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Childhood onset hereditary spastic paraplegia v8.29 BORCS5 Ida Ertmanska gene: BORCS5 was added
gene: BORCS5 was added to Childhood onset hereditary spastic paraplegia. Sources: Literature
Mode of inheritance for gene: BORCS5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BORCS5 were set to 27435318; 40385417; 40621786
Phenotypes for gene: BORCS5 were set to arthrogryposis multiplex congenita, MONDO:0015168; neurodevelopmental disorder, MONDO:0700092
Review for gene: BORCS5 was set to GREEN
Added comment: PMID: 40621786 Fisher et al., 2025
Report of 2 fetal cases in a consanguineous Pakistani family. Exome seq revealed a homozygous nonsense variant c.283C>T, p.(Arg95Ter) in BORCS5 (NM_058169.4). Individuals showed neuroaxonal dystrophy with osteopetrosis.

PMID: 40385417 Mencacci et al., 2025 - pre-print
Report of 12 individuals from 7 unrelated families with biallelic BORCS5 variants (NM_058169.4): two missense variants (c.284G>A, p.R95Q; c.296A>C, p.H99P) and four LoF alleles (c.203–1G>T, p.?; c.316delG, p.A106Pfs*20; c.382_383delAG, p.L128Vfs*86; c.417C>G, p.Y139*).
Table 1 = phenotypic spectrum of 6 individuals from families 1-4: profound ID (6/6), severe spasticity (6/6), seizures (6/6), hyperreflexia (6/6), Parkinsonism/dystonia (3/6), limb contractures (5/6), optic atrophy (5/6), abnormal brain MRI including cerebral atrophy and/or corpus callosum agenesis (5/6), microcephaly (6/6 - severity not stated), muscle atrophy (5/6). Infantile onset.
Neuroimaging in 5 cases showed cerebral atrophy, white matter loss, hypomyelination, small T2-hypointense thalami, thin brainstem, and optic nerve atrophy.

PMID: 27435318 Charng et al., 2016
Patient BAB6775 homozygous for NM_058169.4 BORCS5: c.203-1G>T, with DD, microcephaly, seizures, cortical malformations, polymicrogyria, agenesis of corpus callosum. Also reported with more details in PMID:40385417 (do not count).

Additional functional evidence: Zebrafish borcs5 knockout leads to neurodevelopmental defects:microcephaly, ventriculomegaly, movement disorders and epilepsy.

BORCS5 is not yet associated with a disease in OMIM (accessed 20th Feb 2026).
Sources: Literature
Childhood onset hereditary spastic paraplegia v8.28 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 Developmental and epileptic encephalopathy 5, OMIM:613477; Developmental delay with or without epilepsy, OMIM:620540; Spastic paraplegia 91, autosomal dominant, with or without cerebellar ataxia, OMIM:620538
Childhood onset hereditary spastic paraplegia v8.26 GJC2 Ida Ertmanska Phenotypes for gene: GJC2 were changed from Spastic paraplegia 44, autosomal recessive; Leukodystrophy, hypomyelinating,2, 608804, AR; Spastic paraplegia 44, autosomal recessive, 613206, AR; Lymphatic malformation 3, 613480, AD to ?Spastic paraplegia 44, autosomal recessive , OMIM:613206; Leukodystrophy, hypomyelinating, 2, OMIM:608804
Childhood onset hereditary spastic paraplegia v8.24 GJC2 Ida Ertmanska reviewed gene: GJC2: Rating: AMBER; Mode of pathogenicity: None; Publications: 19056803, 22833003, 31431325, 37915394; Phenotypes: ?Spastic paraplegia 44, autosomal recessive , OMIM:613206; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v8.24 SPG7 Ida Ertmanska changed review comment from: BIALLELIC CASES:
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.

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: BIALLELIC CASES:
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).
Childhood onset hereditary spastic paraplegia v8.24 SPG7 Ida Ertmanska changed review comment from: 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). Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.; to: 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 of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.
Childhood onset hereditary spastic paraplegia v8.24 SPG7 Ida Ertmanska changed review comment from: 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) and possible digenic inheritance with variants in other spasticity-related genes, and SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.; to: 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). Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.
Childhood onset hereditary spastic paraplegia v8.24 SPG7 Ida Ertmanska changed review comment from: Comment on list classification: As reviewed by Lauren Turton, an overwhelming majority of cases with SPG7-related spastic paraplegia 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) and possible digenic inheritance with variants in other spasticity-related genes, and SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.; to: 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) and possible digenic inheritance with variants in other spasticity-related genes, and SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.
Childhood onset hereditary spastic paraplegia v8.24 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 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) and possible digenic inheritance with variants in other spasticity-related genes, and SPG7-interacting genes (emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748). Based on available evidence, the mode of inheritance of inheritance for SPG7 should be changed to BIALLELIC , autosomal or pseudoautosomal.
Childhood onset hereditary spastic paraplegia v8.24 SPG7 Ida Ertmanska changed review comment from: BIALLELIC CASES:
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.

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: BIALLELIC CASES:
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.

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).
Childhood onset hereditary spastic paraplegia v8.24 SPG7 Ida Ertmanska reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: None; Publications: 22964162, 23065789, 24727571, 26506339, 31068484, 31854126, 32548275, 33598982, 33774748, 34405107, 39978794; Phenotypes: Spastic paraplegia 7, autosomal recessive, OMIM:607259, hereditary spastic paraplegia 7, MONDO:0011803; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v8.24 RPS6KC1 Achchuthan Shanmugasundram changed review comment from: PMID:41130203 (2025) reported the identification of biallelic RPS6KC1 variants (both homozygous and compound heterozygous) in 12 individuals from seven independent families and an unrelated 19-week old foetus through whole-exome sequencing. There were 10 different variants identified in total.

The patients presented with a spectrum of conditions including neurodevelopmental delay, subsequent intellectual impairment, hypotonia, spastic paraplegia, brain white matter loss, and dysmorphic features overlapping with Coffin-Lowry syndrome. The affected foetus had hydrops fetalis and prenatal lethality. Spastic paraplegia was reported in six patients from four unrelated families. The age of onset of the syndrome was in infancy/ early childhood.

Functional evidence is available from peripheral blood mononuclear cells (PBMCs), HAP1 RPS6KC1-knockdown cells and from Drosophila melanogaster model recapitulated the defects observed in individuals with RPS6KC1 variants.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM (accessed on 05 January 2026).
Sources: Literature; to: PMID:41130203 (2025) reported the identification of biallelic RPS6KC1 variants (both homozygous and compound heterozygous) in 12 individuals from seven independent families and an unrelated 19-week old foetus through whole-exome sequencing. There were 10 different variants identified in total.

The patients presented with a spectrum of conditions including neurodevelopmental delay, subsequent intellectual impairment, hypotonia, spastic paraplegia, brain white matter loss, and dysmorphic features overlapping with Coffin-Lowry syndrome. The affected foetus had hydrops fetalis and prenatal lethality. Spastic paraplegia was reported in six patients from four unrelated families. The age of onset of the syndrome was in infancy/ early childhood.

Functional evidence is available from peripheral blood mononuclear cells (PBMCs), HAP1 RPS6KC1-knockdown cells and from Drosophila melanogaster model, which recapitulated the defects observed in individuals with RPS6KC1 variants. Functional studies on PBMCs from the different individuals indicated diminished expression and phosphorylation of RPS6, impacting ribosomal protein synthesis, and a decrease in the known interactors PRDX3 and SPHK1, accompanied by marked repression of the mTOR/PI3K pathway. The study also detected a dysregulation of phosphoinositides and sphingoid base levels in plasma samples from the different individuals. Studies in HAP1 RPS6KC1-knockdown cells suggested that RPS6KC1 may regulate PRDX3 and SPHK1 activities by facilitating their endosome anchoring. In Drosophila melanogaster, the knockdown of CG7156, the RPS6KC1 ortholog, resulted in locomotor dysfunction, defective neuromuscular junctions, reduced lifespan, and decreased mTOR activity. Overexpression of mTOR in this model improved motor function and lifespan.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM (accessed on 05 January 2026).
Sources: Literature
Childhood onset hereditary spastic paraplegia v8.24 RPS6KC1 Achchuthan Shanmugasundram changed review comment from: PMID:41130203 (2025) reported the identification of biallelic RPS6KC1 variants (both homozygous and compound heterozygous) in 12 individuals from seven independent families and an unrelated 19-week old foetus through whole-exome sequencing. There were 10 different variants identified in total.

The patients presented with a spectrum of conditions including neurodevelopmental delay, subsequent intellectual impairment, hypotonia, spastic paraplegia, brain white matter loss, and dysmorphic features overlapping with Coffin-Lowry syndrome. The affected foetus had hydrops fetalis and prenatal lethality. Spastic paraplegia was reported in six patients from four unrelated families.

Functional evidence is available from peripheral blood mononuclear cells (PBMCs), HAP1 RPS6KC1-knockdown cells and from Drosophila melanogaster model recapitulated the defects observed in individuals with RPS6KC1 variants.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM (accessed on 05 January 2026).
Sources: Literature; to: PMID:41130203 (2025) reported the identification of biallelic RPS6KC1 variants (both homozygous and compound heterozygous) in 12 individuals from seven independent families and an unrelated 19-week old foetus through whole-exome sequencing. There were 10 different variants identified in total.

The patients presented with a spectrum of conditions including neurodevelopmental delay, subsequent intellectual impairment, hypotonia, spastic paraplegia, brain white matter loss, and dysmorphic features overlapping with Coffin-Lowry syndrome. The affected foetus had hydrops fetalis and prenatal lethality. Spastic paraplegia was reported in six patients from four unrelated families. The age of onset of the syndrome was in infancy/ early childhood.

Functional evidence is available from peripheral blood mononuclear cells (PBMCs), HAP1 RPS6KC1-knockdown cells and from Drosophila melanogaster model recapitulated the defects observed in individuals with RPS6KC1 variants.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM (accessed on 05 January 2026).
Sources: Literature
Childhood onset hereditary spastic paraplegia v8.23 RPS6KC1 Achchuthan Shanmugasundram gene: RPS6KC1 was added
gene: RPS6KC1 was added to Childhood onset hereditary spastic paraplegia. Sources: Literature
Mode of inheritance for gene: RPS6KC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RPS6KC1 were set to 41130203
Phenotypes for gene: RPS6KC1 were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: RPS6KC1 was set to GREEN
Added comment: PMID:41130203 (2025) reported the identification of biallelic RPS6KC1 variants (both homozygous and compound heterozygous) in 12 individuals from seven independent families and an unrelated 19-week old foetus through whole-exome sequencing. There were 10 different variants identified in total.

The patients presented with a spectrum of conditions including neurodevelopmental delay, subsequent intellectual impairment, hypotonia, spastic paraplegia, brain white matter loss, and dysmorphic features overlapping with Coffin-Lowry syndrome. The affected foetus had hydrops fetalis and prenatal lethality. Spastic paraplegia was reported in six patients from four unrelated families.

Functional evidence is available from peripheral blood mononuclear cells (PBMCs), HAP1 RPS6KC1-knockdown cells and from Drosophila melanogaster model recapitulated the defects observed in individuals with RPS6KC1 variants.

This gene has been associated with relevant phenotypes in Gene2Phenotype (with 'moderate' rating on the DD panel), but not yet in OMIM (accessed on 05 January 2026).
Sources: Literature
Childhood onset hereditary spastic paraplegia v8.22 BHLHE22 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - tone abnormalities were present in all individuals, presenting as lower limb or appendicular spasticity in 6 patients.; to: Comment on list classification: There is sufficient evidence to support classification of this gene as Green (tone abnormalities were present in all individuals, presenting as lower limb or appendicular spasticity in 6 patients). However, PMID:39502664 is currently still in pre-print and therefore this gene-disease association should be considered provisional pending peer-reviewed publication.
Childhood onset hereditary spastic paraplegia v8.21 SOD1 Arina Puzriakova changed review comment from: At least 10 individuals from 7 unrelated families have been identified with biallelic variants in the SOD1 gene and progressive spastic tetraplegia with age of onset before 2 years old. A recurrent variant (c.335dupG, p.Cys112Trpfs*11) was found in four apparently unrelated families of Afghan or Lebanese descent, while the other three families carried other homozygous LOF variants (c.357_357+2delGGT, c.52_56del5ins154, c.369_371del). Variants are predicted to lead to a completely non-functional enzyme product. The phenotype comprises early-onset progressive neuromuscular and developmental degeneration, leading to spastic tetraplegia and axial hypotonia. Most patients display global developmental delay (ranging from mild to profound cognitive impairment) and cerebellar atrophy.
Sources: Literature; to: At least 10 individuals from 7 unrelated families have been identified with biallelic variants in the SOD1 gene and progressive spastic tetraplegia with age of onset before 2 years old. A recurrent variant (c.335dupG, p.Cys112Trpfs*11) was found in four apparently unrelated families of Afghan or Lebanese descent, while the other three families carried other homozygous LOF variants (c.357_357+2delGGT, c.52_56del5ins154, c.369_371del). Variants are predicted to lead to a completely non-functional enzyme product. The phenotype comprises early-onset progressive neuromuscular and developmental degeneration, leading to spastic tetraplegia and axial hypotonia. Most patients display global developmental delay (ranging from mild to profound cognitive impairment) and cerebellar atrophy. (PMIDs: 31314961; 31332433; 34380534; 34788402; 36935613; 39629626)

This gene is associated with a relevant phenotype in OMIM - Spastic tetraplegia and axial hypotonia, progressive, OMIM:618598 (accessed on 17-10-2025)
Sources: Literature
Childhood onset hereditary spastic paraplegia v8.21 SOD1 Arina Puzriakova gene: SOD1 was added
gene: SOD1 was added to Childhood onset hereditary spastic paraplegia. Sources: Literature
Q3_25_promote_green tags were added to gene: SOD1.
Mode of inheritance for gene: SOD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SOD1 were set to 31314961; 31332433; 34380534; 34788402; 36935613; 39629626
Phenotypes for gene: SOD1 were set to Spastic tetraplegia and axial hypotonia, progressive, OMIM:618598
Review for gene: SOD1 was set to GREEN
Added comment: At least 10 individuals from 7 unrelated families have been identified with biallelic variants in the SOD1 gene and progressive spastic tetraplegia with age of onset before 2 years old. A recurrent variant (c.335dupG, p.Cys112Trpfs*11) was found in four apparently unrelated families of Afghan or Lebanese descent, while the other three families carried other homozygous LOF variants (c.357_357+2delGGT, c.52_56del5ins154, c.369_371del). Variants are predicted to lead to a completely non-functional enzyme product. The phenotype comprises early-onset progressive neuromuscular and developmental degeneration, leading to spastic tetraplegia and axial hypotonia. Most patients display global developmental delay (ranging from mild to profound cognitive impairment) and cerebellar atrophy.
Sources: Literature
Childhood onset hereditary spastic paraplegia v8.20 ATL1 Achchuthan Shanmugasundram changed review comment from: There are at least 10 unrelated patients reported with early-onset spastic paraplegia and de novo heterozygous variants in ATL1 gene. Monoallelic ATL1 variants have been associated with 'Spastic paraplegia 3A, autosomal dominant' phenotype in OMIM (MIM #182600; OMIM accessed on 13 October 2025) and with 'ATL1-related hereditary spastic paraplegia' phenotype on DD panel of Gene2Phenotype (with 'definitive' rating).

There are five unrelated families reported with homozygous variants in ATL1 gene and with early-onset hereditary spastic paraplegia. Biallelic ATL1 variants have not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.

This gene is rated green with the MOI of 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' on the 'Hereditary Spastic Paraplegia - paediatric' panel from PanelApp Australia (https://panelapp-aus.org/panels/317/gene/ATL1/).; to: There are at least 10 unrelated patients reported with early-onset spastic paraplegia and de novo heterozygous variants in ATL1 gene. The autosomal dominant disorder is generally caused by missense variants, generating a dominant-negative effect. Monoallelic ATL1 variants have been associated with 'Spastic paraplegia 3A, autosomal dominant' phenotype in OMIM (MIM #182600; OMIM accessed on 13 October 2025) and with 'ATL1-related hereditary spastic paraplegia' phenotype on DD panel of Gene2Phenotype (with 'definitive' rating).

There are five unrelated families reported with homozygous variants in ATL1 gene and with early-onset hereditary spastic paraplegia. These include homozygous nonsense and missense variants. Biallelic ATL1 variants have not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.

This gene is rated green with the MOI of 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' on the 'Hereditary Spastic Paraplegia - paediatric' panel from PanelApp Australia (https://panelapp-aus.org/panels/317/gene/ATL1/).
Childhood onset hereditary spastic paraplegia v8.20 ATL1 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: As there is sufficient evidence available for the association of both monoallelic and biallelic ATL1 variants with early-onset spastic paraplegia, the mode of inheritance of this gene can be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.
Childhood onset hereditary spastic paraplegia v8.19 ATL1 Achchuthan Shanmugasundram Phenotypes for gene: ATL1 were changed from Spastic paraplegia 3A, autosomal dominant,182600; Spastic Paraplegia, Dominant to Spastic paraplegia 3A, autosomal dominant, OMIM:182600; hereditary spastic paraplegia 3A, MONDO:0008437
Childhood onset hereditary spastic paraplegia v8.17 ATL1 Achchuthan Shanmugasundram changed review comment from: There are at least 10 unrelated patients reported with early-onset spastic paraplegia and de novo heterozygous variants in ATL1 gene. Monoallelic ATL1 variants have been associated with 'Spastic paraplegia 3A, autosomal dominant' phenotype in OMIM (MIM #182600; OMIM accessed on 13 October 2025) and with 'ATL1-related hereditary spastic paraplegia' phenotype on DD panel of Gene2Phenotype (with 'definitive' rating).

There are five unrelated families reported with homozygous variants in ATL1 gene and with early-onset hereditary spastic paraplegia. Biallelic ATL1 variants have not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.; to: There are at least 10 unrelated patients reported with early-onset spastic paraplegia and de novo heterozygous variants in ATL1 gene. Monoallelic ATL1 variants have been associated with 'Spastic paraplegia 3A, autosomal dominant' phenotype in OMIM (MIM #182600; OMIM accessed on 13 October 2025) and with 'ATL1-related hereditary spastic paraplegia' phenotype on DD panel of Gene2Phenotype (with 'definitive' rating).

There are five unrelated families reported with homozygous variants in ATL1 gene and with early-onset hereditary spastic paraplegia. Biallelic ATL1 variants have not yet been associated with relevant phenotypes either in OMIM or in Gene2Phenotype.

This gene is rated green with the MOI of 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' on the 'Hereditary Spastic Paraplegia - paediatric' panel from PanelApp Australia (https://panelapp-aus.org/panels/317/gene/ATL1/).
Childhood onset hereditary spastic paraplegia v8.17 ATL1 Achchuthan Shanmugasundram reviewed gene: ATL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 18446315, 22378671, 24473461, 25193411, 26888483, 34808209, 35925862, 37927245, 39003427; Phenotypes: Spastic paraplegia 3A, autosomal dominant, OMIM:182600, hereditary spastic paraplegia 3A, MONDO:0008437; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v8.16 FICD Arina Puzriakova edited their review of gene: FICD: Added comment: This gene was reassessed in light of the amber review by John Taylor, highlighting that two distinct phenotypes linked to similar variants located in the catalytic motif of FICD have been assessed differently.

FICD was rated amber on Neonatal diabetes (293) in context of infantile diabetes and neurodevelopmental delay associated with a single variant p.Arg371Ser, in three consanguineous families, two of which shared a common haplotype (PMID: 36704923).

A separate association with severe motor neuron disease (rated green on this panel) is based on four unrelated families from different ethnic backgrounds, who all harbour the p.Arg374His variant, which was homozygous in all but one case where the variant was present in a compound heterozygous state with a frameshift variant, p.Gly370GlufsTer53. One patient from this cohort also had diabetes mellitus. Haplotype analysis did indicate that there is a shared haplotype in all patients with the p.Arg374His variant, strongly suggesting a founder effect (PMID: 36136088).

Recently, an additional four individuals from two families were reported (PMID: 40062579) with variants affecting the Arg374 residue, who presented with complicated HSP and diabetes mellitus, merging these two previously distinct presentations.
The report describes one Serbian family, comprising 2 sibs with cHSP (age of onset: 5 and 6) and diabetes mellitus (age of diagnosis: 25 and 27). The sibs had the recurrent homozygous variant p.Arg374His - however, the haplotype identified in the previous report was not found in this family, suggesting that this is an independent event.
The second was a consanguineous family from Saudi Arabia with 2 sibs affected by progressive HSP and diabetes (one prediabetic) - age of onset unclear but paediatric. This family harboured a novel homozygous variant, p.Arg374Cys. No cognitive deficits were reported in either family.

The coexistence of motor neuron disease and diabetes suggests a broader range of neurological and metabolic effects of FICD dysfunction which does warrant further investigation. It is possible that these presentations may be more related than initially thought - individuals diagnosed with infancy-onset diabetes mellitus may develop spasticity later in life, and vice versa.

Overall the recent report does lend additional support for inclusion of FICD on this panel. This gene will also be added to the Monogenic diabetes (472) panel to cover the diabetes phenotype with later onset than the initial report which was reviewed on the Neonatal diabetes (293) panel.; Changed publications to: 36704923, 36136088, 40062579; Changed phenotypes to: Spastic paraplegia 92, autosomal recessive, OMIM:620911
Childhood onset hereditary spastic paraplegia v8.13 OGDHL Ida Ertmanska commented on gene: OGDHL: Comment on list classification: This gene should be rated Green for Childhood onset hereditary spastic paraplegia. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, the phenotype is highly heterogeneous, and care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.
Childhood onset hereditary spastic paraplegia v8.13 OGDHL Ida Ertmanska changed review comment from: There are at least 24 individuals from 21 unrelated families with biallelic variants in OGDHL (PMIDs: 28017472; 34800363; 38031187). The individuals present with a complex neurodevelopmental disorder, also known as Yoon-Bellen syndrome. The phenotype is highly variable between the cases, including spasticity, hypotonia and muscle atrophy.

10 individuals from 9 unrelated families identified with biallelic variants in OGDHL with Yoon-Bellen Syndrome (PMIDs: 28017472; 34800363). Main clinical features include mild-to-severe DD/ID (9/10), seizures (5/10), gait ataxia (5/10), profound bilateral sensorineural hearing loss (4/10), spasticity (3/10).

PMID: 38031187 Lin et al. 2023 - authors re-evaluate the evidence for the association between Yoon-Bellen neurodevelopmental syndrome and the OGDHL gene. The article reports further 14 individuals from 12 unrelated, diverse families, with biallelic OGDHL variants. Patients presented with a range of heterogeneous symptoms: hypotonia (9/14), short stature and variable dysmorphic facial features (each 8/14), failure to thrive (7/14), developmental delay/intellectual disability (9/14), seizures (4/14), hearing loss (4/14), and microcephaly (3/14), spasticity (3/14). One individual was reported to have spastic cerebral palsy, another presented with spastic quadriplegia.
Due to the highly variable phenotype, authors propose 3 possible hypotheses: ‘biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all’.

In total, 17/21 families reported in the above articles have history of consanguinity. In most cases, additional likely pathogenic mutations were discovered in other genes, which complicates the phenotypic understanding.

Functional evidence: A zebrafish knockout of Ogdhl (78% identical gene ortholog) resulted in a range of phenotypes: smaller head, eye, and body, and heart edema. No seizure manifestation, visual impairment, or hearing deficiencies were observed. Authors note elevated neuronal cell death in the eye, hindbrain, and spinal cord of knockout animals. The phenotype was rescued by injection of human OGDHL. Moreover, OGDHL, OGDH, and DHTKD1 are isoenzymes – through double and triple gene knockouts, authors provide evidence indicating a complex compensatory relationship (PMID: 38031187).

