherty edited their review of gene: MAG: Added comment: As discussed with the GMS Neurology Specialist Test Group webex call 11th September 2019: The Specialist Test Group all agreed that there is only enough evidence to rate this gene Red; Changed rating: RED | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Adult onset neurodegenerative disorder v1.105 | MAG |
Louise Daugherty Source Expert Review Red was added to MAG. Rating Changed from Amber List (moderate evidence) to Red List (low evidence) |
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| Adult onset neurodegenerative disorder v1.101 | MAG | Louise Daugherty commented on gene: MAG: Review and rating from Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group. All the green and amber, except for the genes with triplet repeats, were reviewed. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Adult onset neurodegenerative disorder v1.100 | MAG | Louise Daugherty Source Wessex and West Midlands GLH was added to MAG. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Adult onset neurodegenerative disorder v1.99 | MAG | Tracy Lester reviewed gene: MAG: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic paraplegia 75, autosomal recessive, 616680; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Adult onset neurodegenerative disorder v1.81 | CHCHD2 | Louise Daugherty Publications for gene CHCHD2 were changed from 26067110; Funayama, M., Ohe, K., Amo, T., Furuya, N., Yamaguchi, J., Saiki, S., Li, Y., Ogaki, K., Ando, M., Yoshino, H., Tomiyama, H., Nishioka, K., and 12 others. CHCHD2 mutations in autosomal dominant late-onset Parkinson's disease: a genome-wide linkage and sequencing study. Lancet Neurol. 14: 274-282, 2015; 25662902; 26067114 to Funayama, M., Ohe, K., Amo, T., Furuya, N., Yamaguchi, J., Saiki, S., Li, Y., Ogaki, K., Ando, M., Yoshino, H., Tomiyama, H., Nishioka, K., and 12 others. CHCHD2 mutations in autosomal dominant late-onset Parkinson's disease: a genome-wide linkage and sequencing study. Lancet Neurol. 14: 274-282, 2015; 25662902; 26067114; 26705026; 26067110 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Adult onset neurodegenerative disorder v1.74 | MAG | Louise Daugherty commented on gene: MAG: Review and rating submitted by Nick Beauchamp (Sheffield Diagnostic genetics Service), on behalf of Yorkshire and North East GLH for GMS Neurology specialist test group. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Adult onset neurodegenerative disorder v1.72 | MAG | Nick Beauchamp reviewed gene: MAG: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic paraplegia 75, autosomal recessive, 616680; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Adult onset neurodegenerative disorder v1.67 | MAG | Louise Daugherty Source Yorkshire and North East GLH was added to MAG. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Adult onset neurodegenerative disorder v1.11 | MAG | Louise Daugherty commented on gene: MAG: Review and rating submitted byJames Polke (North Bristol NHS Trust), unless specified in the review comment, on behalf of London North GLH for GMS Neurology specialist test group. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Adult onset neurodegenerative disorder v1.10 | MAG | James Polke reviewed gene: MAG: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Adult onset neurodegenerative disorder v1.8 | MAG | Louise Daugherty Source London North GLH was added to MAG. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Adult onset neurodegenerative disorder v1.7 | MAG | Louise Daugherty reviewed gene: MAG: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Adult onset neurodegenerative disorder v1.6 | MAG | Anthony Dallosso reviewed gene: MAG: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic paraplegia 75, autosomal recessive, 616680; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Adult onset neurodegenerative disorder v1.5 | MAG | Louise Daugherty Source NHS GMS was added to MAG. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Adult onset neurodegenerative disorder v1.4 | MAG | Louise Daugherty Source South West GLH was added to MAG. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Adult onset neurodegenerative disorder v0.2 | MAG | Rebecca Foulger Tag watchlist tag was added to gene: MAG. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Adult onset neurodegenerative disorder v0.2 | MAG |
Rebecca Foulger gene: MAG was added gene: MAG was added to Neurodegenerative disorders - adult onset. Sources: Expert Review Amber Mode of inheritance for gene: MAG was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: MAG were set to 24482476; 26179919 Phenotypes for gene: MAG were set to Spastic paraplegia 75, autosomal recessive, 616680 |
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| Adult onset neurodegenerative disorder v0.2 | CHCHD2 |
Rebecca Foulger gene: CHCHD2 was added gene: CHCHD2 was added to Neurodegenerative disorders - adult onset. Sources: Expert Review Amber Mode of inheritance for gene: CHCHD2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: CHCHD2 were set to 26067110; Funayama, M., Ohe, K., Amo, T., Furuya, N., Yamaguchi, J., Saiki, S., Li, Y., Ogaki, K., Ando, M., Yoshino, H., Tomiyama, H., Nishioka, K., and 12 others. CHCHD2 mutations in autosomal dominant late-onset Parkinson's disease: a genome-wide linkage and sequencing study. Lancet Neurol. 14: 274-282, 2015; 25662902; 26067114 Phenotypes for gene: CHCHD2 were set to Parkinson disease 22, autosomal dominant; 616710 |
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