This gene should be rated Green for Childhood onset hereditary spastic paraplegia. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.
Sources: Literature; to: There are at least 24 individuals from 21 unrelated families with biallelic variants in OGDHL (PMIDs: 28017472; 34800363; 38031187). The individuals present with a childhood-onset complex neurodevelopmental disorder, also known as Yoon-Bellen syndrome. The phenotype is highly variable between the cases, including spasticity, hypotonia and muscle atrophy.

PMIDs: 28017472; 34800363: 10 individuals from 9 unrelated families identified with biallelic variants in OGDHL with Yoon-Bellen Syndrome. Main clinical features include mild-to-severe DD/ID (9/10), seizures (5/10), gait ataxia (5/10), profound bilateral sensorineural hearing loss (4/10), spasticity (3/10).

PMID: 38031187 Lin et al. 2023 - authors re-evaluate the evidence for the association between Yoon-Bellen neurodevelopmental syndrome and the OGDHL gene. The article reports further 14 individuals from 12 unrelated, diverse families, with biallelic OGDHL variants. Patients presented with a range of heterogeneous symptoms: hypotonia (9/14), short stature and variable dysmorphic facial features (each 8/14), failure to thrive (7/14), developmental delay/intellectual disability (9/14), seizures (4/14), hearing loss (4/14), and microcephaly (3/14), spasticity (3/14). One individual was reported to have spastic cerebral palsy, another presented with spastic quadriplegia.
Due to the highly variable phenotype, authors propose 3 possible hypotheses: ‘biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all’.

In total, 17/21 families reported in the above articles have history of consanguinity. In most cases, additional likely pathogenic mutations were discovered in other genes, which complicates the phenotypic understanding.

Functional evidence: A zebrafish knockout of Ogdhl (78% identical gene ortholog) resulted in a range of phenotypes: smaller head, eye, and body, and heart edema. No seizure manifestation, visual impairment, or hearing deficiencies were observed. Authors note elevated neuronal cell death in the eye, hindbrain, and spinal cord of knockout animals. The phenotype was rescued by injection of human OGDHL. Moreover, OGDHL, OGDH, and DHTKD1 are isoenzymes – through double and triple gene knockouts, authors provide evidence indicating a complex compensatory relationship (PMID: 38031187).

This gene should be rated Green for Childhood onset hereditary spastic paraplegia. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.
Sources: Literature
Childhood onset hereditary spastic paraplegia v8.13 OGDHL Ida Ertmanska gene: OGDHL was added
gene: OGDHL was added to Childhood onset hereditary spastic paraplegia. Sources: Literature
Mode of inheritance for gene: OGDHL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OGDHL were set to 28017472; 34800363; 38031187
Phenotypes for gene: OGDHL were set to Yoon-Bellen neurodevelopmental syndrome, MONDO:0859221
Review for gene: OGDHL was set to GREEN
Added comment: There are at least 24 individuals from 21 unrelated families with biallelic variants in OGDHL (PMIDs: 28017472; 34800363; 38031187). The individuals present with a complex neurodevelopmental disorder, also known as Yoon-Bellen syndrome. The phenotype is highly variable between the cases, including spasticity, hypotonia and muscle atrophy.

10 individuals from 9 unrelated families identified with biallelic variants in OGDHL with Yoon-Bellen Syndrome (PMIDs: 28017472; 34800363). Main clinical features include mild-to-severe DD/ID (9/10), seizures (5/10), gait ataxia (5/10), profound bilateral sensorineural hearing loss (4/10), spasticity (3/10).

PMID: 38031187 Lin et al. 2023 - authors re-evaluate the evidence for the association between Yoon-Bellen neurodevelopmental syndrome and the OGDHL gene. The article reports further 14 individuals from 12 unrelated, diverse families, with biallelic OGDHL variants. Patients presented with a range of heterogeneous symptoms: hypotonia (9/14), short stature and variable dysmorphic facial features (each 8/14), failure to thrive (7/14), developmental delay/intellectual disability (9/14), seizures (4/14), hearing loss (4/14), and microcephaly (3/14), spasticity (3/14). One individual was reported to have spastic cerebral palsy, another presented with spastic quadriplegia.
Due to the highly variable phenotype, authors propose 3 possible hypotheses: ‘biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all’.

In total, 17/21 families reported in the above articles have history of consanguinity. In most cases, additional likely pathogenic mutations were discovered in other genes, which complicates the phenotypic understanding.

Functional evidence: A zebrafish knockout of Ogdhl (78% identical gene ortholog) resulted in a range of phenotypes: smaller head, eye, and body, and heart edema. No seizure manifestation, visual impairment, or hearing deficiencies were observed. Authors note elevated neuronal cell death in the eye, hindbrain, and spinal cord of knockout animals. The phenotype was rescued by injection of human OGDHL. Moreover, OGDHL, OGDH, and DHTKD1 are isoenzymes – through double and triple gene knockouts, authors provide evidence indicating a complex compensatory relationship (PMID: 38031187).

This gene should be rated Green for Childhood onset hereditary spastic paraplegia. There is strong evidence for the association between OGDHL and Yoon-Bellen neurodevelopmental syndrome. However, care should be taken not to attribute all clinical symptoms to OGDHL dysfunction.
Sources: Literature
Childhood onset hereditary spastic paraplegia v8.13 TBCB Arina Puzriakova gene: TBCB was added
gene: TBCB was added to Childhood onset hereditary spastic paraplegia. Sources: Literature
watchlist, founder-effect tags were added to gene: TBCB.
Mode of inheritance for gene: TBCB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TBCB were set to 40856104
Phenotypes for gene: TBCB were set to Neurodevelopmental disorder, MONDO:0700092
Review for gene: TBCB was set to AMBER
Added comment: PMID: 40856104 (2025) - 10 individuals from 8 unrelated families of Ashkenazi Jewish descent with the same homozygous founder variant (c.589T>A, p.(Tyr197Asn)) in TBCB. Affected individuals presented during infancy with motor or speech delays and developed late-childhood-onset spastic paraparesis (onset around 9-12 years old), global developmental delay (formal assessment done in 5 individuals, indicating mild ID), and autism spectrum. Brain MRI showed corpus collosum thinning in 3, and decreased white matter in 2.

The c.589T>A (GRCh38: 19-36125492-T-A) variant has an AF of 0.006485 in the Ashkenazi Jewish population in gnomAD v4 with 0 homozygotes. Classified as VUS in ClinVar based on 1 submission.

TBCB protein levels were reduced in patient fibroblasts. Drosophila melanogaster model showed reduced survival and impaired climbing ability.
Sources: Literature
Childhood onset hereditary spastic paraplegia v8.12 BHLHE22 Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - 6/7 individuals available for examination exhibited significant GDD and ID.; to: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - tone abnormalities were present in all individuals, presenting as lower limb or appendicular spasticity in 6 patients.
Childhood onset hereditary spastic paraplegia v8.11 BHLHE22 Arina Puzriakova gene: BHLHE22 was added
gene: BHLHE22 was added to Childhood onset hereditary spastic paraplegia. Sources: Literature
Q3_25_promote_green tags were added to gene: BHLHE22.
Mode of inheritance for gene: BHLHE22 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: BHLHE22 were set to 39502664
Phenotypes for gene: BHLHE22 were set to Neurodevelopmental disorder, MONDO:0700092
Review for gene: BHLHE22 was set to GREEN
Added comment: PMID: 39502664 - 11 individuals from 9 unrelated families with BHLHE22 variants, presenting with a neurodevelopmental disorder including absent or limited speech, impaired motor function, intellectual disability, involuntary movements, autistic traits, abnormal muscle tone. Most had partial or complete agenesis of the corpus callosum, and some also showed epilepsy, dysmorphic features, and eye anomalies.

Four individuals had de novo missense variants within the helix-loop-helix domain, and seven carried a recurrent homozygous frameshift variant, p.(Gly74Alafs*18).

Mice lacking bhlhe22 show nearly complete loss of three brain comminsure, including the corpus callosum, recapitulating the structural anomalies seen in affected humans.
Sources: Literature
Childhood onset hereditary spastic paraplegia v8.10 TNR Arina Puzriakova changed review comment from: Comment on list classification: There is sufficient evidence to rate this gene GREEN at the next major review - at least 7 unrelated cases with cognitive impairment associated with variants in this gene.; to: Comment on list classification: There is sufficient evidence to rate this gene Green at the next GMS panel update. Spastic para- or tetraparesis, apparent from infancy or early childhood, was reported in 13/15 individuals with biallelic variants in this gene.
Childhood onset hereditary spastic paraplegia v8.10 TNR Arina Puzriakova gene: TNR was added
gene: TNR was added to Childhood onset hereditary spastic paraplegia. Sources: Expert list,Expert Review Amber
Q3_25_promote_green tags were added to gene: TNR.
Mode of inheritance for gene: TNR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TNR were set to 28334938; 32099069
Phenotypes for gene: TNR were set to Neurodevelopmental disorder, nonprogressive, with spasticity and transient opisthotonus, OMIM:619653
Childhood onset hereditary spastic paraplegia v8.9 EXOSC8 Arina Puzriakova changed review comment from: Comment on list classification: This gene should be promoted to Green at the next GMS panel update on the basis that spasticity is a significant feature of the disorder associated with biallelic variant in this gene - at least 5 families have been reported (spasticity reported in 11/13 patients, affecting both upper and lower limbs except for one patient who had lower limbs spasticity).; to: Comment on list classification: This gene should be promoted to Green at the next GMS panel update on the basis that spasticity is a significant feature of the complex infantile-onset disorder associated with biallelic variant in this gene - at least 5 families have been reported (spasticity reported in 11/13 patients, affecting both upper and lower limbs except for one patient who had lower limbs spasticity).
Childhood onset hereditary spastic paraplegia v8.9 EXOSC8 Arina Puzriakova changed review comment from: Comment on list classification: Upgraded from Red to Amber but this gene should be promoted to Green at the next GMS panel update on the basis that cerebellar hypoplasia is a significant feature of the disorder associated with biallelic variant in this gene - at least 5 families have been reported.; to: Comment on list classification: This gene should be promoted to Green at the next GMS panel update on the basis that spasticity is a significant feature of the disorder associated with biallelic variant in this gene - at least 5 families have been reported (spasticity reported in 11/13 patients, affecting both upper and lower limbs except for one patient who had lower limbs spasticity).
Childhood onset hereditary spastic paraplegia v8.9 EXOSC8 Arina Puzriakova gene: EXOSC8 was added
gene: EXOSC8 was added to Childhood onset hereditary spastic paraplegia. Sources: Expert Review Amber
Q3_25_promote_green tags were added to gene: EXOSC8.
Mode of inheritance for gene: EXOSC8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXOSC8 were set to 24989451; 38017281; 34210538
Phenotypes for gene: EXOSC8 were set to Pontocerebellar hypoplasia, type 1C, OMIM:616081
Childhood onset hereditary spastic paraplegia v8.7 INPP4A Achchuthan Shanmugasundram gene: INPP4A was added
gene: INPP4A was added to Childhood onset hereditary spastic paraplegia. Sources: Literature
Q3_25_promote_green tags were added to gene: INPP4A.
Mode of inheritance for gene: INPP4A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: INPP4A were set to 39315527; 40748307; 40772914
Phenotypes for gene: INPP4A were set to neurodevelopmental disorder, MONDO:0700092
Review for gene: INPP4A was set to GREEN
Added comment: PMID:39315527 (2025) reported 30 patients from 17 unrelated families with biallelic INPP4A variants and a clinically variable neurodevelopmental disorder. The clinical features include global developmental delay, severe-profound intellectual disability, microcephaly, limb weakness, cerebellar signs, and short stature. A more severe presentation associated with biallelic INPP4A variants downstream of exon 4 has additional features of (ponto)cerebellar hypoplasia, reduced cerebral volume, peripheral spasticity, contractures, intractable seizures, and cortical visual impairment. Nine patients from eight families were reported with spasticity, of which six had LoF variants downstream of exon 4 and the remaining three had missense variants. Although age of onset was not provided for these patients, the age of last examination for eight of nine patients were below 16.

There is also functional evidence available in support of the disease association. Preliminary fibroblast cell lines from an affected individual showed disruption of endocytic pathways as the likely mechanism of disease. All mouse models displayed a phenotype mirroring human INPP4A-related neurodevelopmental disorder.

PMID:40772914 (2025) reported a 34-month old female patient with the same biallelic variant that was reported in family 7 from PMID:39315527 (c.981del/ p.Asp328Ilefs*4) and with INPP4A-related disorder. This patient had spasticity.
Sources: Literature
Childhood onset hereditary spastic paraplegia v8.5 FLVCR1 Eleanor Williams gene: FLVCR1 was added
gene: FLVCR1 was added to Childhood onset hereditary spastic paraplegia. Sources: Literature
Q3_25_promote_green tags were added to gene: FLVCR1.
Mode of inheritance for gene: FLVCR1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FLVCR1 were set to 39306721
Phenotypes for gene: FLVCR1 were set to Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060; neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, MONDO:0976126
Review for gene: FLVCR1 was set to GREEN
Added comment: Associated with Neurodevelopmental disorder with microcephaly, absent speech, and hypotonia, OMIM:621060.

Variants in this gene have been previously associated with a progressive Retinopathy-sensory neuropathy syndrome, OMIM:609033

PMID: 39306721 - Calame et al 2025 report 27 individuals from 20 families with homozygous/compound het variants in this gene (mainly missense, but also nonsense, frameshift and splice variants). 2 families from S Asia share the same variant and haplotype so could be a founder variant in the region.

13/27 individual had profound ID/DD. 3 were stillborn, and 10 others died before the age of 5, including one in the neonatal period. Severe microcephaly (Z score below -3.0) was observed in 12/27 individuals. Epilepsy was reported in 12 individuals, hypotonia in 17, spasticity in 9 (from 6 families), reduced brain volume in 19 , craniofacial malformations in 4 (those that were still born or died in neonatal period), and limb malformations in 7. An eye phenotype (Cortical visual impairment, Optic disk atrophy or Retinitis pigmentosa) was observed in 15 individuals.

All pathogenic FLVCR1 variants were rare and absent in the homozygous state in gnomAD v2.1.13. Functional studies show that pathogenic FLVCR1 missense variants primarily lie within transmembrane domains and reduce choline and ethanolamine transport activity compared with wild-type FLVCR1.

There are more than 3 cases reported with plausible disease causing variants in more than 3 cases for the intellectual disability, epilepsy, severe microcephaly, limb disorders, fetal anomalies and childhood onset hereditary spastic paraplegia panels. The gene will also be included in the Hypotonic infant superpanel through the inclusion on the Intellectual disability panel.
Sources: Literature
Childhood onset hereditary spastic paraplegia v8.4 NOTCH3 Achchuthan Shanmugasundram changed review comment from: PMID:39191170 reported a cohort of 50 patients with biallelic variants in NOTCH3 gene, which includes 25 previously unreported individuals from 17 families and 25 individuals already reported in published literature from 14 families.

Of these, 18 unreported individuals from 10 families and 8 already reported individuals from five families were identified with biallelic loss-of-functional variants. These 26 patients with biallelic LoF variants are reported with a neurodevelopmental disorder characterised by spasticity, childhood-onset stroke, and periatrial white matter volume loss resembling periventricular leukomalacia. 19 of these patients from 11 different families were reported with spasticity.

Seven previously unreported cases from seven different families and 17 previously published cases from nine families were identified with biallelic cysteine-involving missense variants. These 24 patients fall within CADASIL spectrum phenotype with early adulthood onset stroke, dementia, and deep white matter lesions without significant volume loss. Spasticity and ataxia were reported in three and four patients respectively.

Biallelic variants in NOTCH3 are not yet associated with any phenotypes in OMIM or in Gene2Phenotype.; to: PMID:39191170 reported a cohort of 50 patients with biallelic variants in NOTCH3 gene, which includes 25 previously unreported individuals from 17 families and 25 individuals already reported in published literature from 14 families.

Of these, 18 unreported individuals from 10 families and 8 already reported individuals from five families were identified with biallelic loss-of-functional variants. These 26 patients with biallelic LoF variants are reported with a neurodevelopmental disorder characterised by spasticity, childhood-onset stroke, and periatrial white matter volume loss resembling periventricular leukomalacia.

19 of these patients from 11 different families were reported with spasticity. Mean age at the onset of symptoms was 28 months, ranging from congenital to 17 years old.

Seven previously unreported cases from seven different families and 17 previously published cases from nine families were identified with biallelic cysteine-involving missense variants. These 24 patients fall within CADASIL spectrum phenotype with early adulthood onset stroke, dementia, and deep white matter lesions without significant volume loss. Spasticity and ataxia were reported in three and four patients respectively.

Biallelic variants in NOTCH3 are not yet associated with any phenotypes in OMIM or in Gene2Phenotype.
Childhood onset hereditary spastic paraplegia v8.4 NOTCH3 Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Lauren Turton, there is sufficient evidence available for the association of biallelic LoF variants from NOTCH3 gene with childhood-onset spastic paraplegia. Hence, this gene can be promoted to green rating in the next GMS update.
Childhood onset hereditary spastic paraplegia v8.3 NOTCH3 Achchuthan Shanmugasundram Phenotypes for gene: NOTCH3 were changed from Spasticity, stroke, periatrial white matter volume loss to neurodevelopmental disorder, MONDO:0700092
Childhood onset hereditary spastic paraplegia v8.2 ABCD1 Arina Puzriakova Phenotypes for gene: ABCD1 were changed from spastic paraparesis; VLCFA accumulation; adrenal failure; Hereditary spastic paraplegia to Adrenoleukodystrophy, OMIM:300100; Adrenoleukodystrophy, adult, OMIM:300100; Adrenal failure; VLCFA accumulation; Spastic paraparesis
Childhood onset hereditary spastic paraplegia v8.1 NOTCH3 Lauren Turton gene: NOTCH3 was added
gene: NOTCH3 was added to Childhood onset hereditary spastic paraplegia. Sources: NHS GMS
Mode of inheritance for gene: NOTCH3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NOTCH3 were set to 39191170
Phenotypes for gene: NOTCH3 were set to Spasticity, stroke, periatrial white matter volume loss
Review for gene: NOTCH3 was set to GREEN
Added comment: Twenty-five patients from 17 unrelated families harbouring homozygous or compound heterozygous variants in NOTCH3. Among them 18 carried LoF variants.
Patients had a neurodevelopmental disorder characterised by spasticity, childhood-onset stroke, and periatrial white matter volume loss resembling periventricular leukomalacia. Mean age at the onset of symptoms was 28 months, ranging from congenital to 17 years old.
Showed that patients with the biallelic LoF variants had a different phenotype to that seen in CADASIL.
Sources: NHS GMS
Childhood onset hereditary spastic paraplegia v7.14 HMBS Sarah Leigh Phenotypes for gene: HMBS were changed from Leukoencephalopathy, porphyria-related, OMIM:620711; hereditary spastic paraplegia, MONDO:0019064 to Leukoencephalopathy, porphyria-related, OMIM:620711; Encephalopathy, porphyria-related, OMIM:620704
Childhood onset hereditary spastic paraplegia v7.13 HMBS Sarah Leigh Phenotypes for gene: HMBS were changed from Leukoencephalopathy, HP:0002352; hereditary spastic paraplegia, MONDO:0019064 to Leukoencephalopathy, porphyria-related, OMIM:620711; hereditary spastic paraplegia, MONDO:0019064
Childhood onset hereditary spastic paraplegia v7.8 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.
Childhood onset hereditary spastic paraplegia v7.8 SPAST Sarah Leigh Publications for gene: SPAST were set to Hazan et al (1999); 10610178; 10699187; 11039577; 10980739; 15210521; 16832076
Childhood onset hereditary spastic paraplegia v7.7 SPAST Sarah Leigh Tag Q1_25_ MOI tag was added to gene: SPAST.
Childhood onset hereditary spastic paraplegia v7.7 SPAST Sarah Leigh reviewed gene: SPAST: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v7.7 LSM7 Arina Puzriakova gene: LSM7 was added
gene: LSM7 was added to Childhood onset hereditary spastic paraplegia. Sources: Literature,Expert Review Amber
watchlist tags were added to gene: LSM7.
Mode of inheritance for gene: LSM7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LSM7 were set to 35047835; 39420558
Phenotypes for gene: LSM7 were set to Leukodystrophy, MONDO:0019046
Childhood onset hereditary spastic paraplegia v7.4 SPTSSA Sarah Leigh Phenotypes for gene: SPTSSA were changed from Spastic paraplegia 90A, autosomal dominant, OMIM:620416; ?Spastic paraplegia 90B, autosomal recessive, OMIM:620417 to Spastic paraplegia 90A, autosomal dominant, OMIM:620416; spastic paraplegia 90A, autosomal dominant, MONDO:0957308; ?Spastic paraplegia 90B, autosomal recessive, OMIM:620417
Childhood onset hereditary spastic paraplegia v7.3 SPTSSA Sarah Leigh reviewed gene: SPTSSA: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic paraplegia 90A, autosomal dominant, OMIM:620416, spastic paraplegia 90A, autosomal dominant, MONDO:0957308; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v7.2 ZFYVE26 Arina Puzriakova Phenotypes for gene: ZFYVE26 were changed from Spastic paraplegia 15, autosomal recessive, 270700 to Spastic paraplegia 15, autosomal recessive, OMIM:270700
Childhood onset hereditary spastic paraplegia v6.10 FA2H Eleanor Williams Phenotypes for gene: FA2H were changed from Spastic paraplegia 35, autosomal recessive, 612319 to Spastic paraplegia 35, autosomal recessive, OMIM:612319; hereditary spastic paraplegia 35, MONDO:0012866
Childhood onset hereditary spastic paraplegia v6.8 FICD Achchuthan Shanmugasundram gene: FICD was added
gene: FICD was added to Childhood onset hereditary spastic paraplegia. 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.

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
Childhood onset hereditary spastic paraplegia v6.7 RINT1 Achchuthan Shanmugasundram Added comment: Comment on list classification: Three unrelated cases and functional evidence are available in support of the association of this gene with early-onset hereditary spastic paraplegia. Hence, this gene can be promoted to green rating in the next GMS update.
Childhood onset hereditary spastic paraplegia v6.6 RINT1 Achchuthan Shanmugasundram Phenotypes for gene: RINT1 were changed from HSP to hereditary spastic paraplegia, MONDO:0019064
Childhood onset hereditary spastic paraplegia v6.4 RINT1 Achchuthan Shanmugasundram reviewed gene: RINT1: Rating: GREEN; Mode of pathogenicity: None; Publications: 37463447, 38990652; Phenotypes: hereditary spastic paraplegia, MONDO:0019064; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v6.4 BORCS8 Sarah Leigh gene: BORCS8 was added
gene: BORCS8 was added to Childhood onset hereditary spastic paraplegia. Sources: Expert Review Amber,Literature
Q3_24_promote_green tags were added to gene: BORCS8.
Mode of inheritance for gene: BORCS8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BORCS8 were set to 38128568
Phenotypes for gene: BORCS8 were set to neurodevelopmental disorder, MONDO:0700092; intellectual disability, MONDO:0001071
Childhood onset hereditary spastic paraplegia v6.1 RINT1 Dmitrijs Rots gene: RINT1 was added
gene: RINT1 was added to Childhood onset hereditary spastic paraplegia. Sources: Literature
Mode of inheritance for gene: RINT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RINT1 were set to PMID: 38990652
Phenotypes for gene: RINT1 were set to HSP
Review for gene: RINT1 was set to GREEN
Added comment: The PMID: 38990652 reports fourth case with HSP and bialellic RINT1 variants. They also note:
"The exon-intron boundaries around intron 11 may represent a mutational hotspot, given variation at c.1671+2 and c.1672-1 in all reported cases thus far."
Enough evidence for the green rating!
Sources: Literature
Childhood onset hereditary spastic paraplegia v4.42 RTN2 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: As there are sufficient number of cases with biallelic variants and lower limb spasticity, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.
Childhood onset hereditary spastic paraplegia v4.41 RTN2 Achchuthan Shanmugasundram Phenotypes for gene: RTN2 were changed from Spastic paraplegia 12, autosomal dominant, 604805 to Spastic paraplegia 12, autosomal dominant, OMIM:604805; distal hereditary motor neuropathy, MONDO:0018894; Lower limb spasticity, HP:0002061
Childhood onset hereditary spastic paraplegia v4.39 RTN2 Achchuthan Shanmugasundram reviewed gene: RTN2: Rating: GREEN; Mode of pathogenicity: None; Publications: 38527963; Phenotypes: distal hereditary motor neuropathy, MONDO:0018894, Lower limb spasticity, HP:0002061; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v4.39 RTN2 Nour Elkhateeb reviewed gene: RTN2: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 38527963; Phenotypes: Weakness in the distal upper and lower limbs, Lower limb spasticity, Hyperreflexia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v4.39 HMBS Achchuthan Shanmugasundram Added comment: Comment on list classification: There are three unrelated families reported with spastic paraparesis. Hence, this gene can be promoted to green rating in the next GMS review.
Childhood onset hereditary spastic paraplegia v4.38 HMBS Achchuthan Shanmugasundram gene: HMBS was added
gene: HMBS was added to Childhood onset hereditary spastic paraplegia. Sources: Literature
Mode of inheritance for gene: HMBS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HMBS were set to 27558376; 34089223
Phenotypes for gene: HMBS were set to Leukoencephalopathy, HP:0002352; hereditary spastic paraplegia, MONDO:0019064
Review for gene: HMBS was set to GREEN
Added comment: PMID:27558376 reported three siblings with compound heterozygous missense HMBS variants (c.500G>A/ p.Arg167Gln & c.674G>A/ p.Arg225Gln) and a disease characterised by childhood-onset slowly progressive spastic paraparesis, cerebellar ataxia, peripheral neuropathy, and in 2 patients, optic atrophy as well as vertical gaze and convergence palsies and nystagmus. They had a similar MRI pattern characterized by symmetrical signal abnormalities in the periventricular and deep cerebral white matter, thalami, and central part of the pons, and cerebellar atrophy was present in advanced disease stages.

PMID:34089223 reported two patients from a family with homozygous variant (c.251C>A/ p.Ala84Asp) and another patient from a different family with the same compound heterozygous variants as the siblings reported in PMID:27558376 (c.500G>A/ p.Arg167Gln & c.674G>A/ p.Arg225Gln). All patients presented with slowly progressive spasticity, ataxia, peripheral neuropathy, with or without mild cognitive impairment, and/or ocular disease with onset in childhood or adolescence. Their brain MRIs show mainly confluent signal abnormalities in the periventricular and deep white matter and bilateral thalami. However, the onset of the disease was during childhood in individuals with the homozygous variant (7 years and late childhood), while the onset was at 22 years of age in the third individual with compound heterozygous variants.

Monoallelic variants in HMBS gene have been associated with acute intermittent porphyria (MIM #176000) in OMIM, but biallelic variants have not yet been associated with any phenotypes either in OMIM or in Gene2Phenotype.
Sources: Literature
Childhood onset hereditary spastic paraplegia v4.37 ACBD6 Arina Puzriakova gene: ACBD6 was added
gene: ACBD6 was added to Childhood onset hereditary spastic paraplegia. Sources: Expert Review Amber
Q1_24_promote_green tags were added to gene: ACBD6.
Mode of inheritance for gene: ACBD6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACBD6 were set to 21937992; 32108178; 36457943; 37951597
Phenotypes for gene: ACBD6 were set to Neurodevelopmental disorder, MONDO:0700092
Penetrance for gene: ACBD6 were set to Complete
Childhood onset hereditary spastic paraplegia v4.36 CLDN11 Achchuthan Shanmugasundram changed review comment from: PMID:33313762 reported three unrelated individuals with early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including nystagmus and hypermetropia. Two different heterozygous de novo stop-loss variants were identified in these patients. One of the variants did not lead to a loss of CLDN11 expression on RNA level in fibroblasts indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein.


This gene has been associated with hypomyelinating leukodystrophy in OMIM, which includes spasticity as one of the clinical presentations. However, this gene has not yet been associated with phenotypes in Gene2Phenotype.
Sources: Literature; to: PMID:33313762 reported three unrelated individuals with early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including nystagmus and hypermetropia. Two different heterozygous de novo stop-loss variants were identified in these patients. One of the variants did not lead to a loss of CLDN11 expression on RNA level in fibroblasts indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein.

This gene has been associated with hypomyelinating leukodystrophy in OMIM, which includes spasticity as one of the clinical presentations. However, this gene has not yet been associated with phenotypes in Gene2Phenotype.
Sources: Literature
Childhood onset hereditary spastic paraplegia v4.34 CLDN11 Achchuthan Shanmugasundram changed review comment from: PMID:33313762 reported three unrelated individuals with early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including hypermetropia. Two different heterozygous de novo stop-loss variants were identified in these patients. One of the variants did not lead to a loss of CLDN11 expression on RNA level in fibroblasts indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein.


This gene has been associated with hypomyelinating leukodystrophy in OMIM, which includes spasticity as one of the clinical presentations. However, this gene has not yet been associated with phenotypes in Gene2Phenotype.
Sources: Literature; to: PMID:33313762 reported three unrelated individuals with early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including nystagmus and hypermetropia. Two different heterozygous de novo stop-loss variants were identified in these patients. One of the variants did not lead to a loss of CLDN11 expression on RNA level in fibroblasts indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein.


This gene has been associated with hypomyelinating leukodystrophy in OMIM, which includes spasticity as one of the clinical presentations. However, this gene has not yet been associated with phenotypes in Gene2Phenotype.
Sources: Literature
Childhood onset hereditary spastic paraplegia v4.33 CLDN11 Achchuthan Shanmugasundram gene: CLDN11 was added
gene: CLDN11 was added to Childhood onset hereditary spastic paraplegia. Sources: Literature
Mode of inheritance for gene: CLDN11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CLDN11 were set to 33313762
Phenotypes for gene: CLDN11 were set to Leukodystrophy, hypomyelinating, 22, OMIM:619328
Review for gene: CLDN11 was set to GREEN
Added comment: PMID:33313762 reported three unrelated individuals with early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including hypermetropia. Two different heterozygous de novo stop-loss variants were identified in these patients. One of the variants did not lead to a loss of CLDN11 expression on RNA level in fibroblasts indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein.


This gene has been associated with hypomyelinating leukodystrophy in OMIM, which includes spasticity as one of the clinical presentations. However, this gene has not yet been associated with phenotypes in Gene2Phenotype.
Sources: Literature
Childhood onset hereditary spastic paraplegia v4.32 ALK Achchuthan Shanmugasundram Added comment: Comment on list classification: As reviewed by Zornitza Stark, PMID:32989326 reported a large cohort study of cerebral palsy, where two patients were identified with monoallelic ALK variants and presented with spastic diplegia with mild tremor or spastic-dystonic diplegia. Hence, this gene can be rated amber with current evidence.
Childhood onset hereditary spastic paraplegia v4.31 ALK Achchuthan Shanmugasundram reviewed gene: ALK: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: spastic diplegia, MONDO:0001167; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood onset hereditary spastic paraplegia v4.31 RETREG1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of RETREG1 gene with spastic paraplegia and hence this gene can be promoted to green rating in the next GMS review.
Childhood onset hereditary spastic paraplegia v4.28 RETREG1 Achchuthan Shanmugasundram changed review comment from: PMID:24327336 - Spastic gait was reported in two siblings of Turkish ancestry presenting with hereditary sensory and autonomic neuropathy and identified with biallelic RETREG1 variant (c.826delA).

PMID:30643655 - Mutilating sensory loss and spastic paraplegia were reported in two affected individuals from two unrelated Saudi families identified with nonsense RETREG1 variant (c.926 C>G/ p.Ser309Ter); to: PMID:24327336 - Spastic gait was reported in two siblings of Turkish ancestry presenting with hereditary sensory and autonomic neuropathy and identified with biallelic RETREG1 variant (c.826delA).

PMID:30643655 - Mutilating sensory loss and spastic paraplegia were reported in two affected individuals from two unrelated Saudi families identified with nonsense RETREG1 variant (c.926 C>G/ p.Ser309Ter).

Gavin Ryan also mentioned in his review that LoF homozygous variant in this gene was identified via Diagnostic Discovery in 100K and GMS WGS patient with features of Progressive spasticity, facial hypotonia, dysarthria, and fatiguable weakness.
Childhood onset hereditary spastic paraplegia v4.28 RETREG1 Achchuthan Shanmugasundram commented on gene: RETREG1: PMID:24327336 - Spastic gait was reported in two siblings of Turkish ancestry presenting with hereditary sensory and autonomic neuropathy and identified with biallelic RETREG1 variant (c.826delA).

PMID:30643655 - Mutilating sensory loss and spastic paraplegia were reported in two affected individuals from two unrelated Saudi families identified with nonsense RETREG1 variant (c.926 C>G/ p.Ser309Ter)
Childhood onset hereditary spastic paraplegia v4.28 RETREG1 Gavin Ryan gene: RETREG1 was added
gene: RETREG1 was added to Childhood onset hereditary spastic paraplegia. Sources: NHS GMS
Mode of inheritance for gene: RETREG1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RETREG1 were set to 24327336
Penetrance for gene: RETREG1 were set to unknown
Review for gene: RETREG1 was set to GREEN
Added comment: Aydinlar et al identified individuals with hereditary neuropathy caused by variant in this gene who also had spasticity. Further, LoF homozygous variant in this gene identified via Diagnostic Discovery in 100K and GMS WGS patient with features of Progressive spasticity, facial hypotonia, dysarthria, and fatiguable weakness.
Sources: NHS GMS
Childhood onset hereditary spastic paraplegia v4.25 SPTSSA Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: There are two unrelated cases (with the same variant) in support of the association of this gene with the autosomal dominant spastic paraplegia. Although there is only one case with the autosomal recessive condition, homozygous knockout mouse model is available in support of the association. Functional evidence is also available for both homozygous and heterozygous variants.

Hence, the rating should be amber and the MOI should be set to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal'.
Childhood onset hereditary spastic paraplegia v4.24 SPTSSA Achchuthan Shanmugasundram changed review comment from: Two unrelated patients were identified with the same de novo missense heterozygous variant (p.Thr51Ile) and the third patient was identified with a homozygous truncation variant (c.171_172del) in SPTSSA gene. All these patients were reported with a complex form of paediatric-onset hereditary spastic paraplegia associated with progressive motor impairment and spasticity and variable language/cognitive impact.

Functional studies in fibroblasts showed dysregulation of the sphingolipid (SL) synthesis pathway, showing that both variants impair ORMDL regulation of the pathway leading to various levels of increased SL. Over expression of human SPTSSA was shown to lead to motor development in Drosophila, rescued by expression of ORMDL for WT SPTSSA but not mutant SPTSSA. The heterozygous p.Thr51Ile variant was shown to impact regulation more than the homozygous truncation variant, while the truncated region was previously shown to be important for ORMDL regulation.

Mice model with a homozygous knockout of the functional equivalent sptssb had early onset ataxia and died prematurely, with evidence of axonic degeneration.
Sources: Literature; to: Two unrelated patients were identified with the same de novo missense heterozygous variant (p.Thr51Ile) and the third patient was identified with a homozygous truncation variant (c.171_172del) in SPTSSA gene. All these patients were reported with a complex form of paediatric-onset hereditary spastic paraplegia associated with progressive motor impairment and spasticity and variable language/cognitive impact (PMID:36718090).

Functional studies in fibroblasts showed dysregulation of the sphingolipid (SL) synthesis pathway, showing that both variants impair ORMDL regulation of the pathway leading to various levels of increased SL. Over expression of human SPTSSA was shown to lead to motor development in Drosophila, rescued by expression of ORMDL for WT SPTSSA but not mutant SPTSSA. The heterozygous p.Thr51Ile variant was shown to impact regulation more than the homozygous truncation variant, while the truncated region was previously shown to be important for ORMDL regulation (PMID:36718090).

Mice model with homozygous ssSPTa null mutants are embryonic lethal (PMID:33662400). However, homozygous knockout of the functional equivalent ssSPTb had early onset ataxia and died prematurely, with evidence of axonic degeneration (PMID:26438849).

This gene has already been associated with relevant phenotypes in OMIM (MIMs #620416 & #620417).
Sources: Literature
Childhood onset hereditary spastic paraplegia v4.24 SPTSSA Achchuthan Shanmugasundram changed review comment from: Two unrelated patients were identified with the same heterozygous variant (p.Thr51Ile) and the third patient was identified with a homozygous variant (c.171_172del) in SPTSSA gene. All these patients were reported with a complex form of paediatric-onset hereditary spastic paraplegia associated with progressive motor impairment and spasticity and variable language/cognitive impact.
Sources: Literature; to: Two unrelated patients were identified with the same de novo missense heterozygous variant (p.Thr51Ile) and the third patient was identified with a homozygous truncation variant (c.171_172del) in SPTSSA gene. All these patients were reported with a complex form of paediatric-onset hereditary spastic paraplegia associated with progressive motor impairment and spasticity and variable language/cognitive impact.

Functional studies in fibroblasts showed dysregulation of the sphingolipid (SL) synthesis pathway, showing that both variants impair ORMDL regulation of the pathway leading to various levels of increased SL. Over expression of human SPTSSA was shown to lead to motor development in Drosophila, rescued by expression of ORMDL for WT SPTSSA but not mutant SPTSSA. The heterozygous p.Thr51Ile variant was shown to impact regulation more than the homozygous truncation variant, while the truncated region was previously shown to be important for ORMDL regulation.

Mice model with a homozygous knockout of the functional equivalent sptssb had early onset ataxia and died prematurely, with evidence of axonic degeneration.
Sources: Literature
Childhood onset hereditary spastic paraplegia v4.24 SPTSSA Achchuthan Shanmugasundram changed review comment from: Sources: Literature; to: Two unrelated patients were identified with the same heterozygous variant (p.Thr51Ile) and the third patient was identified with a homozygous variant (c.171_172del) in SPTSSA gene. All these patients were reported with a complex form of paediatric-onset hereditary spastic paraplegia associated with progressive motor impairment and spasticity and variable language/cognitive impact.
Sources: Literature
Childhood onset hereditary spastic paraplegia v4.24 SPTSSA Achchuthan Shanmugasundram gene: SPTSSA was added
gene: SPTSSA was added to Childhood onset hereditary spastic paraplegia. Sources: Literature
Mode of inheritance for gene: SPTSSA was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SPTSSA were set to 36718090
Phenotypes for gene: SPTSSA were set to Spastic paraplegia 90A, autosomal dominant, OMIM:620416; ?Spastic paraplegia 90B, autosomal recessive, OMIM:620417
Review for gene: SPTSSA was set to AMBER
Added comment: Sources: Literature
Childhood onset hereditary spastic paraplegia v4.23 PPFIBP1 Arina Puzriakova gene: PPFIBP1 was added
gene: PPFIBP1 was added to Childhood onset hereditary spastic paraplegia. Sources: Literature,Expert Review Amber
Q2_23_promote_green tags were added to gene: PPFIBP1.
Mode of inheritance for gene: PPFIBP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PPFIBP1 were set to 35830857; 30214071
Phenotypes for gene: PPFIBP1 were set to Neurodevelopmental disorder with seizures, microcephaly, and brain abnormalities, OMIM:620024
Penetrance for gene: PPFIBP1 were set to Complete
Childhood onset hereditary spastic paraplegia v4.21 HECTD4 Arina Puzriakova gene: HECTD4 was added
gene: HECTD4 was added to Childhood onset hereditary spastic paraplegia. Sources: Literature,NHS GMS,Expert Review Green
Mode of inheritance for gene: HECTD4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HECTD4 were set to 36401616
Phenotypes for gene: HECTD4 were set to Neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosum, OMIM:620250
Childhood onset hereditary spastic paraplegia v4.18 SPTAN1 Achchuthan Shanmugasundram Added comment: Comment on mode of inheritance: Although there are three unrelated cases reported with biallelic SPTAN1 variants and hereditary spastic paraplegia, the age of onset of these cases were 33, 15 and 12 years (PMID:31515523; PMID:34526651). As the number of childhood-onset biallelic cases are not sufficient for green rating, the MOI should remain as "MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted".
Childhood onset hereditary spastic paraplegia v4.17 SPTAN1 Sarah Leigh Phenotypes for gene: SPTAN1 were changed from Developmental and epileptic encephalopathy 5, OMIM:613477; Cerebellar ataxia, MONDO:0000437; Hereditary spastic paraplegia, MONDO:0019064 to Developmental and epileptic encephalopathy 5, OMIM:613477; developmental and epileptic encephalopathy, 5, MONDO:0013277
Childhood onset hereditary spastic paraplegia v4.16 LETM1 Sarah Leigh changed review comment from: LETM1 variants have been associated with Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, OMIM:620089 and as moderate Gen2Phen gene for LETM1-related neurodevelopmental disorder.
PMID: 36055214 reports 10 LETM1 variants in 18 patients from 11 unrelated families with childhood-onset neurodegeneration with multisystem involvement, many of whom were gathered using the GeneMatcher Program. The most common clinical features of this cohort, where an assessment could be made, were: mitochondrial respiratory complex deficiencies 11/11 (100%), global developmental delay / intellectual disability 17/18 (94%), bilateral sensorineural hearing loss 11/14 (78%) , impaired vision 10/10 (100%), cerebellar ataxia 7/9 (78%), seizures 10/15 (67%), hypotonia 11/18 (61%) (PMID: 36055214, figure 1c).; to: LETM1 variants have been associated with Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, OMIM:620089 and as moderate Gen2Phen gene for LETM1-related neurodevelopmental disorder.
PMID: 36055214 reports 10 LETM1 variants in 18 patients from 11 unrelated families with childhood-onset neurodegeneration with multisystem involvement, many of whom were gathered using the GeneMatcher Program. The most common clinical features of this cohort, where an assessment could be made, were: mitochondrial respiratory complex deficiencies 11/11 (100%), global developmental delay / intellectual disability 17/18 (94%), bilateral sensorineural hearing loss 11/14 (78%) , impaired vision 10/10 (100%), cerebellar ataxia 7/9 (78%), seizures 10/15 (67%), hypotonia 11/18 (61%), spasticity 8/15 (53%) (PMID: 36055214, figure 1c).
Childhood onset hereditary spastic paraplegia v4.16 LETM1 Sarah Leigh gene: LETM1 was added
gene: LETM1 was added to Childhood onset hereditary spastic paraplegia. Sources: Expert Review,Expert Review Amber
Q3_23_promote_green, Q3_23_NHS_review, Q3_23_MOI tags were added to gene: LETM1.
Mode of inheritance for gene: LETM1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LETM1 were set to 36055214; 33815143
Phenotypes for gene: LETM1 were set to Neurodegeneration, childhood-onset, with multisystem involvement due to mitochondrial dysfunction, OMIM:620089
Childhood onset hereditary spastic paraplegia v4.15 UCHL1 Sarah Leigh Phenotypes for gene: UCHL1 were changed from Spastic paraplegia 79, autosomal recessive, OMIM:615491; early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome, MONDO:0014209; Spastic paraplegia 79A, autosomal dominant, OMIM:620221 to Spastic paraplegia 79B, autosomal recessive, OMIM:615491; early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome, MONDO:0014209; Spastic paraplegia 79A, autosomal dominant, OMIM:620221
Childhood onset hereditary spastic paraplegia v4.14 UCHL1 Sarah Leigh Phenotypes for gene: UCHL1 were changed from Spastic paraplegia 79, autosomal recessive, OMIM:615491 to Spastic paraplegia 79, autosomal recessive, OMIM:615491; early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome, MONDO:0014209; Spastic paraplegia 79A, autosomal dominant, OMIM:620221
Childhood onset hereditary spastic paraplegia v4.13 AMFR Achchuthan Shanmugasundram changed review comment from: PMID:37119330 - 20 individuals from 8 unrelated consanguineous families of various origins were identified with autosomal recessive variants in AMFR gene. All patients had early disease onset (<3 years), including motor delay, lower limb hyperreflexia and spastic paraplegia that match the typical phenotypes of hereditary spastic paraplegia.
Sources: Literature; to: PMID:37119330 - 20 individuals from 8 unrelated consanguineous families of various origins were identified with autosomal recessive variants in AMFR gene. All patients had early disease onset (<3 years), including motor delay, lower limb hyperreflexia and spastic paraplegia that match the typical phenotypes of hereditary spastic paraplegia.

This gene has been associated with relevant phenotypes in OMIM (MIM #620379), but not in Gene2Phenotype.
Sources: Literature
Childhood onset hereditary spastic paraplegia v4.12 AMFR Achchuthan Shanmugasundram gene: AMFR was added
gene: AMFR was added to Childhood onset hereditary spastic paraplegia. Sources: Literature
Mode of inheritance for gene: AMFR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AMFR were set to 37119330
Phenotypes for gene: AMFR were set to Spastic paraplegia 89, autosomal recessive, OMIM:620379
Review for gene: AMFR was set to GREEN
Added comment: PMID:37119330 - 20 individuals from 8 unrelated consanguineous families of various origins were identified with autosomal recessive variants in AMFR gene. All patients had early disease onset (<3 years), including motor delay, lower limb hyperreflexia and spastic paraplegia that match the typical phenotypes of hereditary spastic paraplegia.
Sources: Literature
Childhood onset hereditary spastic paraplegia v4.9 CCDC82 Achchuthan Shanmugasundram gene: CCDC82 was added
gene: CCDC82 was added to Childhood onset hereditary spastic paraplegia. Sources: Literature
Mode of inheritance for gene: CCDC82 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CCDC82 were set to 35118659; 35373332
Phenotypes for gene: CCDC82 were set to neurodevelopmental disorder, MONDO:0700092; hereditary spastic paraplegia, MONDO:0019064
Review for gene: CCDC82 was set to AMBER
Added comment: PMID: 35118659 reported two siblings presenting with global global developmental delay (last evaluation at 4 years and 9 months) and spasticity. They also had a common history of infantile spasms with the elder developing GTC convulsions with spontaneous resolution and both presented with microcephaly (<-2 and <-3SD). They harboured homozygous variant c.535C>T ( p.Arg179Ter).

PMID: 35373332 reported a 21 years old male who presented with features included short stature, intellectual disability, spastic paraparesis (at the age of 3 years). Gelastic seizures were suspected but not confirmed (repeated normal EEGs). This patient harboured a homozygous frameshift CCDC82 variant c.183del (p.Phe61Leufs*27) and the parents were heterozygous carriers. There was another homozygous variant, albeit classified as VUS and not thought to fit the clinical presentation.
Sources: Literature
Childhood onset hereditary spastic paraplegia v4.7 CHMP3 Arina Puzriakova gene: CHMP3 was added
gene: CHMP3 was added to Childhood onset hereditary spastic paraplegia. Sources: Literature
Mode of inheritance for gene: CHMP3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CHMP3 were set to 35710109
Phenotypes for gene: CHMP3 were set to Complex spastic quadriplegia associated with developmental delay and seizures
Added comment: Cohen-Barak et al., 2022 (PMID: 35710109) reported on a consanguineous family, in which five individuals presented with intellectual and progressive motor disabilities, seizures and spastic quadriplegia, associated with a homozygous variant in CHMP3. Patient derived fibroblasts expressed ultrastructural and molecular features of impaired autophagy, partially rescued by ectopic expression of WT-CHMP3.
Sources: Literature
Childhood onset hereditary spastic paraplegia v4.4 ATAD3A Arina Puzriakova edited their review of gene: ATAD3A: Added comment: PMID: 34387651 - one patient with spastic diplegic gait that appeared stable since early infancy, harbouring the same p.(Gly355Asp) variant in ATAD3A as seen in the patient previously reported by Cooper et al. 2017 (PMID: 28158749). This is the second case where the early phenotype was notable for spasticity in early childhood and therefore upgrading the rating from Red to Amber.; Changed publications to: 28158749, 27640307, 33845882, 34387651; Changed mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Childhood onset hereditary spastic paraplegia v4.3 SPG7 Sarah Leigh Phenotypes for gene: SPG7 were changed from Spastic paraplegia 7, autosomal recessive, 607259 to Spastic paraplegia 7, autosomal recessive, OMIM:607259; hereditary spastic paraplegia 7, MONDO:0011803
Childhood onset hereditary spastic paraplegia v4.1 WASHC5 Achchuthan Shanmugasundram reviewed gene: WASHC5: Rating: RED; Mode of pathogenicity: None; Publications: 17160902, 23455931, 26572744, 31814071, 33662919; Phenotypes: Spastic paraplegia 8, autosomal dominant, OMIM:603563; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood onset hereditary spastic paraplegia v3.28 Arina Puzriakova List of related panels changed from Childhood onset hereditary spastic paraplegia; Hereditary spastic paraplegia - childhood onset; R61 to Hereditary spastic paraplegia - childhood onset; R61
Childhood onset hereditary spastic paraplegia v3.27 Eleanor Williams Panel name changed from Hereditary spastic paraplegia - childhood onset to Childhood onset hereditary spastic paraplegia
List of related panels changed from Childhood onset hereditary spastic paraplegia; R61 to Childhood onset hereditary spastic paraplegia; Hereditary spastic paraplegia - childhood onset; R61
Childhood onset hereditary spastic paraplegia v3.25 RNF170 Achchuthan Shanmugasundram Phenotypes for gene: RNF170 were changed from Hereditary spastic paraplegia to Spastic paraplegia 85, autosomal recessive, OMIM:619686
Childhood onset hereditary spastic paraplegia v3.23 RNF170 Achchuthan Shanmugasundram changed review comment from: PMID:31636353 reported 9 patients from 4 unrelated families with childhood-onset spastic paraplegia. The age of onset of the condition ranged from 2 to 5 years of age and they were all identified with a homozygous variant in RNF170 gene. It is a neurological disorder characterised by the onset of motor symptoms in the first few years of life. Affected individuals have spasticity and hyperreflexia of the lower limbs resulting in gait abnormalities, with oilder patients also having upper limb involvement and axonal polyneuropathy.

PMID:33165979 reported four members from a single family carrying a homozygous stop gain variant in RNF170 and diagnosed with hereditary spastic paraplegia.

PMID:35041108 reported a 7 year old girl with novel homozygous missense variant in RNF170 and she presented with progressive difficulty in walking that started when she was 3 years old, lower limb predominant spastic paraparesis, and mild upper limbs involvement with slight tremor in the hands, all occurring in the absence of neurodevelopmental or growth delays.; to: PMID:31636353 reported 9 patients from 4 unrelated families with childhood-onset spastic paraplegia. The age of onset of the condition ranged from 2 to 5 years of age and they were all identified with a homozygous variant in RNF170 gene. It is a neurological disorder characterised by the onset of motor symptoms in the first few years of life. Affected individuals have spasticity and hyperreflexia of the lower limbs resulting in gait abnormalities, with oilder patients also having upper limb involvement and axonal polyneuropathy.

PMID:33165979 reported four members from a single family carrying a homozygous stop gain variant in RNF170 and diagnosed with hereditary spastic paraplegia.

PMID:35041108 reported a 7 year old girl with novel homozygous missense variant in RNF170 and she presented with progressive difficulty in walking that started when she was 3 years old, lower limb predominant spastic paraparesis, and mild upper limbs involvement with slight tremor in the hands, all occurring in the absence of neurodevelopmental or growth delays.

This gene has been associated with relevant phenotypes in OMIM (MIM #619686), but not yet in Gene2Phenotype.
Childhood onset hereditary spastic paraplegia v3.23 RNF170 Achchuthan Shanmugasundram reviewed gene: RNF170: Rating: GREEN; Mode of pathogenicity: None; Publications: 31636353, 33165979, 35041108; Phenotypes: Spastic paraplegia 85, autosomal recessive, OMIM:619686; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v3.22 RAB3GAP2 Achchuthan Shanmugasundram changed review comment from: PMID:32740904 reported 9 cases identified with biallelic variants in RAB3GAP2 gene. Seven of them were diagnosed with Martsolf syndrome 1 (MIM #212720) and the remaining two with Warburg micro syndrome 2 (MIM #614225). All of them presented with spasticity (either paraparesis or quadriparesis) as one of the clinical manifestations. The age of patients ranged from 1 year 4 months to 14 years old, with six ion them under 10 years old.

This gene has been associated with phenotypes in both OMIM and Gene2Phenotype.; to: PMID:32740904 reported 9 cases identified with biallelic variants in RAB3GAP2 gene. Seven of them were diagnosed with Martsolf syndrome 1 (MIM #212720) and the remaining two with Warburg micro syndrome 2 (MIM #614225). All of them presented with spasticity (either paraparesis or quadriparesis) as one of the clinical manifestations. The age of patients ranged from 1 year 4 months to 14 years old, with six of them under 10 years old.

This gene has been associated with phenotypes in both OMIM and Gene2Phenotype.
Childhood onset hereditary spastic paraplegia v3.20 SPAST Sarah Leigh Phenotypes for gene: SPAST were changed from Spastic paraplegia 4, autosomal dominant, 182601 to Spastic paraplegia 4, autosomal dominant, OMIM:182601; hereditary spastic paraplegia 4, MONDO:0008438
Childhood onset hereditary spastic paraplegia v3.17 MAG Arina Puzriakova Added comment: Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update.

At least 12 individuals from 8 families have been identified with biallelic variants in this gene. Clinical features are characterised by spasticity (9/13), neuropathy (8/13), optic atrophy (7/13), variable cognitive deficits (7/13), and cerebellar signs (10/13) including ataxia in some (8/13) although 3/10 showed normal brain MRI results.
Childhood onset hereditary spastic paraplegia v3.16 MAG Arina Puzriakova Phenotypes for gene: MAG were changed from Spastic paraplegia 75, autosomal recessive, 616680 to Spastic paraplegia 75, autosomal recessive, OMIM:616680
Childhood onset hereditary spastic paraplegia v3.14 KLC2 Arina Puzriakova Phenotypes for gene: KLC2 were changed from Spastic paraplegia, optic atrophy, and neuropathy, MIM#609541 to Spastic paraplegia, optic atrophy, and neuropathy, OMIM:609541
Childhood onset hereditary spastic paraplegia v3.11 SPTAN1 Achchuthan Shanmugasundram changed review comment from: Comment on classification: This gene should be rated Green as there are several unrelated cases (>3 cases identified with different variants) reported with childhood/ early-onset spastic paraplegia.

Two of three patients identified with SPTAN1 variants in PMID:20493457 were reported with spastic quadriplegia whose age of onset were three years and seven years, while it has also been reported in one year old male from PMID:22656320. Out of 22 patients from 14 families identified with SPTAN1 variants in PMID:35150594, fifteen patients from seven families displaying p.Arg19Trp variant were reported with hereditary spastic paraplegia with age of onset ranging from congenital to adolescence.
Sources: Literature; to: Comment on classification: This gene should be rated Green as there are several unrelated cases (>3 cases identified with different variants) reported with childhood/ early-onset spastic paraplegia.

Two of three patients identified with SPTAN1 variants in PMID:20493457 were reported with spastic quadriplegia whose age of onset were three years and seven years, while it has also been reported in one year old male from PMID:22656320. Out of 22 patients from 14 families identified with SPTAN1 variants in PMID:35150594, fifteen patients from seven families displaying p.Arg19Trp variant were reported with hereditary spastic paraplegia with age of onset ranging from congenital to adolescence (2 cases with congenital, 11 with childhood and 2 with adolescence-onset).
Sources: Literature
Childhood onset hereditary spastic paraplegia v3.11 SPTAN1 Achchuthan Shanmugasundram gene: SPTAN1 was added
gene: SPTAN1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature
Mode of inheritance for gene: SPTAN1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: SPTAN1 were set to 20493457; 22656320; 35150594
Phenotypes for gene: SPTAN1 were set to Developmental and epileptic encephalopathy 5, OMIM:613477; Cerebellar ataxia, MONDO:0000437; Hereditary spastic paraplegia, MONDO:0019064
Review for gene: SPTAN1 was set to GREEN
Added comment: Comment on classification: This gene should be rated Green as there are several unrelated cases (>3 cases identified with different variants) reported with childhood/ early-onset spastic paraplegia.

Two of three patients identified with SPTAN1 variants in PMID:20493457 were reported with spastic quadriplegia whose age of onset were three years and seven years, while it has also been reported in one year old male from PMID:22656320. Out of 22 patients from 14 families identified with SPTAN1 variants in PMID:35150594, fifteen patients from seven families displaying p.Arg19Trp variant were reported with hereditary spastic paraplegia with age of onset ranging from congenital to adolescence.
Sources: Literature
Childhood onset hereditary spastic paraplegia v3.10 ISCA-46304-Gain Arina Puzriakova Region: ISCA-46304-Gain was added
Region: ISCA-46304-Gain was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review Green,ClinGen
Mode of inheritance for Region: ISCA-46304-Gain was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for Region: ISCA-46304-Gain were set to 22679399; 29141583; 29618507; 32043567
Childhood onset hereditary spastic paraplegia v3.7 TECPR2 Mafalda Gomes Phenotypes for gene: TECPR2 were changed from Spastic paraplegia 49, autosomal recessive, 615031 to Neuropathy, hereditary sensory and autonomic, type IX, with developmental delay, OMIM:615031
Childhood onset hereditary spastic paraplegia v3.2 DDX3X Arina Puzriakova changed review comment from: This gene is associated with a syndromic ID phenotype. A subset (~45%) of affected individuals develop movement disorders. This can comprise progressive spasticity which in some cases forms a presenting feature that is as key as ID, indicating that inclusion of DDX3X on this panel is likely to be beneficial in a diagnostic setting. Therefore, recommending that this gene is rated Green at the next GMS panel update.
Sources: Literature; to: This gene is associated with a syndromic ID phenotype. A subset (~45%) of affected individuals develop a movement disorder. This can comprise progressive spasticity which in some cases forms a presenting feature that is as key as ID, indicating that inclusion of DDX3X on this panel is likely to be beneficial in a diagnostic setting. Therefore, recommending that this gene is rated Green at the next GMS panel update.
Sources: Literature
Childhood onset hereditary spastic paraplegia v3.2 DDX3X Arina Puzriakova gene: DDX3X was added
gene: DDX3X was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature
Q4_22_promote_green tags were added to gene: DDX3X.
Mode of inheritance for gene: DDX3X was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Phenotypes for gene: DDX3X were set to Intellectual developmental disorder, X-linked syndromic, Snijders Blok type, OMIM:300958
Review for gene: DDX3X was set to GREEN
Added comment: This gene is associated with a syndromic ID phenotype. A subset (~45%) of affected individuals develop movement disorders. This can comprise progressive spasticity which in some cases forms a presenting feature that is as key as ID, indicating that inclusion of DDX3X on this panel is likely to be beneficial in a diagnostic setting. Therefore, recommending that this gene is rated Green at the next GMS panel update.
Sources: Literature
Childhood onset hereditary spastic paraplegia v2.153 KDM5C Arina Puzriakova Phenotypes for gene: KDM5C were changed from Intellectual disability; developmental delay; epilepsy; progressive spasticity; Mental retardation, X-linked, syndromic, Claes-Jensen type, 300534; hypothyroidism to Intellectual developmental disorder, X-linked syndromic, Claes-Jensen type, OMIM:300534
Childhood onset hereditary spastic paraplegia v2.151 CTNNB1 Arina Puzriakova gene: CTNNB1 was added
gene: CTNNB1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature
Q4_22_promote_green tags were added to gene: CTNNB1.
Mode of inheritance for gene: CTNNB1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: CTNNB1 were set to 23033978; 24614104; 25326669; 26968164; 27915094; 34321325
Phenotypes for gene: CTNNB1 were set to Neurodevelopmental disorder with spastic diplegia and visual defects, OMIM:615075
Review for gene: CTNNB1 was set to GREEN
Added comment: Childhood-onset spasticity is a key feature of the neurodevelopmental phenotype caused by pathogenic monoallelic variants in the CTNNB1 gene. Over 15 unrelated cases reported in literature, almost all of which developed spasticity which significantly affected ability to walk.
Sources: Literature
Childhood onset hereditary spastic paraplegia v2.149 NRCAM Sarah Leigh gene: NRCAM was added
gene: NRCAM was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature,Expert Review Amber
Q3_22_rating, Q3_22_MOI tags were added to gene: NRCAM.
Mode of inheritance for gene: NRCAM was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NRCAM were set to 35108495
Phenotypes for gene: NRCAM were set to Neurodevelopmental disorder with neuromuscular and skeletal abnormalities, OMIM:619833
Penetrance for gene: NRCAM were set to Complete
Childhood onset hereditary spastic paraplegia v2.147 BLOC1S1 Arina Puzriakova gene: BLOC1S1 was added
gene: BLOC1S1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature
watchlist tags were added to gene: BLOC1S1.
Mode of inheritance for gene: BLOC1S1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BLOC1S1 were set to 33875846
Phenotypes for gene: BLOC1S1 were set to severe intellectual disability; severe global developmental delay; epilepsy
Penetrance for gene: BLOC1S1 were set to unknown
Childhood onset hereditary spastic paraplegia v2.146 NDUFA12 Arina Puzriakova gene: NDUFA12 was added
gene: NDUFA12 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review Amber,PanelApp,South West GLH
Q3_22_rating tags were added to gene: NDUFA12.
Mode of inheritance for gene: NDUFA12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NDUFA12 were set to 21617257; 33715266; 35141356
Phenotypes for gene: NDUFA12 were set to Mitochondrial complex I deficiency, nuclear type 23, OMIM:618244
Childhood onset hereditary spastic paraplegia v2.145 TAF8 Arina Puzriakova gene: TAF8 was added
gene: TAF8 was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature,Expert Review Amber
Q3_22_rating tags were added to gene: TAF8.
Mode of inheritance for gene: TAF8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TAF8 were set to 29648665; 35759269
Phenotypes for gene: TAF8 were set to Neurodevelopmental disorder with severe motor impairment, absent language, cerebral hypomyelination, and brain atrophy, OMIM:619972
Penetrance for gene: TAF8 were set to unknown
Childhood onset hereditary spastic paraplegia v2.143 KPNA3 Eleanor Williams Phenotypes for gene: KPNA3 were changed from Infantile onset spastic paraplegia; developmental delay to autosomal dominant pure spastic paraplegia, MONDO:0015088
Childhood onset hereditary spastic paraplegia v2.140 KPNA3 Eleanor Williams reviewed gene: KPNA3: Rating: GREEN; Mode of pathogenicity: None; Publications: 34564892; Phenotypes: autosomal dominant pure spastic paraplegia, MONDO:0015088; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Childhood onset hereditary spastic paraplegia v2.140 NSRP1 Arina Puzriakova gene: NSRP1 was added
gene: NSRP1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review Amber,Literature
Q3_22_rating tags were added to gene: NSRP1.
Mode of inheritance for gene: NSRP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NSRP1 were set to 34385670
Phenotypes for gene: NSRP1 were set to NSRP1-associated developmental delay, epilepsy and microcephaly
Childhood onset hereditary spastic paraplegia v2.138 TMEM63C Sarah Leigh gene: TMEM63C was added
gene: TMEM63C was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature
Q3_22_rating tags were added to gene: TMEM63C.
Mode of inheritance for gene: TMEM63C was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TMEM63C were set to 35718349
Phenotypes for gene: TMEM63C were set to hereditary spastic paraplegia, MONDO:0019064
Review for gene: TMEM63C was set to GREEN
Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID:35718349 reports four TMEM63C variants in seven individuals from three unrelated families with childhood onset hereditary spastic paraplegia, with mild intellectual disability in some cases. Functional studies in PMID:35718349, reveal a role for TMEM63C in regulating both endoplasmic reticulum and mitochondrial morphologies.
Sources: Literature
Childhood onset hereditary spastic paraplegia v2.135 HSPD1 Arina Puzriakova Added comment: Comment on mode of inheritance: Changed from 'monoallelic' to 'biallelic' as per the review by Zornitza Stark (Australian Genomics) stating that only biallelic variants cause a more severe phenotype including spasticity with onset in childhood.
Childhood onset hereditary spastic paraplegia v2.134 HSPD1 Arina Puzriakova Phenotypes for gene: HSPD1 were changed from Spastic paraplegia 13, autosomal dominant, 605280 to Leukodystrophy, hypomyelinating, 4, OMIM:612233
Childhood onset hereditary spastic paraplegia v2.133 C19orf12 Sarah Leigh Phenotypes for gene: C19orf12 were changed from Spastic paraplegia 43, autosomal recessive, 615043; Neurodegeneration with brain iron accumulation 4, 614298 to ?Spastic paraplegia 43, autosomal recessive, OMIM:615043; Neurodegeneration with brain iron accumulation 4, OMIM: 614298
Childhood onset hereditary spastic paraplegia v2.131 ACER3 Arina Puzriakova gene: ACER3 was added
gene: ACER3 was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature,Expert Review Amber
Q1_22_rating tags were added to gene: ACER3.
Mode of inheritance for gene: ACER3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ACER3 were set to 26792856; 32816236; 34281620
Phenotypes for gene: ACER3 were set to Leukodystrophy, progressive, early childhood-onset, OMIM:617762
Childhood onset hereditary spastic paraplegia v2.122 SPATA5L1 Ivone Leong gene: SPATA5L1 was added
gene: SPATA5L1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review Amber,Literature
Q1_22_rating tags were added to gene: SPATA5L1.
Mode of inheritance for gene: SPATA5L1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPATA5L1 were set to 34626583
Phenotypes for gene: SPATA5L1 were set to Neurodevelopmental disorder with hearing loss and spasticity, OMIM:619616
Childhood onset hereditary spastic paraplegia v2.121 PI4KA Evan Reid commented on gene: PI4KA: This paper supports the idea that mutations in this gene can cause a relatively pure spastic paraplegia (PMID: 34415322 PMCID: PMC8557332 DOI: 10.1093/brain/awab124), which I think would justify inclusion of the gene on the HSP panel.
Childhood onset hereditary spastic paraplegia v2.121 PI4KA Evan Reid reviewed gene: PI4KA: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 34415322; Phenotypes: spastic paraplegia, leukodystrophy, white matter abnromality, seizures, intellectual disability; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v2.120 RNASEH2B Arina Puzriakova Added comment: Comment on list classification: Sufficient evidence of childhood-onset spasticity associated with variants in this gene. Upgraded from Red to Amber but should be promoted to Green at the next GMS panel update.
Childhood onset hereditary spastic paraplegia v2.119 RNASEH2B Arina Puzriakova Phenotypes for gene: RNASEH2B were changed from Aicardi-Goutieres syndrome 2, 610181; spastic paraparesis to Aicardi-Goutieres syndrome 2, OMIM:61018
Childhood onset hereditary spastic paraplegia v2.118 RAB3GAP2 Arina Puzriakova Phenotypes for gene: RAB3GAP2 were changed from spastic paraplegia to Martsolf syndrome 1, OMIM:212720
Childhood onset hereditary spastic paraplegia v2.116 MAPK8IP3 Arina Puzriakova Added comment: Comment on list classification: 18 individuals from 17 families reported with de novo variants in this gene (PMIDs: 30612693; 30945334) of which 8 subjects presented with spasticity, among other features. Overall there is sufficient evidence to promote this gene to Green at the next GMS panel update.
Childhood onset hereditary spastic paraplegia v2.115 IFIH1 Arina Puzriakova Added comment: Comment on list classification: Spasticity can be a prominent feature of Aicardi-Goutières syndrome (OMIM:615846) and has been reported as an early presenting sign in some cases. There has also been a case of spastic paraplegia without other common manifestations such as abnormal brain imaging and impaired cognitive development.

Overall there is value in including IFIH1 on this panel and therefore this gene should be promoted to Green at the next GMS panel update.
Childhood onset hereditary spastic paraplegia v2.113 IBA57 Arina Puzriakova Phenotypes for gene: IBA57 were changed from ?Spastic paraplegia 74, autosomal recessive, 616451 to ?Spastic paraplegia 74, autosomal recessive, OMIM:616451
Childhood onset hereditary spastic paraplegia v2.112 IBA57 Arina Puzriakova changed review comment from: Comment on list classification: No further evidence was emerged since initial curation and clinical review in 2019 and therefore will maintain the Amber gene rating on spasticity panels at this time.; to: Comment on list classification: No further evidence has emerged since initial curation and clinical review in 2019 and therefore will maintain the Amber gene rating on spasticity panels at this time.
Childhood onset hereditary spastic paraplegia v2.112 IBA57 Arina Puzriakova Added comment: Comment on list classification: No further evidence was emerged since initial curation and clinical review in 2019 and therefore will maintain the Amber gene rating on spasticity panels at this time.
Childhood onset hereditary spastic paraplegia v2.110 GPT2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark. There is sufficient evidence to promote this gene to Green at the next GMS panel update. Spastic paraplegia is a frequently reported sign which develops later in the course of disease but is often severe. As this is a prominent feature of the condition there is value in including GPT2 on this panel. This gene is associated with a relevant phenotype in OMIM (OMIM:616281) but is not yet listed in G2P.
Childhood onset hereditary spastic paraplegia v2.109 GPT2 Arina Puzriakova Phenotypes for gene: GPT2 were changed from Mental retardation, autosomal recessive 49 MIM#616281 to Neurodevelopmental disorder with microcephaly and spastic paraplegia, OMIM:616281
Childhood onset hereditary spastic paraplegia v2.108 EXOSC3 Arina Puzriakova Added comment: Comment on list classification: Rating Amber as only two families have been reported to date with early-onset spastic paraplegia associated with biallelic variants in this gene. Other features included variable cognitive impairment and cerebellar atrophy but normal pons.
Childhood onset hereditary spastic paraplegia v2.105 ELOVL1 Arina Puzriakova reviewed gene: ELOVL1: Rating: GREEN; Mode of pathogenicity: None; Publications: 23689133, 29496980, 30487246, 32123819; Phenotypes: Ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic facies, OMIM:618527; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Childhood onset hereditary spastic paraplegia v2.105 ELOVL1 Arina Puzriakova Phenotypes for gene: ELOVL1 were changed from Ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic facies, MIM# 618527 to Ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic facies, OMIM:618527
Childhood onset hereditary spastic paraplegia v2.102 CPT1C Arina Puzriakova Phenotypes for gene: CPT1C were changed from ?Spastic paraplegia 73, autosomal dominant, 616282, AD to Spastic paraplegia 73, autosomal dominant, OMIM:616282
Childhood onset hereditary spastic paraplegia v2.100 AP5Z1 Arina Puzriakova reviewed gene: AP5Z1: Rating: ; Mode of pathogenicity: None; Publications: 24833714, 27606357, 33543803; Phenotypes: Spastic paraplegia 48, autosomal recessive, OMIM:613647; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v2.100 AP5Z1 Arina Puzriakova Phenotypes for gene: AP5Z1 were changed from Spastic paraplegia 48, autosomal recessive, OMIM:613647 to Spastic paraplegia 48, autosomal recessive, OMIM:613647
Childhood onset hereditary spastic paraplegia v2.99 AP5Z1 Arina Puzriakova Phenotypes for gene: AP5Z1 were changed from Spastic Paraplegia, Recessive; Spastic paraplegia 48, autosomal recessive to Spastic paraplegia 48, autosomal recessive, OMIM:613647
Childhood onset hereditary spastic paraplegia v2.98 KIDINS220 Arina Puzriakova Phenotypes for gene: KIDINS220 were changed from Spastic paraplegia, intellectual disability, nystagmus, and obesity, 617296 to Spastic paraplegia, intellectual disability, nystagmus, and obesity, OMIM:617296
Childhood onset hereditary spastic paraplegia v2.87 PI4KA Ivone Leong edited their review of gene: PI4KA: Added comment: After consulting with the Genomics England Clinical Team it was decided that this gene should be added to the Hereditary spastic paraplegia - childhood onset panel with an Amber rating.

Helen Brittain:
"I think the spasticity is likely to be secondary to the CNS findings and therefore might opt for amber at this stage, as it is perhaps unlikely to be clearly relevant to the more typical cohort with isolated spasticity that will be targeted by that panel."; Changed rating: AMBER
Childhood onset hereditary spastic paraplegia v2.87 PI4KA Ivone Leong changed review comment from: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype.

PMID: 25855803. From OMIM: "3 fetuses were all diagnosed in utero with multiple congenital anomalies resulting in the termination of pregnancy between 16 and 34 weeks' gestation. All fetuses had bilateral perisylvian polymicrogyria and cerebellar hypoplasia or dysplasia. One had a small pons. Additional features included severe talipes equinovarus, externally rotated hips, and variable contractures of the limbs or fingers."

PMID:34415322. 10 patients from 10 unrelated families with biallelic varaints in PI4KA. Patients showed a spectrum of severe global neurodevelopmental delay (8/10 moderate to severe ID), hypomyelination, cerebellar hyoplasia (1/10), cerebellar atrophy (5/10), bilateral perisylvian polymicrogyria (1/10), immunological problems (hypogammaglobulinaemia, lymphopaenia, and autoimmune neutorpaenia - 4/10), bowl dysfunction (4/10). Age of onset ranged from newborn to 17 years.

PMID: 34415310. 7 unrelated families. Family 1: Amish. Severe extensive multiple intestinal atresia, IBD and combined immunodeficiency (2/4). Families 3 - 8 all have 1 affected individual, (Turkish, Indian, German and Italian). Global developmental delay (all), ID (severe to mild), cerebellar and/or brainstem anomalies (3/6), spasticity (all), immature gyral pattern (1/6), leukodystrophy (6/6), multiple intestinal atresia (0/6), IBD (3/6), combined immunodeficiency (2/6). Early age of onset.; to: This gene is associated with a relevant phenotype in OMIM and Gene2Phenotype.

PMID: 25855803. From OMIM: "3 fetuses were all diagnosed in utero with multiple congenital anomalies resulting in the termination of pregnancy between 16 and 34 weeks' gestation. All fetuses had bilateral perisylvian polymicrogyria and cerebellar hypoplasia or dysplasia. One had a small pons. Additional features included severe talipes equinovarus, externally rotated hips, and variable contractures of the limbs or fingers."

PMID:34415322. 10 patients from 10 unrelated families with biallelic varaints in PI4KA. Patients showed a spectrum of severe global neurodevelopmental delay (8/10 moderate to severe ID), hypomyelination, cerebellar hyoplasia (1/10), cerebellar atrophy (5/10), bilateral perisylvian polymicrogyria (1/10), immunological problems (hypogammaglobulinaemia, lymphopaenia, and autoimmune neutorpaenia - 4/10), bowl dysfunction (4/10). Age of onset ranged from newborn to 17 years.

PMID: 34415310. 7 unrelated families. Family 1: Amish. Severe extensive multiple intestinal atresia, IBD and combined immunodeficiency (2/4). Families 3 - 8 all have 1 affected individual, (Turkish, Indian, German and Italian). Global developmental delay (all), ID (severe to mild), cerebellar and/or brainstem anomalies (3/6), spasticity (all), immature gyral pattern (1/6), leukodystrophy (6/6), multiple intestinal atresia (0/6), IBD (3/6), combined immunodeficiency (2/6). Early age of onset.
Childhood onset hereditary spastic paraplegia v2.87 PI4KA Ivone Leong gene: PI4KA was added
gene: PI4KA was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review Amber
Q3_21_rating tags were added to gene: PI4KA.
Mode of inheritance for gene: PI4KA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PI4KA were set to 25855803; 34415322; 34415310
Phenotypes for gene: PI4KA were set to Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis, OMIM:616531
Childhood onset hereditary spastic paraplegia v2.85 GJA1 Arina Puzriakova commented on gene: GJA1: Regarding inclusion of this gene on the childhood-onset panel, Helen Brittain (Genomics England Clinical Team) suggests - "As you say, there are sufficient cases albeit seemingly edge cases. I would be inclined to include it on the paediatric panel, as they are outlining the spasticity as a feature of ODDD, rather than a separate clinical entity. ODDD would be a paediatric-age diagnosis to make and the fact that it is clinically recognisable could aid in interpretation of variants of uncertain significance"
Childhood onset hereditary spastic paraplegia v2.85 GJA1 Arina Puzriakova Entity copied from Hereditary spastic paraplegia - adult onset v1.73
Childhood onset hereditary spastic paraplegia v2.85 GJA1 Arina Puzriakova gene: GJA1 was added
gene: GJA1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list,Expert Review Amber
Q3_21_rating tags were added to gene: GJA1.
Mode of inheritance for gene: GJA1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: GJA1 were set to 18660473; 22214631; 29927410; 31023660; 33190326; 33612672
Phenotypes for gene: GJA1 were set to Oculodentodigital dysplasia, OMIM:164200; Spastic paraplegia
Childhood onset hereditary spastic paraplegia v2.84 KPNA3 Dmitrijs Rots gene: KPNA3 was added
gene: KPNA3 was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature
Mode of inheritance for gene: KPNA3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KPNA3 were set to PMID: 34564892
Phenotypes for gene: KPNA3 were set to Infantile onset spastic paraplegia; developmental delay
Penetrance for gene: KPNA3 were set to unknown
Mode of pathogenicity for gene: KPNA3 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Review for gene: KPNA3 was set to GREEN
Added comment: 8 reported families with de novo missense variants, that segregates with pure HSP with infantile onset and some functional data PMID: 34564892
Sources: Literature
Childhood onset hereditary spastic paraplegia v2.84 BSCL2 Arina Puzriakova Phenotypes for gene: BSCL2 were changed from Silver spastic paraplegia syndrome, OMIM:270685 to Silver spastic paraplegia syndrome, OMIM:270685; Neuropathy, distal hereditary motor, type VC, OMIM:619112
Childhood onset hereditary spastic paraplegia v2.83 ABHD16A Ivone Leong gene: ABHD16A was added
gene: ABHD16A was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review Amber,Literature
Q4_21_rating tags were added to gene: ABHD16A.
Mode of inheritance for gene: ABHD16A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ABHD16A were set to 34587489
Phenotypes for gene: ABHD16A were set to Spastic paraplegia; Intellectual disability
Childhood onset hereditary spastic paraplegia v2.82 SLC25A15 Arina Puzriakova changed review comment from: Comment on list classification: New gene added by Zornitza Stark. There is enough evidence to support a gene-disease association. Spasticity can be a predominant presenting feature, and inclusion on the adult onset panel would ensure later onset, as well as edge cases are identified. SLC25A15 should be promoted to Green at the next GMS panel update.; to: Comment on list classification: New gene added by Zornitza Stark. There is enough evidence to support a gene-disease association. Spasticity can be a predominant presenting feature, particularly in early-onset cases. SLC25A15 should be promoted to Green at the next GMS panel update.
Childhood onset hereditary spastic paraplegia v2.82 SLC25A15 Arina Puzriakova Entity copied from Hereditary spastic paraplegia - adult onset v1.68
Childhood onset hereditary spastic paraplegia v2.82 SLC25A15 Arina Puzriakova gene: SLC25A15 was added
gene: SLC25A15 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list,Expert Review Amber
Q3_21_rating tags were added to gene: SLC25A15.
Mode of inheritance for gene: SLC25A15 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC25A15 were set to 11355015; 16376511; 18978333; 22465082; 28592010; 33314525
Phenotypes for gene: SLC25A15 were set to Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome, OMIM:238970
Childhood onset hereditary spastic paraplegia v2.80 GALC Arina Puzriakova gene: GALC was added
gene: GALC was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature
Q3_21_rating tags were added to gene: GALC.
Mode of inheritance for gene: GALC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GALC were set to 20886637; 21070211; 26396125; 28547031; 30089515; 31185936
Phenotypes for gene: GALC were set to Krabbe disease OMIM:245200
Review for gene: GALC was set to GREEN
Added comment: Biallelic variants in GALC are associated with Krabbe disease (MIM# 245200). Most patients present within the first 6 months of life with extreme irritability, spasticity, and developmental delay. A subset of cases also have later onset, including onset in the juvenile and adolescence period - all of which are relevant to this panel.
Sources: Literature
Childhood onset hereditary spastic paraplegia v2.79 CHP1 Arina Puzriakova gene: CHP1 was added
gene: CHP1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review Amber,Literature
watchlist tags were added to gene: CHP1.
Mode of inheritance for gene: CHP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CHP1 were set to 23904602; 29379881; 32787936
Phenotypes for gene: CHP1 were set to Spastic ataxia 9, autosomal recessive, OMIM:618438
Childhood onset hereditary spastic paraplegia v2.78 ALDH3A2 Arina Puzriakova Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). Childhood-onset spastic paraparesis is a feature of the condition associated with biallelic variants in this gene (MIM# 270200). There are sufficient unrelated cases (>3) to rate as Green at the next GMS panel update.
Childhood onset hereditary spastic paraplegia v2.73 L1CAM Arina Puzriakova Phenotypes for gene: L1CAM were changed from Hereditary spastic paraplegia; X-linked hydrocephalus, MASA syndrome, 303350 to CRASH syndrome, OMIM:303350; MASA syndrome, OMIM:303350; Hydrocephalus due to aqueductal stenosis, OMIM:307000; Hydrocephalus with congential idiopathic intestinal pseudoobstruction, OMIM:307000; Hydrocephalus with Hirschsprung disease, OMIM:307000
Childhood onset hereditary spastic paraplegia v2.72 C12orf65 Arina Puzriakova Phenotypes for gene: C12orf65 were changed from Spastic paraplegia 55, autosomal recessive, 615035; optic atrophy and spasticity, tibial muscle weakness and atrophy, peripheral neuropathy; Combined oxidative phosphorylation deficiency 7, 613559 to Spastic paraplegia 55, autosomal recessive, OMIM:615035
Childhood onset hereditary spastic paraplegia v2.71 WDR45B Arina Puzriakova Phenotypes for gene: WDR45B were changed from profound developmental delay, early-onset refractory epilepsy, progressive spastic quadriplegia and contractures, and brain malformations.; Neurodevelopmental disorder with spastic quadriplegia and brain abnormalities with or without seizures, 617977 to Neurodevelopmental disorder with spastic quadriplegia and brain abnormalities with or without seizures, OMIM:617977
Childhood onset hereditary spastic paraplegia v2.70 TFG Arina Puzriakova Phenotypes for gene: TFG were changed from ?Spastic paraplegia 57, autosomal recessive, 615658, AR; Hereditary motor and sensory neuropathy, Okinawa type, 604484, AD to Spastic paraplegia 57, autosomal recessive, OMIM:615658
Childhood onset hereditary spastic paraplegia v2.68 TFG Arina Puzriakova Added comment: Comment on mode of inheritance: MOI should be changed from 'both mono- and biallelic' to 'biallelic' only at the next GMS panel update.

Monoallelic variants are associated with an adult onset neuropathy (MIM# 604484), a disorder that does not include spasticity and is therefore not relevant to this panel.
Childhood onset hereditary spastic paraplegia v2.66 SPART Arina Puzriakova Phenotypes for gene: SPART were changed from Troyer syndrome, 275900; Spastic paraplegia 20 to Troyer syndrome, OMIM:275900; Spastic paraplegia 20
Childhood onset hereditary spastic paraplegia v2.61 NKX6-2 Arina Puzriakova Phenotypes for gene: NKX6-2 were changed from Spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy, 617560 to Spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy, 617560
Childhood onset hereditary spastic paraplegia v2.59 KIF1C Arina Puzriakova Phenotypes for gene: KIF1C were changed from Spastic ataxia 2, autosomal recessive, 611302 to Spastic ataxia 2, autosomal recessive, OMIM:611302
Childhood onset hereditary spastic paraplegia v2.54 ENTPD1 Arina Puzriakova Phenotypes for gene: ENTPD1 were changed from Spasticparaplegia 64, 615683 to Spastic paraplegia 64, autosomal recessive, OMIM:615683
Childhood onset hereditary spastic paraplegia v2.53 ARG1 Arina Puzriakova Phenotypes for gene: ARG1 were changed from Progressive spastic tetraplegia; Argininaemia, 207800 to Argininemia, OMIM:207800
Childhood onset hereditary spastic paraplegia v2.52 ALS2 Arina Puzriakova Phenotypes for gene: ALS2 were changed from Spastic paralysis, infantile onset ascending,autosomal recessive, 607225; Primary lateral sclerosis, juvenile, autosomal recessive, 606353; Amyotrophic lateral sclerosis 2, autosomal recessive, juvenile, 205100 to Amyotrophic lateral sclerosis 2, juvenile, OMIM:205100; Primary lateral sclerosis, juvenile, OMIM:606353; Spastic paralysis, infantile onset ascending, OMIM:607225
Childhood onset hereditary spastic paraplegia v2.48 KIF1A Arina Puzriakova Phenotypes for gene: KIF1A were changed from Spastic paraplegia 30, autosomal recessive, 610357; Mental retardation, autosomal dominant 9, 614255, AD; Neuropathy, hereditary sensory, type IIC, 614213 to Spastic paraplegia 30, autosomal dominant, OMIM:610357; Spastic paraplegia 30, autosomal recessive, OMIM:610357; NESCAV syndrome, OMIM:614255
Childhood onset hereditary spastic paraplegia v2.47 WASHC5 Ivone Leong Phenotypes for gene: WASHC5 were changed from Spastic paraplegia 8, autosomal dominant, 603563 to Spastic paraplegia 8, autosomal dominant, OMIM:603563
Childhood onset hereditary spastic paraplegia v2.46 BSCL2 Arina Puzriakova Phenotypes for gene: BSCL2 were changed from Silver spastic paraplegia syndrome, 270685 to Silver spastic paraplegia syndrome, OMIM:270685
Childhood onset hereditary spastic paraplegia v2.45 ATAD3A Arina Puzriakova Phenotypes for gene: ATAD3A were changed from Harel-Yoon syndrome, 617183 to Harel-Yoon syndrome, OMIM:617183; Spastic paraplegia
Childhood onset hereditary spastic paraplegia v2.44 ATAD3A Arina Puzriakova reviewed gene: ATAD3A: Rating: ; Mode of pathogenicity: None; Publications: 28158749, 27640307, 33845882; Phenotypes: Harel-Yoon syndrome, OMIM:617183, Spastic paraplegia; Mode of inheritance: None
Childhood onset hereditary spastic paraplegia v2.44 ARL6IP1 Eleanor Williams Phenotypes for gene: ARL6IP1 were changed from Spastic paraplegia to Spastic paraplegia 61, autosomal recessive, OMIM:615685; hereditary spastic paraplegia 61, MONDO:0014304
Childhood onset hereditary spastic paraplegia v2.41 ARL6IP1 Eleanor Williams reviewed gene: ARL6IP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24482476, 31272422, 30980493, 28471035; Phenotypes: Spastic paraplegia 61, autosomal recessive, OMIM:615685; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v2.41 FAR1 Arina Puzriakova changed review comment from: Associated with relevant phenotype in OMIM and has a 'confirmed' disease confidence rating for 'Severe intellectual disability, epilepsy, and cataracts' in Gene2Phenotype.

Both biallelic and monoallelic variants have been linked to disease; both supported by functional data but showing distinct biochemical phenotypes. Spastic quadriparesis or spasticity were reported in 5/5 patients (4 families - 2 with same founder variant) with biallelic variants (PMIDs: 25439727; 30561787) and spastic paraparesis was a feature in 12/12 patients with heterozygous de novo variants (PMID: 33239752). Paediatric onset.
Sources: Literature; to: Associated with relevant phenotype in OMIM and has a 'confirmed' disease confidence rating for 'Severe intellectual disability, epilepsy, and cataracts' in Gene2Phenotype.

Both biallelic and monoallelic variants have been linked to disease; both supported by functional data but showing distinct biochemical phenotypes. Spastic quadriparesis or spasticity were reported in 5/5 patients (4 families - 2 with same founder variant) with biallelic variants (PMIDs: 25439727; 30561787) and spastic paraparesis was a feature in 12/12 patients with heterozygous de novo variants affecting the Arg480 residue (PMID: 33239752). Paediatric onset.
Sources: Literature
Childhood onset hereditary spastic paraplegia v2.41 BCAS3 Arina Puzriakova gene: BCAS3 was added
gene: BCAS3 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review Amber,Literature
Q2_21_rating tags were added to gene: BCAS3.
Mode of inheritance for gene: BCAS3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: BCAS3 were set to 34022130
Phenotypes for gene: BCAS3 were set to Syndromic neurodevelopmental disorder
Childhood onset hereditary spastic paraplegia v2.40 CYP7B1 Arina Puzriakova Phenotypes for gene: CYP7B1 were changed from Spastic paraplegia 5A, autosomal recessive, 270800 to Spastic paraplegia 5A, autosomal recessive, OMIM:270800
Childhood onset hereditary spastic paraplegia v2.39 HIKESHI Ivone Leong gene: HIKESHI was added
gene: HIKESHI was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review Amber,Expert list
Mode of inheritance for gene: HIKESHI was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HIKESHI were set to 26545878; 28000699
Phenotypes for gene: HIKESHI were set to Leukodystrophy, hypomyelinating, 13, OMIM:616881
Childhood onset hereditary spastic paraplegia v2.37 GLRX5 Ivone Leong Phenotypes for gene: GLRX5 were changed from Spasticity, childhood-onset, with hyperglycinemia 616859 to Spasticity, childhood-onset, with hyperglycinemia, OMIM:616859
Childhood onset hereditary spastic paraplegia v2.36 POLR3K Ivone Leong gene: POLR3K was added
gene: POLR3K was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature,Expert Review Amber
watchlist, founder-effect tags were added to gene: POLR3K.
Mode of inheritance for gene: POLR3K was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLR3K were set to 30584594; 33659930
Phenotypes for gene: POLR3K were set to Leukodystrophy, hypomyelinating, 21, OMIM:619310
Childhood onset hereditary spastic paraplegia v2.35 AFG3L2 Sarah Leigh reviewed gene: AFG3L2: Rating: ; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic ataxia 5, autosomal recessive OMIM:614487, spastic ataxia 5 MONDO:0013776, Spinocerebellar ataxia 28 OMIM:610246, spinocerebellar ataxia type 28 MONDO:0012450; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v2.35 AFG3L2 Sarah Leigh Phenotypes for gene: AFG3L2 were changed from Ataxia, spastic, 5, autosomal recessive; Spastic ataxia 5, autosomal recessive, 614487 to Spastic ataxia 5, autosomal recessive OMIM:614487; spastic ataxia 5 MONDO:0013776; Spinocerebellar ataxia 28 OMIM:610246; spinocerebellar ataxia type 28 MONDO:0012450
Childhood onset hereditary spastic paraplegia v2.32 UCHL1 Arina Puzriakova Phenotypes for gene: UCHL1 were changed from Spastic paraplegia 79, autosomal recessive, 615491, AR to Spastic paraplegia 79, autosomal recessive, OMIM:615491
Childhood onset hereditary spastic paraplegia v2.29 FAR1 Arina Puzriakova gene: FAR1 was added
gene: FAR1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature
Q2_21_rating tags were added to gene: FAR1.
Mode of inheritance for gene: FAR1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: FAR1 were set to 25439727; 30561787; 33239752
Phenotypes for gene: FAR1 were set to Peroxisomal fatty acyl-CoA reductase 1 disorder, OMIM:616154
Review for gene: FAR1 was set to GREEN
Added comment: Associated with relevant phenotype in OMIM and has a 'confirmed' disease confidence rating for 'Severe intellectual disability, epilepsy, and cataracts' in Gene2Phenotype.

Both biallelic and monoallelic variants have been linked to disease; both supported by functional data but showing distinct biochemical phenotypes. Spastic quadriparesis or spasticity were reported in 5/5 patients (4 families - 2 with same founder variant) with biallelic variants (PMIDs: 25439727; 30561787) and spastic paraparesis was a feature in 12/12 patients with heterozygous de novo variants (PMID: 33239752). Paediatric onset.
Sources: Literature
Childhood onset hereditary spastic paraplegia v2.28 HPDL Cristina Dias reviewed gene: HPDL: Rating: GREEN; Mode of pathogenicity: None; Publications: PMID: 32707086, 33188300; Phenotypes: microcephaly, spastic paraplegia, seizures, demyelinating neuropathy, regression, developmental delay, chronic progression, movement disorder; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v2.28 HPDL Arina Puzriakova Phenotypes for gene: HPDL were changed from spastic paraplegia; spastic tetraplegia; microcephaly; brain atrophy; epilepsy; severe intellectual and motor disability to Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities, OMIM:619026; Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities, MONDO:0033613; Spastic paraplegia 83, autosomal recessive, OMIM:619027; Spastic paraplegia 83, autosomal recessive, MONDO:0033614
Childhood onset hereditary spastic paraplegia v2.25 HPDL Arina Puzriakova reviewed gene: HPDL: Rating: GREEN; Mode of pathogenicity: None; Publications: 32707086, 33188300; Phenotypes: Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities, OMIM:619026, Neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities, MONDO:0033613, Spastic paraplegia 83, autosomal recessive, OMIM:619027, Spastic paraplegia 83, autosomal recessive, MONDO:0033614; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v2.25 HPDL Evan Reid gene: HPDL was added
gene: HPDL was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature
Mode of inheritance for gene: HPDL was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HPDL were set to PMID: 32707086; 33188300
Phenotypes for gene: HPDL were set to spastic paraplegia; spastic tetraplegia; microcephaly; brain atrophy; epilepsy; severe intellectual and motor disability
Penetrance for gene: HPDL were set to Complete
Review for gene: HPDL was set to GREEN
Added comment: Newly identified gene that can give a phenotype ranging from infantile epileptic encephalopathy to juvenile onset progressive spastic paraplegia.
Sources: Literature
Childhood onset hereditary spastic paraplegia v2.25 RNU7-1 Arina Puzriakova Added comment: Comment on list classification: Rating Amber but should be promoted to Green at the next GMS panel update (added 'for-review' tag) - spasticity (with or without dystonia) was a feature in all 11 families reported with biallelic variants in this gene (PMID:33230297)
Childhood onset hereditary spastic paraplegia v2.24 RNU7-1 Arina Puzriakova gene: RNU7-1 was added
gene: RNU7-1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature
for-review tags were added to gene: RNU7-1.
Mode of inheritance for gene: RNU7-1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNU7-1 were set to 33230297
Phenotypes for gene: RNU7-1 were set to Type I interferonopathy; Aicardi-Goutières syndrome
Review for gene: RNU7-1 was set to GREEN
Added comment: Not associated with any phenotype in OMIM or Gene2Phenotype.

- PMID: 33230297 (2020) - 16 individuals from 11 families with biallelic variants in the RNU7-1 gene. Clinical features were typical of Aicardi–Goutières syndrome, including spasticity, dystonia, epilepsy, peripheral neuropathy, brain calcification, mild skin involvement and delayed psychomotor development. Upregulated interferon signalling was detected in patient blood and fibroblasts. 4/12 variants were observed in 2 or more families - several from different ethnic backgrounds. 8 variants are recorded in gnomAD but at a frequency of ≤0.005, and no biallelic variants were identified in control populations. Some functional data showing a disturbance of histone RNA processing in patient-derived compared to control fibroblasts.
Sources: Literature
Childhood onset hereditary spastic paraplegia v2.23 AP4E1 Arina Puzriakova Phenotypes for gene: AP4E1 were changed from Spastic paraplegia 51, autosomal recessive, 613744 to Spastic paraplegia 51, autosomal recessive, OMIM:613744; Hereditary spastic paraplegia 51, MONDO:0013401
Childhood onset hereditary spastic paraplegia v2.22 AP4B1 Arina Puzriakova Phenotypes for gene: AP4B1 were changed from Spastic paraplegia 47, autosomal recessive, 614066 to Spastic paraplegia 47, autosomal recessive, OMIM:614066; Hereditary spastic paraplegia 47, MONDO:0013551
Childhood onset hereditary spastic paraplegia v2.20 STN1 Sarah Leigh gene: STN1 was added
gene: STN1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature
for-review tags were added to gene: STN1.
Mode of inheritance for gene: STN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: STN1 were set to 27432940; 32627942
Phenotypes for gene: STN1 were set to Cerebroretinal microangiopathy with calcifications and cysts 2 OMIM:617341
Review for gene: STN1 was set to GREEN
Added comment: Comments from Zornitza Stark (Australian Genomics) Three individuals from unrelated families described with a multisystem disorder characterized by premature aging, pancytopaenia, hypocellular bone marrow, osteopenia, liver fibrosis, and vascular telangiectasia resulting in gastrointestinal bleeding, as well as intracranial calcifications and leukodystrophy, resulting in spasticity, ataxia, or dystonia. Gene belongs on multiple panels.
Sources: Literature
Childhood onset hereditary spastic paraplegia v2.19 ALK Zornitza Stark gene: ALK was added
gene: ALK was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature
Mode of inheritance for gene: ALK was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ALK were set to 32989326
Phenotypes for gene: ALK were set to Spastic-dystonic diplegia
Review for gene: ALK was set to AMBER
Added comment: Variants in this gene are linked to susceptibility to neuroblastoma.

PMID: 32989326 - Large cohort study of cerebral palsy cases identified two de novo variants in two patients with spastic diplegia with mild tremor, scattered subcortical hyperintensities and an atrial septal defect; and spastic-dystonic diplegia, white matter abnormalities and epilepsy, respectively, with no evidence of neuroblastoma in either patient.
Sources: Literature
Childhood onset hereditary spastic paraplegia v2.19 RHOB Zornitza Stark gene: RHOB was added
gene: RHOB was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature
Mode of inheritance for gene: RHOB was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RHOB were set to 32989326
Phenotypes for gene: RHOB were set to Cerebral palsy
Review for gene: RHOB was set to AMBER
Added comment: Recurrent de novo missense variant reported in 2 unrelated families from a 'cerebral palsy' cohort with supporting functional studies.
Sources: Literature
Childhood onset hereditary spastic paraplegia v2.15 WASHC5 Zornitza Stark reviewed gene: WASHC5: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Spastic paraplegia 8, autosomal dominant, 603563; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood onset hereditary spastic paraplegia v2.15 TECPR2 Zornitza Stark reviewed gene: TECPR2: Rating: GREEN; Mode of pathogenicity: None; Publications: 23176824, 26542466; Phenotypes: Spastic paraplegia 49, autosomal recessive, 615031, Autonomic-sensory neuropathy; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Childhood onset hereditary spastic paraplegia v2.15 RNF170 Zornitza Stark gene: RNF170 was added
gene: RNF170 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list
Mode of inheritance for gene: RNF170 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNF170 were set to 31636353
Phenotypes for gene: RNF170 were set to Hereditary spastic paraplegia
Review for gene: RNF170 was set to GREEN
Added comment: Four families reported with a complicated HSP phenotype.
Sources: Expert list
Childhood onset hereditary spastic paraplegia v2.15 MAPK8IP3 Zornitza Stark gene: MAPK8IP3 was added
gene: MAPK8IP3 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list
Mode of inheritance for gene: MAPK8IP3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: MAPK8IP3 were set to 30612693; 30945334
Phenotypes for gene: MAPK8IP3 were set to Neurodevelopmental disorder with or without variable brain abnormalities, MIM# 618443
Review for gene: MAPK8IP3 was set to GREEN
gene: MAPK8IP3 was marked as current diagnostic
Added comment: PMID: 30612693 - 13 unrelated children patients with de novo variants, supported by functional studies. Patients have developmental delay (13/13), spasticity (4/13), ataxia (2/13), unstable gait (1/13), microcephaly (3/13), generalized seizures (3/13). No signs of regression, but cerebellar atrophy (3/12), thin corpus callosum (4/10), perisylvian polymicrogyria (2/12), white matter loss (4/12) was noted

PMID: 30945334 - 5 child patients (4 families) with spastic diplegia (4/5), ID (5/5), epilepsy (2/5) and cerebellar atrophy (5/5), corpus callosum hypoplasia (5/5).

Overall 8/18 individuals with spasticity.
Sources: Expert list
Childhood onset hereditary spastic paraplegia v2.15 MAG Zornitza Stark reviewed gene: MAG: Rating: GREEN; Mode of pathogenicity: None; Publications: 24482476, 26179919, 31402626, 32629324; Phenotypes: Spastic paraplegia 75, autosomal recessive, MIM# 616680; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Childhood onset hereditary spastic paraplegia v2.15 KLC2 Zornitza Stark gene: KLC2 was added
gene: KLC2 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list
Mode of inheritance for gene: KLC2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: KLC2 were set to Spastic paraplegia, optic atrophy, and neuropathy, MIM#609541
Review for gene: KLC2 was set to GREEN
gene: KLC2 was marked as current diagnostic
Added comment: In 73 Brazilian patients and 2 sibs of Egyptian descent with SPOAN, a homozygous 216-bp deletion in the noncoding upstream region of the KLC2 gene was identified. Gene is associated with disease, however deletion may not be tractable by all testing methods and/or this association may be better defined as a CNV.
Sources: Expert list
Childhood onset hereditary spastic paraplegia v2.15 IFIH1 Zornitza Stark gene: IFIH1 was added
gene: IFIH1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list
Mode of inheritance for gene: IFIH1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: IFIH1 were set to 25243380; 31427910; 24686847; 24995871
Phenotypes for gene: IFIH1 were set to Aicardi-Goutieres syndrome 7 MIM#615846
Review for gene: IFIH1 was set to GREEN
Added comment: At least four cases reported with spastic paraparesis as a feature of the condition.
Sources: Expert list
Childhood onset hereditary spastic paraplegia v2.15 IBA57 Zornitza Stark reviewed gene: IBA57: Rating: GREEN; Mode of pathogenicity: None; Publications: 25609768, 30258207; Phenotypes: Spastic paraplegia 74, autosomal recessive MIM#616451; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Childhood onset hereditary spastic paraplegia v2.15 HSPD1 Zornitza Stark reviewed gene: HSPD1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Leukodystrophy, hypomyelinating, 4, MIM# 612233, Spastic paraplegia 13, autosomal dominant, MIM# 605280; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Childhood onset hereditary spastic paraplegia v2.15 GPT2 Zornitza Stark gene: GPT2 was added
gene: GPT2 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list
Mode of inheritance for gene: GPT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GPT2 were set to 29882329; 31471722; 27601654
Phenotypes for gene: GPT2 were set to Mental retardation, autosomal recessive 49 MIM#616281
Review for gene: GPT2 was set to GREEN
gene: GPT2 was marked as current diagnostic
Added comment: Paediatric onset spastic paraglegia is a prominent feature of the condition, >3 unrelated families reported.
Sources: Expert list
Childhood onset hereditary spastic paraplegia v2.15 GLRX5 Zornitza Stark gene: GLRX5 was added
gene: GLRX5 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list
Mode of inheritance for gene: GLRX5 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GLRX5 were set to 24334290; 30770271
Phenotypes for gene: GLRX5 were set to Spasticity, childhood-onset, with hyperglycinemia 616859
Review for gene: GLRX5 was set to GREEN
gene: GLRX5 was marked as current diagnostic
Added comment: Spasticity is a key presenting feature of this condition.
Sources: Expert list
Childhood onset hereditary spastic paraplegia v2.15 EXOSC3 Zornitza Stark gene: EXOSC3 was added
gene: EXOSC3 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list
Mode of inheritance for gene: EXOSC3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EXOSC3 were set to 25149867; 23975261
Phenotypes for gene: EXOSC3 were set to Complicated hereditary spastic paraplegia
Review for gene: EXOSC3 was set to AMBER
Added comment: Two families with a complicated HSP phenotype.
Sources: Expert list
Childhood onset hereditary spastic paraplegia v2.15 ELOVL1 Zornitza Stark gene: ELOVL1 was added
gene: ELOVL1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list
Mode of inheritance for gene: ELOVL1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: ELOVL1 were set to 29496980; 32123819; 30487246
Phenotypes for gene: ELOVL1 were set to Ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic facies, MIM# 618527
Review for gene: ELOVL1 was set to GREEN
gene: ELOVL1 was marked as current diagnostic
Added comment: Ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic features (IKSHD) is characterized by epidermal hyperproliferation and increased keratinization, resulting in ichthyosis; hypomyelination of central white matter, causing spastic paraplegia and central nystagmus; and optic atrophy, resulting in reduction of peripheral vision and visual acuity. Affected individuals have mild facial dysmorphism.

Same two individuals reported in two publications. Both had the same variant, p.S165F, which arose de novo, suggesting the residue is important in pathogenesis. Mouse model.
Sources: Expert list
Childhood onset hereditary spastic paraplegia v2.15 CPT1C Zornitza Stark reviewed gene: CPT1C: Rating: RED; Mode of pathogenicity: None; Publications: 25751282; Phenotypes: Spastic paraplegia 73, autosomal dominant, 616282; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Childhood onset hereditary spastic paraplegia v2.15 AP5Z1 Zornitza Stark reviewed gene: AP5Z1: Rating: AMBER; Mode of pathogenicity: None; Publications: 26085577; Phenotypes: Spastic paraplegia 48, autosomal recessive, MIM# 613647; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v2.15 ALDH3A2 Zornitza Stark gene: ALDH3A2 was added
gene: ALDH3A2 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list
Mode of inheritance for gene: ALDH3A2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALDH3A2 were set to 8528251; 29704247
Phenotypes for gene: ALDH3A2 were set to Sjogren-Larsson syndrome, MIM#270200
Review for gene: ALDH3A2 was set to GREEN
Added comment: Early-onset spastic paraparesis is a feature of the condition. >3 families reported with biallelic variants.
Sources: Expert list
Childhood onset hereditary spastic paraplegia v2.15 ATAD3A Ivone Leong gene: ATAD3A was added
gene: ATAD3A was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature
Mode of inheritance for gene: ATAD3A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ATAD3A were set to 28158749
Phenotypes for gene: ATAD3A were set to Harel-Yoon syndrome, 617183
Review for gene: ATAD3A was set to RED
Added comment: Added as a Red gene based on the available literature. There is only one case. PMID: 28158749 describes a family with monoallelic variant (c.1064 G>A, G355D) where affected mother and son do not have optic atrophy nor HCM but have hereditary spastic paraplegia.
Sources: Literature
Childhood onset hereditary spastic paraplegia v2.13 SARS2 Sarah Leigh gene: SARS2 was added
gene: SARS2 was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature
Mode of inheritance for gene: SARS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SARS2 were set to 21255763; 24034276; 27279129
Phenotypes for gene: SARS2 were set to Hyperuricemia, pulmonary hypertension, renal failure, and alkalosis 613845; Progressive Spastic Paresis
Review for gene: SARS2 was set to AMBER
Added comment: PMID 27279129 reports a child with progressive spastic paresis with a homozygous splicing variant (c.1347G>A (NM_017827.3)), which was shown in vitro to result in retention of intron 14 and premature chain termination, leading to diminished levels of the synthetase in patient's fibroblasts.
Sources: Literature
Childhood onset hereditary spastic paraplegia v2.12 ARL6IP1 Zornitza Stark reviewed gene: ARL6IP1: Rating: GREEN; Mode of pathogenicity: None; Publications: 24482476, 31272422, 30980493, 28471035; Phenotypes: Spastic paraplegia 61, autosomal recessive, MIM#615685; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal; Current diagnostic: yes
Childhood onset hereditary spastic paraplegia v2.11 PCYT2 Rebecca Foulger gene: PCYT2 was added
gene: PCYT2 was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature
Mode of inheritance for gene: PCYT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PCYT2 were set to 31637422
Phenotypes for gene: PCYT2 were set to Spastic paraplegia 82, autosomal recessive, 618770
Added comment: PMID:31637422. In 5 patients from 4 unrelated families with autosomal recessive spastic paraplegia-82 (MIM:618770), Vaz et al. (2019) identified homozygous or compound heterozygous mutations in the PCYT2 gene. The variants segregated with the disorder in all families. Functional studies showed reduced (not absent) PYCT2 activity.
Sources: Literature
Childhood onset hereditary spastic paraplegia v2.6 Ellen McDonagh List of related panels changed from Childhood onset hereditary spastic paraplegia; Childhood onset hereditary spastic paraplegia; R61 to Childhood onset hereditary spastic paraplegia; R61
Childhood onset hereditary spastic paraplegia v2.5 Ellen McDonagh List of related panels changed from Childhood onset hereditary spastic paraplegia; R61 to Childhood onset hereditary spastic paraplegia; Childhood onset hereditary spastic paraplegia; R61
Childhood onset hereditary spastic paraplegia v2.3 RNASEH2B Louise Daugherty Phenotypes for gene: RNASEH2B were changed from hereditary spastic paraparesis to Aicardi-Goutieres syndrome 2, 610181; spastic paraparesis
Childhood onset hereditary spastic paraplegia v2.2 RNASEH2B Louise Daugherty Added comment: Comment on list classification: New Green rated gene added by reviewer after panel sign off to V1.0- to be reviewed at next panel update with the Neurology Test Group for GMS. The 100,000 Genomes Project has identified one case and recent publications have reported RNASEH2B variants in homozygous status in patients with spastic paraplegia. Appropriate phenotypes, sufficient cases, and external review comment all support gene-disease association.
Childhood onset hereditary spastic paraplegia v2.0 RNASEH2B Zerin Hyder gene: RNASEH2B was added
gene: RNASEH2B was added to Hereditary spastic paraplegia - childhood onset. Sources: Other
Mode of inheritance for gene: RNASEH2B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: RNASEH2B were set to PMID:30223285, PMID:25243380, PMID:29691679 and PMID:28762473
Phenotypes for gene: RNASEH2B were set to hereditary spastic paraparesis
Penetrance for gene: RNASEH2B were set to unknown
Mode of pathogenicity for gene: RNASEH2B was set to Other
Review for gene: RNASEH2B was set to GREEN
Added comment: Above publications report the association of pure, childhood-onset spastic paraparesis in association with missense recessive variants in RNASEH2B.
Sources: Other
Childhood onset hereditary spastic paraplegia v1.180 Louise Daugherty List of related panels changed from Childhood onset hereditary spastic paraplegia;R61 to Childhood onset hereditary spastic paraplegia; R61
Panel types changed to GMS Rare Disease Virtual; GMS signed-off
Childhood onset hereditary spastic paraplegia v1.179 Louise Daugherty List of related panels changed from Childhood onset hereditary spastic paraplegia to Childhood onset hereditary spastic paraplegia;R61
Childhood onset hereditary spastic paraplegia v1.167 FXN Louise Daugherty gene: FXN was added
gene: FXN was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review
Mode of inheritance for gene: FXN was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FXN were set to 8596916; 9150176; 9737785; 21830088
Phenotypes for gene: FXN were set to Friedreich ataxia, 229300
Review for gene: FXN was set to GREEN
Added comment: New Green gene added and agreed from the GMS Neurology Specialist Test Group Webex on 17th May 2019. Single nucleotide variants can cause the disease (often compound het STR + SNV)
Sources: Expert Review
Childhood onset hereditary spastic paraplegia v1.164 SPAST Louise Daugherty Deleted their comment
Childhood onset hereditary spastic paraplegia v1.158 ALS2 Louise Daugherty Phenotypes for gene: ALS2 were changed from Spastic paralysis, infantile onset ascending, 607225 to Spastic paralysis, infantile onset ascending,autosomal recessive, 607225; Primary lateral sclerosis, juvenile, autosomal recessive, 606353; Amyotrophic lateral sclerosis 2, autosomal recessive, juvenile, 205100
Childhood onset hereditary spastic paraplegia v1.156 AMPD2 Louise Daugherty Phenotypes for gene: AMPD2 were changed from Hereditary Spastic Paraplegia?; Pontocerebellar hypolplasia (biallelic) to ?Spastic paraplegia 63, 615686, AR; Pontocerebellar hypoplasia, type 9, 615809, AR
Childhood onset hereditary spastic paraplegia v1.145 C12orf65 Louise Daugherty Phenotypes for gene: C12orf65 were changed from Spastic paraplegia 55, autosomal recessive, 615035 to Spastic paraplegia 55, autosomal recessive, 615035; optic atrophy and spasticity, tibial muscle weakness and atrophy, peripheral neuropathy; Combined oxidative phosphorylation deficiency 7, 613559
Childhood onset hereditary spastic paraplegia v1.133 KIDINS220 Louise Daugherty Phenotypes for gene: KIDINS220 were changed from Spastic paraplegia, intellectual disability, nystagmus, and obesity 617296 to Spastic paraplegia, intellectual disability, nystagmus, and obesity, 617296
Childhood onset hereditary spastic paraplegia v1.131 KIF1A Louise Daugherty Phenotypes for gene: KIF1A were changed from Spastic paraplegia 30, autosomal recessive, 610357 to Spastic paraplegia 30, autosomal recessive, 610357; Mental retardation, autosomal dominant 9, 614255, AD; Neuropathy, hereditary sensory, type IIC, 614213
Childhood onset hereditary spastic paraplegia v1.123 NIPA1 Louise Daugherty Phenotypes for gene: NIPA1 were changed from Spastic paraplegia 6,autosomal dominant, 600363 to Spastic paraplegia 6, autosomal dominant, 600363
Childhood onset hereditary spastic paraplegia v1.113 REEP2 Louise Daugherty Phenotypes for gene: REEP2 were changed from ?Spastic paraplegia 72, autosomal dominant,615625; ?Spastic paraplegia 72, autosomal recessive, 615625 to Spastic paraplegia 72, autosomal dominant,615625; Spastic paraplegia 72, autosomal recessive, 615625
Childhood onset hereditary spastic paraplegia v1.107 SPART Louise Daugherty Phenotypes for gene: SPART were changed from Troyer syndrome, 275900 to Troyer syndrome, 275900; Spastic paraplegia 20
Childhood onset hereditary spastic paraplegia v1.105 SPAST Louise Daugherty Publications for gene: SPAST were set to Hazan et al (1999)
Childhood onset hereditary spastic paraplegia v1.104 SPAST Louise Daugherty Phenotypes for gene: SPAST were changed from Spastic paraplegia 4, autosomal dominant to Spastic paraplegia 4, autosomal dominant, 182601
Childhood onset hereditary spastic paraplegia v1.98 VPS37A Louise Daugherty Phenotypes for gene: VPS37A were changed from Spastic paraplegia 53, autosomal recessive to Spastic paraplegia 53, 614898, AR
Childhood onset hereditary spastic paraplegia v1.94 ARL6IP1 Louise Daugherty Phenotypes for gene: ARL6IP1 were changed from to Spastic paraplegia
Childhood onset hereditary spastic paraplegia v1.92 CDK16 Louise Daugherty Phenotypes for gene: CDK16 were changed from Intellectual disability and spastic paraplegia to Intellectual disability and spastic paraplegia, x-linked
Childhood onset hereditary spastic paraplegia v1.90 ENTPD1 Louise Daugherty Phenotypes for gene: ENTPD1 were changed from Spasticparaplegia64,615683 to Spasticparaplegia 64, 615683
Childhood onset hereditary spastic paraplegia v1.88 GAD1 Louise Daugherty Phenotypes for gene: GAD1 were changed from Cerebralpalsy,spasticquadriplegic,1,603513 to Cerebralpalsy, spasticquadriplegic, 1, 603513
Childhood onset hereditary spastic paraplegia v1.86 WDR48 Louise Daugherty Phenotypes for gene: WDR48 were changed from to spastic paraplegia
Childhood onset hereditary spastic paraplegia v1.75 SPAST Louise Daugherty Source Yorkshire and North East GLH was added to SPAST.
Childhood onset hereditary spastic paraplegia v1.74 SPAST Nick Beauchamp reviewed gene: SPAST: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted; Current diagnostic: yes
Childhood onset hereditary spastic paraplegia v1.74 SPAST Louise Daugherty commented on gene: SPAST: Rating and review submitted on behalf of James Polke (Neurogenetics Laboratory,Institute of Neurology, London), on behalf of London North GLH for GMS Neurology specialist test group.
Childhood onset hereditary spastic paraplegia v1.71 VPS37A Louise Daugherty commented on gene: VPS37A: Red rating on Hereditary spastic paraplegia panel 1.198

Comment when marking as ready: single founder Arab mutation further evidence required. A founder mutation in Vps37A causes autosomal recessive complex hereditary spastic paraparesis. Zivony-Elboum Y1, Westbroek W, Kfir N, Savitzki D, Shoval Y, Bloom A, Rod R, Khayat M, Gross B, Samri W, Cohen H, Sonkin V, Freidman T, Geiger D, Fattal-Valevski A, Anikster Y, Waters AM, Kleta R, Falik-Zaccai TC.
emma baple (Genomics England Curator), 10 May 2016. Submitted Red rating
Childhood onset hereditary spastic paraplegia v1.71 VAMP1 Louise Daugherty commented on gene: VAMP1: Red rating on Hereditary spastic paraplegia panel 1.198

Added 'founder effect' tag based on Emma Baple's review of PMID:22958904.
Rebecca Foulger (Genomics England curator), 24 Oct 2017

Comment on mode of inheritance: Monoallelic mode of inheritance supported by OMIM.
Rebecca Foulger (Genomics England curator), 12 Oct 2017

Comment when marking as ready: Newfoundland founder mutation described. Further evidence required Bourassa, C. V., Meijer, I. A., Merner, N. D., Grewal, K. K., Stefanelli, M. G., Hodgkinson, K., Ives, E. J., Pryse-Phillips, W., Jog, M., Boycott, K., Grimes, D. A., Goobie, S., Leckey, R., Dion, P. A., Rouleau, G. A. VAMP1 mutation causes dominant hereditary spastic ataxia in Newfoundland families. Am. J. Hum. Genet. 91: 548-552, 2012
emma baple (Genomics England Curator), 10 May 2016
Childhood onset hereditary spastic paraplegia v1.68 TFG Louise Daugherty commented on gene: TFG: Amber rating on Hereditary spastic paraplegia panel 1.198

Beetz (2013, 23479643) Initial report. Exome study, 2 sibs with early-onset spastic paraplegia, optic atrophy, and neuropathy, with hom c.316C>T (p.R106C). In vitro defect shown in self-assembly. Harlalka (2016, 27492651) also described a c.317G>A (p.R106H) homozygous family, and proposed a founder origin for the c.316C>T variant, as well as a c.316_317 hotspot. further mt invitro studies supportive evidence. Elsayed (2016, 27601211) implicated TGF in one family; homozygous c.64C>T (p.(Arg22Trp) with HSP In Sheffield diagnostic HSP panel
Chris Buxton (North Bristol NHS Trust), 27 Nov 2018

Comment when marking as ready: Single Indian family currently described in association with HSP
emma baple (Genomics England Curator), 10 May 2016
Childhood onset hereditary spastic paraplegia v1.68 TECPR2 Louise Daugherty commented on gene: TECPR2: Red rating on Hereditary spastic paraplegia panel 1.198

Oz-Levi (2012, 23176824 ), ?founder fs deletion in Jewish Bukharian families with HSP-related phenotype. Some functional studies supporting an association. Zhu (2015, 25590979), different homozygous fs deletion. Pt had overlapping manifestations with SPG49. No functional studies. Currently included in Sheffield's HSP panel
Chris Buxton (North Bristol NHS Trust), 27 Nov 2018. Submitted Amber rating.

PMID:26542466 (2016) report 3 additional patients from unrelated non-Bukharian families, harboring two novel variants (c.1319delT, c.C566T) in TECPR2, suggesting that variants are not restricted to Bukharian origin.
Rebecca Foulger (Genomics England curator), 31 Oct 2017

Comment when marking as ready: limited evidence founder Jewish mutation
emma baple (Genomics England Curator), 10 May 2016
Childhood onset hereditary spastic paraplegia v1.67 SLC33A1 Louise Daugherty commented on gene: SLC33A1: Amber rating on Hereditary spastic paraplegia panel 1.198

helen kingston (CMFT NHS Foundation Trust, Manchester)
5 Nov 2017 Submitted Green review.

Comment when marking as ready: Very clear association of autosomal recessive mutations with congenital cataracts, hearing loss, and neurodegeneration. Limited evidence currently for HSP
emma baple (Genomics England Curator), 10 May 2016

A mutation in this gene has been described in one chinese family affected by pure HSP, showing autosomal dominant inheritance with reduced penetrance. A subsequent screen of 220 pure HSP patients of mostly caucasian origin failed to identify mutations with this gene.
Arianna Tucci (Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square), 13 Jan 2016. Submitted Amber rating
Childhood onset hereditary spastic paraplegia v1.66 SLC25A46 Louise Daugherty commented on gene: SLC25A46: Green rating on Hereditary spastic paraplegia panel 1.198
Associated with phenotype in OMIM, not in G2P. At least 10 variants reported
Sarah Leigh (Genomics England Curator), 15 Sep 2017
Childhood onset hereditary spastic paraplegia v1.65 REEP2 Louise Daugherty commented on gene: REEP2: Amber rating on Hereditary spastic paraplegia panel 1.198

Roda (2017, 28491902). de novo REEP2 missense (c.119T > G, p.Met40Arg) at a highly-conserved residue very close to another known pathogenic missense change. No functional studies.
Chris Buxton (North Bristol NHS Trust), 27 Nov 2018. Submitted Amber rating.

Comment on list classification: changed from red to amber based on upon two families
Louise Daugherty (Genomics England Curator), 30 Nov 2017

Known to be a movement disorder associated gene. Associated with phenotype in OMIM. At least 3 variants reported in 2 large unrelated families, Autosomal dominant inheritance was reported in one family and autosomal recessive inheritance in another. Observed clinical phenotype includes difficulty in walking and stiff legs associated with hyperreflexia and extensor plantar responses in early childhood. Cognition, speech, and ocular function are normal (summary by Esteves et al., PMID:24388663)
Louise Daugherty (Genomics England Curator), 27 Nov 2017
Childhood onset hereditary spastic paraplegia v1.65 PSEN1 Louise Daugherty commented on gene: PSEN1: Red rating on Hereditary spastic paraplegia panel 1.198.

helen kingston (CMFT NHS Foundation Trust, Manchester)
5 Nov 2017 Submitted Green rating.

Comment when marking as ready: Given the primary association is with dementia and this is gene is included on the associated panel we have excluded it here.
emma baple (Genomics England Curator), 10 May 2016. Submitted Red rating.
Childhood onset hereditary spastic paraplegia v1.62 MTPAP Louise Daugherty commented on gene: MTPAP: Amber rating on Hereditary spastic paraplegia panel 1.198

2 entries on HGMD Pro Crosby (2010, 20970105); variant proposed as cause of spastic paraplegia in Amish population as founder mutation. p.N478D: Slowly progressive autosomal-recessive neurodegenerative condition, the key features of which are cerebellar ataxia, spastic paraparesis, dysarthria, optic atrophy, learning difficulties. Functional studies showed loss of polyadenylation of mitochondrial transcripts Additional functional characterisation in Wilson (2014, 25008111) Al-Shamsi (2016, 27391121) Biparental, homozygous c.1468G > T (p.V490L). 2 sibs with developmental delay and regression at 8 months of age, central hypotonia, short stature, failure to thrive, cerebellar atrophy, absence-like episodes, and hip dislocation. Parents were heterozygous. no functional studies.
Chris Buxton (North Bristol NHS Trust), 27 Nov 2018 Submitted Amber rating
Childhood onset hereditary spastic paraplegia v1.60 MARS2 Louise Daugherty commented on gene: MARS2: Amber rating on Hereditary spastic paraplegia panel 1.198


Bayat (2012, 22448145) Approx 300b deletion /?duplication/rearrangement, Complex genomic MARS2 rearrangements identified in 54 affected French-Canadian cases belonging to 38 families with a mean age of onset of 24.4 (2–59). Lots of in vivo studies. No HGMD/Pubmed reports of MARS2 rearrangements since this paper, but probably inst being widely tested and if so, large rearrangements aren't particularly amenable to ngs
Chris Buxton (North Bristol NHS Trust), 27 Nov 2018 Submitted Green review.

helen kingston (CMFT NHS Foundation Trust, Manchester) Submitted Green review.
Childhood onset hereditary spastic paraplegia v1.60 MAG Louise Daugherty commented on gene: MAG: Amber rating on Hereditary spastic paraplegia panel 1.198

Comment on list classification: Updated rating from Grey to Amber: Gene added and rated red by Chris Buxton (Bristol NHS) based on 1 family in PMID:24482476. One additional family reported in PMID:26179919 but require at least one further case for diagnostic rating.
Rebecca Foulger (Genomics England curator), 18 Dec 2018

In 3 siblings with AR spastic paraplegia born of consanguineous Palestinian parents, Lossos et al. (2015, PMID:26179919) identified a homozygous c.399C-G transversion in the MAG gene (S133R).
Rebecca Foulger (Genomics England curator), 18 Dec 2018

PMID:24482476 (Novarino et al 2014) identified MAG as a HSP candidate gene based on the HSPome (network analysis). In 2 affected sisters from a consanguineous family (family 1226) with AR spastic paraplegia-75, PMID:24482476 identified homozygosity for a c.1288T-G transversion in the MAG gene (C430G).
Rebecca Foulger (Genomics England curator), 18 Dec 2018

1 family Novarino (2014, 24482476). Homozygous Cys430Gly with HSp phenotype. No other detail. 1 family. Limited evidence Diagnostic on Sheffield HSP panel Sources: Literature
Chris Buxton (North Bristol NHS Trust), 27 Nov 2018. Submitted Red rating.
Childhood onset hereditary spastic paraplegia v1.59 LYST Louise Daugherty edited their review of gene: LYST: Added comment: Amber rating on Hereditary spastic paraplegia panel 1.198

Comment on publications: PMIDs:25519960 and 25519961 are in Japanese.
Rebecca Foulger (Genomics England curator), 8 Jan 2019

Comment on list classification: Updated rating from Red to Amber. Gene added to panel by Chris Buxton (Bristol NHS) based on one family in PMID:24521565. In addition, progressive spastic paraparesis seen in affected siblings in PMID:26307451, and PMIDs 25519960 and 25519961 describe LYST as a potential HSP locus. Further cases required for a diagnostic rating.
Rebecca Foulger (Genomics England curator), 8 Jan 2019

PMID:26307451 (Desai et al 2016) report 3 affected siblings with the late-onset form of CHS, and phenotypes including progressive spastic paraparesis.
Rebecca Foulger (Genomics England curator), 8 Jan 2019

PMID:24521565 (Shimazaki et al 2014) include 2 patients in a Japanese family with parents who are first cousins. They detected a homozygous missense variant (c.4189T>G, p.F1397V) in the LYST gene. The patients had adult Chediak-Higashi syndrome (CHS) presenting spastic paraplegia with cerebellar ataxia and neuropathy.
Rebecca Foulger (Genomics England curator), 8 Jan 2019

Comment on list classification: This gene is awaiting curator evaluation and rating.
Sarah Leigh (Genomics England Curator), 19 Dec 2018

Shimazaki (2014, 24521565), homozygous LYST (c.4189T>G, p.F1397V). Gene predominantly associated with Chediak-Higashi syndrome. one publication describing a HSP like phenotype. Diagnostic on Sheffield HSP panel Sources: Literature
Chris Buxton (North Bristol NHS Trust), 28 Nov 2018; Changed publications: 25519960, 25519961, 24521565, 26307451, 25519960, 25519961
Childhood onset hereditary spastic paraplegia v1.58 KIF1C Louise Daugherty commented on gene: KIF1C: Amber rating on Hereditary spastic paraplegia panel 1.198

More familailes listed on OMIM (Nov 2018): In affected members of 2 unrelated families with SPAX2, Dor et al. (2014) identified 2 different homozygous mutations in the KIF1C gene (R731X, 603060.0001 and R169W, 603060.0002). The mutations were found using a combination of homozygosity mapping and whole-exome sequencing. Functional studies were not performed. In 2 consanguineous families with SPAX2, Novarino et al. (2014) identified homozygous mutations in the KIF1C gene: the R731X mutation previously identified by Dor et al. (2014) and a splice site mutation (603060.0003). Novarino et al. (2014) also identified a homozygous deletion of exons 14-18 of the KIF1C gene (603060.0004) in affected members of the Moroccan family with SPAX2 reported by Bouslam et al. (2007).
Chris Buxton (North Bristol NHS Trust), 26 Nov 2018 Amber rating submitted

One patient in Gel cohort found to have compound heterozygous VUS but uncertain significance. To review literature when panel next reviewed
Alice Gardham (Genomics England), 19 Jan 2017

Comment when marking as ready: Still only limited evidence
emma baple (Genomics England Curator), 10 May 2016
Childhood onset hereditary spastic paraplegia v1.57 KDM5C Louise Daugherty commented on gene: KDM5C: Amber rating on Hereditary spastic paraplegia panel 1.198

Comment on list classification: Updated rating from Red to Amber. Gene added to panel and rated Red by Chris Buxton (Bristol NHS). MIM:300534 is characterized by ID, progressive spastic paraplegia, short stature, microcephaly, and dysmorphic facial appearance. Chris Buxton reports 2 families from the literature (PMIDs10982473; 15586325; 26919706) with KDM5C variants and spastic paraplegia symptoms. Therefore Amber awaiting further cases.
Rebecca Foulger (Genomics England curator), 8 Jan 2019

PMID:26919706 investigated a family of 3 boys with ID and among them identified two different variants in KDM5C: Two affected boys have c.633delG and the other has c.631delC. The boys presented with severe DD, progressive spasticity (predominantly in the lower limbs), epilepsy and subclinical hypothyroidism. The mother has two different frameshift mutations: a heterozygous germline mutation, c.631delC, and a low-prevalence somatic mutation, c.633delG.
Rebecca Foulger (Genomics England curator), 8 Jan 2019

PMID:15586325 (Jensen 2005) identifed a L731F variant in 4 members of a family with X-linked complicated spastic paraplegia previously described by Claes et al (2000, PMID:10982473).
Rebecca Foulger (Genomics England curator), 8 Jan 2019

Comment on list classification: This gene is awaiting curator evaluation and rating.
Sarah Leigh (Genomics England Curator), 19 Dec 2018

Claes (2000, 10982473) reported candidate HSP locus Xp21.1-Xq21.3. Jensen (2005, 15586325) identified as JARID1C(syn)/KDM5C gene: c.2191C>T Leu731Phe. 4 males in same pedigree: two generations present with severe MR, slowly progressive spastic paraplegia, facial hypotonia, and maxillary hypoplasia. Additional features are aggressive behavior and strabismus; Fujita (2016, 26919706). Two different fs deletion variants. maternal reversion mechanims? Progressive spasticity component to phenotype. Currently diagnostic on Sheffield's HSP panel Sources: Literature
Chris Buxton (North Bristol NHS Trust), 27 Nov 2018 Red rating submitted
Childhood onset hereditary spastic paraplegia v1.56 IBA57 Louise Daugherty commented on gene: IBA57: Amber rating on Hereditary spastic paraplegia panel 1.198

Comment on list classification: Kept rating as Amber following clinical review by Helen Brittain, who notes that it is possible that the varied phenotypes are part of the spectrum of presentations within IBA57 regarding its mitochondrial function (the more commonly reported recessive phenotype of mitochondrial dysfunction encompasses spasticity in several patients). IBA57 is green on the 'Mitochondrial disorders' panel which is the better route for detecting this broader phenotype. Ideally, further cases with an understanding of the spectrum of pathogenic variants and detailed phenotypic information will help in being confident about inclusion on this HSP panel.
Rebecca Foulger (Genomics England curator), 2 Mar 2019

Comment on list classification: Updated rating from Grey to Amber: Gene added and rated Red by Chris Buxton (Bristol NHS) based on 1 family in PMID:25609768. 2 additional families in PMID:30258207 (2018) but phenotype is variable and 2 Jewish brothers with same compound het variants have different symptoms. Therefore rated Amber awaiting clinical feedback.
Rebecca Foulger (Genomics England curator), 18 Dec 2018

PMID:30258207 (Hamanaka et al, 2018) performed whole-exome sequencing in 2 unrelated families (Sepharadi Jewish and Japanese) with leukodystrophy. The 29-year-old Sepharadi Jewish male had clinically asymptomatic leukodystrophy. His 19-year-old younger brother, with the same compound heterozygous IBA57 variants, had a similar clinical course until 7 years of age when he developed a rapidly progressive spastic paraparesis following a febrile illness. A 7-year-old Japanese girl had developmental regression, spastic quadriplegia, and abnormal periventricular white matter. Therefore HSP symptoms amongst the individuals but phenotypes are very varied.
Rebecca Foulger (Genomics England curator), 18 Dec 2018

In affected members of a large consanguineous Arab family with AR spastic paraplegia, Lossos et al. (2015, PMID:25609768) identified a homozygous splice site variant in IBA57.
Rebecca Foulger (Genomics England curator), 18 Dec 2018

Lossos (2015, 25609768). Homozygous donor splice-site mutation in the IBA57. mRNA studies done, some protein studies support pathogenicity. 1 family, limited evidence. Sources: Literature Provided in Sheffield Lab diagnostic HSP panel
Chris Buxton (North Bristol NHS Trust), 27 Nov 2018. Red rating submitted.
Childhood onset hereditary spastic paraplegia v1.55 GJC2 Louise Daugherty commented on gene: GJC2: Red rating on Hereditary spastic paraplegia panel 1.198

Lots of accounts linking this gene with "Pelizaeus-Merzbacher-like" disorder. Needs more expert curation in case PLP is a ddx for HSP, but given that PLP1 isnt in HSP panel this looks unlikely
Chris Buxton (North Bristol NHS Trust), 27 Nov 2018. Amber rating submitted.

This gene is on the Hereditary Spastic Paraplagia (HSP) NGS Panel in the UCLH National Hospital for Neurology and Neurosurgery & Institute of Neurology (NHNN) Neurogenetics genetic testing manual: "GJC2 encodes a gap junction protein which plays a key role in central myelination and is involved in peripheral myelination in humans. Mutations in this gene have been associated with autosomal recessive Pelizaeus-Merzbacher-like disease-1 (SPG44)." It is a confirmed DD gene for spastic paraplegia 44, with monoallelic inheritance (OMIM states recessive inheritance).
Ellen McDonagh (Genomics England Curator), 14 Jun 2016

Only a single family described with this phenotype, many more cases with the above phenotypes
emma baple (Genomics England Curator), 7 Feb 2016 Red rating submitted
Childhood onset hereditary spastic paraplegia v1.54 GCH1 Louise Daugherty commented on gene: GCH1: Amber rating on Hereditary spastic paraplegia panel 1.198

Comment on list classification: Kept rating as Amber following clinical review from Helen Brittain- Amber rating is appropriate for now, based upon the two cases and some phenotypic queries.
Rebecca Foulger (Genomics England curator), 2 Mar 2019

Comment on mode of inheritance: Both literature cases (PMID:24509643; 21935284) are heterozygous, so have kept MOI as Monoallelic for now while gene is rated Amber. Note that OMIM displays AR and AD inheritance for Dystonia, DOPA-responsive, with or without hyperphenylalaninemia (MIM:128230).
Rebecca Foulger (Genomics England curator), 28 Jan 2019

Comment on list classification: Updated rating from Grey to Amber awaiting feedback from clinical team. 2 literature cases of HSP phenotype in PMIDs:24509643,21935284 both of which involved previous misdiagnosis of DRD/cerebral palsy.
Rebecca Foulger (Genomics England curator), 18 Dec 2018

PMID:21935284 (Lee et al. 2011) report a novel initiation codon mutation (c.1A>T; p.Met1Leu) in GCH1 in a patient with dopa-responsive dystonia (DRD) that had previously been mis-diagnosed as cerbral palsy.
Rebecca Foulger (Genomics England curator), 18 Dec 2018

PMID:24509643 (Fan et al 2014) identified a heterozygous GCH1 variant (R216X) by WES in a patient presenting with progressive spastic paraplegia. The R216X variant had been previously reported as causal for dopa-responsive dystonia (MIM:128230), a phenotype that can resemble HSP.
Rebecca Foulger (Genomics England curator), 18 Dec 2018

Fan (2014, 24509643) het for nonsense variant previously associated with dopa-responsive dystonia. Authors observe that Dopa-responsive Dystonia can resemble HSP Lee (2011, 21935284), another example of DRD misdiagnosed as Cerebral palsy with GCH1 c.1A>T; p.Met1Leu missense Diagnostic on Sheffield HSP panel Sources: Literature
Chris Buxton (North Bristol NHS Trust), 27 Nov 2018. Green rating submitted.
Childhood onset hereditary spastic paraplegia v1.52 DSTYK Louise Daugherty commented on gene: DSTYK: Red rating on Hereditary spastic paraplegia panel 1.198

Added 'Founder effect' tag based on haplotype analysis in Lee et al. (2017, PMID:28157540) which indicates a founder effect- the same deletion/insertion was identified in 3 unrelated families. At the time of curation, PMID:28157540 provides all evidence for the disease:gene association.
Rebecca Foulger (Genomics England curator), 11 May 2017

In affected members of 3 unrelated families of Middle Eastern descent with spastic paraplegia-23 (MIM:270750) Lee et al. (2017, PMID:28157540) identified a homozygous intragenic deletion/insertion in the DSTYK gene. The deletion segregated with the disorder in all 3 families. Haplotype analysis indicated a founder effect. The deletion insertion consisted of a 4-kb deletion associated with a 20-bp insertion, resulting in the removal of the last 2 exons of DSTYK (exons 12 and 13) along with part of the 3-prime untranslated region.
Rebecca Foulger (Genomics England curator), 11 May 2017
Childhood onset hereditary spastic paraplegia v1.52 DARS Louise Daugherty commented on gene: DARS: Comment on list classification: Updated rating from Red to Amber to match expert review and literature evidence. Added to panel and rated Amber by Chris Buxton (Bristol NHS). 2 patients in PMID:25527264 with onset in late adolescence who presented with subacute spastic paraplegia.
Rebecca Foulger (Genomics England curator), 8 Jan 2019

Wolf (2015, 25527264) report 3 patients with variants in DARS. One patient had typical infantile presentation but 2 patients with onset in late adolescence presented with subacute spastic paraplegia. Patient 1 was compound heterozygous for c.599C>G; p.Ser200Cys and c.830C>T; p.Ser277Phe. Patient 2 was homozygous for c.1277T>C; p.Leu426Ser, and patient 3 compound heterozygous for c.839A>T; p.His280Leu and c.1099G>C; p.Asp367His.
Rebecca Foulger (Genomics England curator), 8 Jan 2019

Amber rating on Hereditary spastic paraplegia panel 1.198

Comment on list classification: This gene is awaiting curator evaluation and rating.
Sarah Leigh (Genomics England Curator), 19 Dec 2018

HGMD: 15 missense, 1 ins associated with: Hypomyelination with brain stem and spinal cord involvement and leg spasticity: An autosomal recessive leukoencephalopathy characterized by onset in the first year of life of severe spasticity, mainly affecting the lower limbs and resulting in an inability to achieve independent ambulation Taft (2013, 23643384) identiofied compound-heterozygous and homozygous DARS missense variants in 7 unrelated families with severe lower limb spasticity associated with leukoencephalopathy Phenotype expanded by Wolf (2015, 25527264) to later onset and subacute spastic paraplegia. Sources: Literature
Chris Buxton (North Bristol NHS Trust), 28 Nov 2018
Childhood onset hereditary spastic paraplegia v1.51 CDK16 Louise Daugherty commented on gene: CDK16: Amber rating on Hereditary spastic paraplegia panel 1.198
Not associated with phenotype in OMIM and as a possible G2P. At least 1 truncating variant identified in 4 affected members of a family with ID and spastic paraplegia, also present in 3 obligate female carriers but not in one unaffected male.
Sarah Leigh (Genomics England Curator), 19 Dec 2017
Childhood onset hereditary spastic paraplegia v1.51 AP5Z1 Louise Daugherty commented on gene: AP5Z1: Rated Red on Hereditary spastic paraplegia panel 1.198.

Amber rating : Hirst et al 2016 (4 families) since PanelApp review (2016)
Chris Buxton (North Bristol NHS Trust), 26 Nov 2018

Red rating: Only one family described to date, further evidence required.
emma baple (Genomics England Curator), 7 Feb 2016
Childhood onset hereditary spastic paraplegia v1.50 AMPD2 Louise Daugherty edited their review of gene: AMPD2: Added comment: Red rating on Hereditary spastic paraplegia panel 1.198

nonsense variant in single family in exome study. Low evidence
Chris Buxton (North Bristol NHS Trust), 27 Nov 2018

Comment when marking as ready: Single family only - more evidence required
emma baple (Genomics England Curator), 8 Feb 2016; Changed rating: RED
Childhood onset hereditary spastic paraplegia v1.49 UBAP1 Louise Daugherty gene: UBAP1 was added
gene: UBAP1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Literature
Mode of inheritance for gene: UBAP1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: UBAP1 were set to 30929741
Phenotypes for gene: UBAP1 were set to Hereditary spastic paraplegia
Review for gene: UBAP1 was set to GREEN
Added comment: From PMID:30929741: reported the identification of an autosomal-dominant gene for hereditary spastic paraplegia (HSP) in 10 families that are of diverse geographic origin and whose affected members all carry unique truncating changes in a circumscript region of UBAP1. They identified pathological truncating variants in UBAP1 in affected persons from Iran, USA, Germany, Canada, Spain, and Bulgarian Roma. The genetic support ranges from linkage in the largest family (LOD = 8.3) to three confirmed de novo mutations. They also showed that mRNA in the fibroblasts of affected individuals escapes nonsense-mediated decay and thus leads to the expression of truncated proteins; in addition, concentrations of the full-length protein are reduced in comparison to those in controls.
Sources: Literature
Sources: Literature
Childhood onset hereditary spastic paraplegia v1.48 SPAST Louise Daugherty reviewed gene: SPAST: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Childhood onset hereditary spastic paraplegia v1.38 UCHL1 Louise Daugherty Phenotypes for gene: UCHL1 were changed from to Spastic paraplegia 79, autosomal recessive, 615491, AR
Childhood onset hereditary spastic paraplegia v1.35 TFG Louise Daugherty Phenotypes for gene: TFG were changed from to ?Spastic paraplegia 57, autosomal recessive, 615658, AR; Hereditary motor and sensory neuropathy, Okinawa type, 604484, AD
Childhood onset hereditary spastic paraplegia v1.31 SLC33A1 Louise Daugherty Phenotypes for gene: SLC33A1 were changed from Spastic paraplegia 42, autosomal dominant, to Congenital cataracts, hearing loss, and neurodegeneration, 614482, AR; Spastic paraplegia 42, autosomal dominant
Childhood onset hereditary spastic paraplegia v1.27 MTPAP Louise Daugherty Phenotypes for gene: MTPAP were changed from Ataxia, spastic, 4; Spastic ataxia 4, autosomal recessive to Ataxia, spastic, 4; Spastic ataxia 4, autosomal recessive; ?Spastic ataxia 4, autosomal recessive, 613672
Childhood onset hereditary spastic paraplegia v1.25 MARS2 Louise Daugherty Phenotypes for gene: MARS2 were changed from Spastic ataxia 3, autosomal recessive to Spastic ataxia 3, autosomal recessive, 611390
Childhood onset hereditary spastic paraplegia v1.23 KIF1C Louise Daugherty Phenotypes for gene: KIF1C were changed from Spastic ataxia 2,autosomal recessive to Spastic ataxia 2, autosomal recessive, 611302
Childhood onset hereditary spastic paraplegia v1.21 KCNA2 Louise Daugherty Phenotypes for gene: KCNA2 were changed from to hereditary spastic paraplegia and ataxia
Childhood onset hereditary spastic paraplegia v1.19 GJC2 Louise Daugherty Phenotypes for gene: GJC2 were changed from Spastic paraplegia 44, autosomal recessive to Spastic paraplegia 44, autosomal recessive; Leukodystrophy, hypomyelinating,2, 608804, AR; Spastic paraplegia 44, autosomal recessive, 613206, AR; Lymphatic malformation 3, 613480, AD
Childhood onset hereditary spastic paraplegia v1.15 DSTYK Louise Daugherty Phenotypes for gene: DSTYK were changed from Spastic paraplegia 23, 270750 to Spastic paraplegia 23, 270750; ongenital anomalies of kidney and urinary tract 1, 610805, AD; Spastic paraplegia 23, 270750, AR
Childhood onset hereditary spastic paraplegia v1.12 CPT1C Louise Daugherty Phenotypes for gene: CPT1C were changed from to ?Spastic paraplegia 73, autosomal dominant, 616282, AD
Childhood onset hereditary spastic paraplegia v1.6 ZFYVE26 James Polke reviewed gene: ZFYVE26: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic paraplegia 15, autosomal recessive, 270700; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 WDR45B James Polke reviewed gene: WDR45B: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Profound developmental delay, early-onset refractory epilepsy, progressive spastic quadriplegia and contractures, and brain malformations, Omim-Neurodevelopmental disorder with spastic quadriplegia and brain abnormalities with or without seizures, 617977; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 WASHC5 James Polke reviewed gene: WASHC5: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic paraplegia 8, autosomal dominant; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Childhood onset hereditary spastic paraplegia v1.6 VPS37A James Polke reviewed gene: VPS37A: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic paraplegia 53, autosomal recessive 614898, AR; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 VAMP1 James Polke reviewed gene: VAMP1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic ataxia 1, autosomal dominant, 108600; Mode of inheritance:
Childhood onset hereditary spastic paraplegia v1.6 UCHL1 James Polke reviewed gene: UCHL1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic paraplegia 79, autosomal recessive, 615491, AR; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 TFG James Polke reviewed gene: TFG: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ?Spastic paraplegia 57, autosomal recessive, 615658, AR, Hereditary motor and sensory neuropathy, Okinawa type, 604484, AD; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 TECPR2 James Polke reviewed gene: TECPR2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic paraplegia 49, autosomal recessive, 615031; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 SPG7 James Polke reviewed gene: SPG7: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic paraplegia 7, autosomal recessive; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 SPG21 James Polke reviewed gene: SPG21: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic Paraplegia, Recessive -Mast syndrome, 248900; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 SPG11 James Polke reviewed gene: SPG11: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic paraplegia 11, autosomal recessive, 604360, Amyotrophic lateral sclerosis 5, juvenile, 602099, AR, Charcot-Marie-Tooth disease, axonal, type 2X 616668, AR; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 SPAST James Polke reviewed gene: SPAST: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic paraplegia 4, autosomal dominant, 182601; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Childhood onset hereditary spastic paraplegia v1.6 SPART James Polke reviewed gene: SPART: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic paraplegia 20, autosomal recessive, Troyer syndrome; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 SLC33A1 James Polke reviewed gene: SLC33A1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Congenital cataracts, hearing loss, and neurodegeneration, 614482, AR, Spastic paraplegia 42, autosomal dominant 612539, AD; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 SLC1A4 James Polke reviewed gene: SLC1A4: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic tetraplegia, thin corpus callosum, and progressive microcephaly, 616657; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 SACS James Polke reviewed gene: SACS: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic ataxia, Charlevoix-Saguenay type, 270550; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 RTN2 James Polke reviewed gene: RTN2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic paraplegia 12, autosomal dominant, 604805; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Childhood onset hereditary spastic paraplegia v1.6 REEP2 James Polke reviewed gene: REEP2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ?Spastic paraplegia 72, autosomal recessive, 615625, ?Spastic paraplegia 72, autosomal dominant, 615625; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 REEP1 James Polke reviewed gene: REEP1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic paraplegia 31, autosomal dominant, 610250; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Childhood onset hereditary spastic paraplegia v1.6 PSEN1 James Polke reviewed gene: PSEN1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Alzheimer disease, type 3, with spastic paraparesis, apraxia and unusual plaques; Mode of inheritance:
Childhood onset hereditary spastic paraplegia v1.6 PNPLA6 James Polke reviewed gene: PNPLA6: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic paraplegia 39, autosomal recessive, 612020; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 PLP1 James Polke reviewed gene: PLP1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic paraplegia 2, X-linked recessive, 312920; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Childhood onset hereditary spastic paraplegia v1.6 NT5C2 James Polke reviewed gene: NT5C2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic paraplegia 45, autosomal recessive, 613162, AR; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 NKX6-2 James Polke reviewed gene: NKX6-2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy, 617560; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 NIPA1 James Polke reviewed gene: NIPA1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spasticparaplegia6,autosomal dominant, pseudoautosomal, NOT imprinted, 600363; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Childhood onset hereditary spastic paraplegia v1.6 MTPAP James Polke reviewed gene: MTPAP: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ?Spastic ataxia 4, autosomal recessive, 613672; Mode of inheritance:
Childhood onset hereditary spastic paraplegia v1.6 MARS2 James Polke reviewed gene: MARS2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic ataxia 3, autosomal recessive, 611390; Mode of inheritance:
Childhood onset hereditary spastic paraplegia v1.6 MAG James Polke reviewed gene: MAG: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic paraplegia 75, autosomal recessive, 616680; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 LYST James Polke reviewed gene: LYST: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: spastic paraplegia, Chediak-Higashi syndrome, 214500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 L1CAM James Polke reviewed gene: L1CAM: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: X-linked hydrocephalus, 307000, MASA syndrome 303350, Hereditary spastic paraplegia, 308840; Mode of inheritance: X-LINKED recessive: hemizygous mutation in males, biallelic mutations in females
Childhood onset hereditary spastic paraplegia v1.6 KIF5A James Polke reviewed gene: KIF5A: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic paraplegia 10, autosomal dominant or pseudoautosomal, NOT imprinted, 604187; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Childhood onset hereditary spastic paraplegia v1.6 KIF1C James Polke reviewed gene: KIF1C: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic ataxia 2, autosomal recessive, 611302; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 KIF1A James Polke reviewed gene: KIF1A: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic paraplegia 30, autosomal recessive, 610357, Mental retardation, autosomal dominant 9, 614255, AD, Neuropathy, hereditary sensory, type IIC, 614213; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 KIDINS220 James Polke reviewed gene: KIDINS220: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic paraplegia, intellectual disability, nystagmus, and obesity, autosomal dominant, 617296; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Childhood onset hereditary spastic paraplegia v1.6 KDM5C James Polke reviewed gene: KDM5C: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Mental retardation, X-linked, syndromic, Claes-Jensen type, 300534, Intellectual disability, developmental delay, progressive spasticity, epilepsy, hypothyroidism; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Childhood onset hereditary spastic paraplegia v1.6 KCNA2 James Polke reviewed gene: KCNA2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: hereditary spastic paraplegia and ataxia; Mode of inheritance:
Childhood onset hereditary spastic paraplegia v1.6 IBA57 James Polke reviewed gene: IBA57: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ?Spastic paraplegia 74, autosomal recessive, 616451; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 HSPD1 James Polke reviewed gene: HSPD1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic paraplegia 13, autosomal dominant or pseudoautosomal, NOT imprinted, 605280, Leukodystrophy, hypomyelinating, 4, autosomal recessive, 612233; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Childhood onset hereditary spastic paraplegia v1.6 HACE1 James Polke reviewed gene: HACE1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic paraplegia, psychomotor retardation, seizure, Spastic paraplegia and psychomotor retardation with or without seizures, 616756; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 GJC2 James Polke reviewed gene: GJC2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Leukodystrophy, hypomyelinating,2, 608804, AR, Spastic paraplegia 44, autosomal recessive, 613206, AR, Lymphatic malformation 3, 613480, AD; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 GCH1 James Polke reviewed gene: GCH1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Dystonia, Spastic paraplegia, progressive spastic paraplegia, Dystonia, DOPA-responsive, with or without hyperphenylalaninemia, 128230; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Childhood onset hereditary spastic paraplegia v1.6 GBA2 James Polke reviewed gene: GBA2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic paraplegia 46, autosomal recessive, 614409; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 FARS2 James Polke reviewed gene: FARS2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic paraplegia 77, autosomal recessive, 617046; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 FA2H James Polke reviewed gene: FA2H: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic paraplegia 35, autosomal recessive, 611026; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 ERLIN2 James Polke reviewed gene: ERLIN2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic paraplegia 18, autosomal recessive, 611225, Spastic paraplegia, autosomal dominant, hereditary spastic paraplegia, neurodegeneration; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 ERLIN1 James Polke reviewed gene: ERLIN1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Hereditary spastic paraplegia, Spastic paraplegia 62, 615681; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 DSTYK James Polke reviewed gene: DSTYK: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Congenital anomalies of kidney and urinary tract 1, 610805, AD, Spastic paraplegia 23, 270750, AR; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 DDHD2 James Polke reviewed gene: DDHD2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic paraplegia 54, autosomal recessive, 615033; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 DDHD1 James Polke reviewed gene: DDHD1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic paraplegia 28, autosomal recessive, 609340; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 DARS James Polke reviewed gene: DARS: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Brain stem and spinal cord Hypomyelination, leg spasticity, Hypomyelination with brainstem and spinal cord involvement and leg spasticity, 615281; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 CYP7B1 James Polke reviewed gene: CYP7B1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic paraplegia 5A, autosomal recessive, 270800; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 CYP2U1 James Polke reviewed gene: CYP2U1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic paraplegia 56, autosomal recessive, 615030; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 CYP27A1 James Polke reviewed gene: CYP27A1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Cerebrotendinous xanthomatosis, 213700, progressive lower extremity spasticity,often disproportionate to any degree of weakness; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 CPT1C James Polke reviewed gene: CPT1C: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ?Spastic paraplegia 73, autosomal dominant, 616282, AD; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 CDK16 James Polke reviewed gene: CDK16: Rating: RED; Mode of pathogenicity: ; Publications: ; Phenotypes: Intellectual disability and spastic paraplegia, x-linked; Mode of inheritance: X-LINKED: hemizygous mutation in males, biallelic mutations in females
Childhood onset hereditary spastic paraplegia v1.6 CAPN1 James Polke reviewed gene: CAPN1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic paraplegia 76 autosomal recessive, 616907; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 C19orf12 James Polke reviewed gene: C19orf12: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic paraplegia 43, autosomal recessive, 615043, Neurodegeneration with brain iron accumulation 4, 614298; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 C12orf65 James Polke reviewed gene: C12orf65: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic paraplegia 55,autosomal recessive,615035, optic atrophy and spasticity, tibial muscle weakness and atrophy, peripheral neuropathy, Combined oxidative phosphorylation deficiency 7, 613559; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 BSCL2 James Polke reviewed gene: BSCL2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Silver spastic paraplegia syndrome; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Childhood onset hereditary spastic paraplegia v1.6 B4GALNT1 James Polke reviewed gene: B4GALNT1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic paraplegia 26, autosomal recessive, 609195; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 ATP13A2 James Polke reviewed gene: ATP13A2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Adult-onset lower-limb predominant spastic paraparesis, Spastic paraplegia 78, autosomal recessive, 617225, complicated hereditary spastic paraplegia, Kufor-Rakeb syndrome, 606693 AR; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 ATL1 James Polke reviewed gene: ATL1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic paraplegia 3A, 182600, autosomal dominant, Spastic Paraplegia, Dominant, Neuropathy, hereditary sensory, type ID, 613708; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Childhood onset hereditary spastic paraplegia v1.6 ARG1 James Polke reviewed gene: ARG1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Argininaemia, 207800, Progressive spastic tetraplegia; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 AP5Z1 James Polke reviewed gene: AP5Z1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic paraplegia 48, autosomal recessive 613647, AR; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 AP4S1 James Polke reviewed gene: AP4S1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic paraplegia 52, autosomal recessive, 614067, developmental delay, seizures; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 AP4M1 James Polke reviewed gene: AP4M1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic paraplegia 50, autosomal recessive, 612936; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 AP4E1 James Polke reviewed gene: AP4E1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic paraplegia 51, autosomal recessive, 613744; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 AP4B1 James Polke reviewed gene: AP4B1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic paraplegia 47, autosomal recessive, 614066 ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 AMPD2 James Polke reviewed gene: AMPD2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ?Spastic paraplegia 63, 615686, AR, Pontocerebellar hypoplasia, type 9, 615809, AR ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 ALS2 James Polke reviewed gene: ALS2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic paralysis, infantile onset ascending,autosomal recessive, 607225, Primary lateral sclerosis, juvenile, autosomal recessive, 606353, Amyotrophic lateral sclerosis 2, autosomal recessive, juvenile, 205100; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 ALDH18A1 James Polke reviewed gene: ALDH18A1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Spastic paraplegia 9A, autosomal dominant 601162, Spastic paraplegia 9B, autosomal recessive 616586, Cutis laxa, autosomal dominant 3 616603, Cutis laxa, autosomal recessive, type IIIA 219150 , ADCL3 AUTOSOMAL RECESSIVE MENTAL RETARDATION-JOINT HYPERMOBILITY-SKIN LAXITY WITH OR WITHOUT METABOLIC ABNORMALITIES (MRJHSL) SPASTIC PARAPLEGIA 9, AUTOSOMAL DOMINANT, SPG9; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 AFG3L2 James Polke reviewed gene: AFG3L2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Ataxia, spastic, 5, autosomal recessive, Spastic ataxia 5, autosomal recessive. Spinocerebellar ataxia 28, autosomal dominant, 610246; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Childhood onset hereditary spastic paraplegia v1.6 ABCD1 James Polke reviewed gene: ABCD1: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Hereditary spastic paraplegia, adrenal failure, VLCFA accumulation, spastic paraparesis, Adrenoleukodystrophy, 300100; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Childhood onset hereditary spastic paraplegia v1.5 SPAST Louise Daugherty Source NHS GMS was added to SPAST.
Childhood onset hereditary spastic paraplegia v1.4 UCHL1 Louise Daugherty gene: UCHL1 was added
gene: UCHL1 was added to Hereditary spastic paraplegia - childhood onset. Sources: London North GLH
Mode of inheritance for gene: UCHL1 was set to
Childhood onset hereditary spastic paraplegia v1.4 SPAST Louise Daugherty Source London North GLH was added to SPAST.
Childhood onset hereditary spastic paraplegia v1.4 KCNA2 Louise Daugherty gene: KCNA2 was added
gene: KCNA2 was added to Hereditary spastic paraplegia - childhood onset. Sources: London North GLH
Mode of inheritance for gene: KCNA2 was set to
Childhood onset hereditary spastic paraplegia v1.4 CPT1C Louise Daugherty gene: CPT1C was added
gene: CPT1C was added to Hereditary spastic paraplegia - childhood onset. Sources: London North GLH
Mode of inheritance for gene: CPT1C was set to
Childhood onset hereditary spastic paraplegia v1.3 ZFYVE27 Louise Daugherty Added phenotypes Spastic paraplegia 33, autosomal dominant for gene: ZFYVE27
Childhood onset hereditary spastic paraplegia v1.3 VPS37A Louise Daugherty Added phenotypes Spastic paraplegia 53, autosomal recessive for gene: VPS37A
Childhood onset hereditary spastic paraplegia v1.3 VAMP1 Louise Daugherty Added phenotypes Spastic ataxia 1, autosomal dominant, 108600 for gene: VAMP1
Childhood onset hereditary spastic paraplegia v1.3 TECPR2 Louise Daugherty Added phenotypes Spastic paraplegia 49, autosomal recessive, 615031 for gene: TECPR2
Childhood onset hereditary spastic paraplegia v1.3 SLC33A1 Louise Daugherty Added phenotypes Spastic paraplegia 42, autosomal dominant, for gene: SLC33A1
Childhood onset hereditary spastic paraplegia v1.3 RAB3GAP2 Louise Daugherty Added phenotypes spastic paraplegia for gene: RAB3GAP2
Childhood onset hereditary spastic paraplegia v1.3 PSEN1 Louise Daugherty Added phenotypes Alzheimer disease, type 3, with spastic paraparesis and apraxia; Alzheimer disease, type 3, with spastic paraparesis and unusual plaques for gene: PSEN1
Childhood onset hereditary spastic paraplegia v1.3 MTPAP Louise Daugherty Added phenotypes Ataxia, spastic, 4; Spastic ataxia 4, autosomal recessive for gene: MTPAP
Childhood onset hereditary spastic paraplegia v1.3 MARS2 Louise Daugherty Added phenotypes Spastic ataxia 3, autosomal recessive for gene: MARS2
Childhood onset hereditary spastic paraplegia v1.3 KLC4 Louise Daugherty Added phenotypes spastic paraplegia; progressive complicated spastic paraplegia for gene: KLC4
Childhood onset hereditary spastic paraplegia v1.3 KIF1C Louise Daugherty Added phenotypes Spastic ataxia 2,autosomal recessive for gene: KIF1C
Publications for gene KIF1C were changed from 17273843; 24482476; 24319291 to 24482476; 17273843; 24319291
Childhood onset hereditary spastic paraplegia v1.3 GJC2 Louise Daugherty Added phenotypes Spastic paraplegia 44, autosomal recessive for gene: GJC2
Childhood onset hereditary spastic paraplegia v1.3 GAD1 Louise Daugherty Added phenotypes Cerebralpalsy,spasticquadriplegic,1,603513 for gene: GAD1
Childhood onset hereditary spastic paraplegia v1.3 ENTPD1 Louise Daugherty Added phenotypes Spasticparaplegia64,615683 for gene: ENTPD1
Childhood onset hereditary spastic paraplegia v1.3 DSTYK Louise Daugherty Added phenotypes Spastic paraplegia 23, 270750 for gene: DSTYK
Childhood onset hereditary spastic paraplegia v1.3 CCT5 Louise Daugherty Added phenotypes Sensory Neuropathy with Spastic Paraplegia; Neuropathy, hereditary sensory, with spastic paraplegia for gene: CCT5
Childhood onset hereditary spastic paraplegia v1.3 AP5Z1 Louise Daugherty Added phenotypes Spastic Paraplegia, Recessive; Spastic paraplegia 48, autosomal recessive for gene: AP5Z1
Childhood onset hereditary spastic paraplegia v1.3 AMPD2 Louise Daugherty Added phenotypes Hereditary Spastic Paraplegia?; Pontocerebellar hypolplasia (biallelic) for gene: AMPD2
Childhood onset hereditary spastic paraplegia v1.3 REEP2 Louise Daugherty Added phenotypes ?Spastic paraplegia 72, autosomal dominant,615625; ?Spastic paraplegia 72, autosomal recessive, 615625 for gene: REEP2
Childhood onset hereditary spastic paraplegia v1.3 MAG Louise Daugherty Added phenotypes Spastic paraplegia 75, autosomal recessive, 616680 for gene: MAG
Publications for gene MAG were changed from 24482476; 26179919 to 26179919; 24482476
Childhood onset hereditary spastic paraplegia v1.3 LYST Louise Daugherty Added phenotypes spastic paraplegia; Chediak-Higashi syndrome, 214500 for gene: LYST
Publications for gene LYST were changed from 24521565; 26307451; 25519960; 25519961 to 24521565; 26307451; 25519961; 25519960
Childhood onset hereditary spastic paraplegia v1.3 KDM5C Louise Daugherty Added phenotypes Intellectual disability; developmental delay; epilepsy; progressive spasticity; Mental retardation, X-linked, syndromic, Claes-Jensen type, 300534; hypothyroidism for gene: KDM5C
Publications for gene KDM5C were changed from 26919706; 15586325; 10982473 to 10982473; 26919706; 15586325
Childhood onset hereditary spastic paraplegia v1.3 IBA57 Louise Daugherty Added phenotypes ?Spastic paraplegia 74, autosomal recessive, 616451 for gene: IBA57
Childhood onset hereditary spastic paraplegia v1.3 HSPD1 Louise Daugherty Added phenotypes Spastic paraplegia 13, autosomal dominant, 605280 for gene: HSPD1
Childhood onset hereditary spastic paraplegia v1.3 GCH1 Louise Daugherty Added phenotypes Dystonia, DOPA-responsive, with or without hyperphenylalaninemia, 128230; Dystonia; progressive spastic paraplegia; Spastic paraplegia for gene: GCH1
Publications for gene GCH1 were changed from 21935284; 24509643 to 24509643; 21935284
Childhood onset hereditary spastic paraplegia v1.3 DARS Louise Daugherty Added phenotypes leg spasticity; Brain stem and spinal cord Hypomyelination; Hypomyelination with brainstem and spinal cord involvement and leg spasticity, 615281 for gene: DARS
Publications for gene DARS were changed from 25527264; 23643384 to 23643384; 25527264
Childhood onset hereditary spastic paraplegia v1.3 CDK16 Louise Daugherty Added phenotypes Intellectual disability and spastic paraplegia for gene: CDK16
Childhood onset hereditary spastic paraplegia v1.3 CAPN1 Louise Daugherty Added phenotypes Spastic paraplegia 76 autosomal recessive, 616907 for gene: CAPN1
Childhood onset hereditary spastic paraplegia v1.3 SLC2A1 Louise Daugherty Added phenotypes spastic paraplegia; seizure; Dystonia 9, 601042; Developmental delay; paroxysmal choreoathetosis for gene: SLC2A1
Rating Changed from Green List (high evidence) to Green List (high evidence)
Childhood onset hereditary spastic paraplegia v1.3 NT5C2 Louise Daugherty Added phenotypes Spastic paraplegia 45, autosomal recessive, 613162 for gene: NT5C2
Publications for gene NT5C2 were changed from 29123918; 28884889; 24482476; 28327087 to 28327087; 28884889; 24482476; 29123918
Rating Changed from Green List (high evidence) to Green List (high evidence)
Childhood onset hereditary spastic paraplegia v1.3 HACE1 Louise Daugherty Added phenotypes Spastic paraplegia and psychomotor retardation with or without seizures, 616756; Spastic paraplegia; seizure; psychomotor retardation for gene: HACE1
Publications for gene HACE1 were changed from 26437029; 26424145 to 26424145; 26437029
Rating Changed from Green List (high evidence) to Green List (high evidence)
Childhood onset hereditary spastic paraplegia v1.3 ERLIN1 Louise Daugherty Added phenotypes Hereditary spastic paraplegia; Spastic paraplegia 62, 615681 for gene: ERLIN1
Rating Changed from Green List (high evidence) to Green List (high evidence)
Childhood onset hereditary spastic paraplegia v1.3 CYP27A1 Louise Daugherty Added phenotypes Cerebrotendinous xanthomatosis, 213700; progressive lower extremity spasticity,often disproportionate to any degree of weakness for gene: CYP27A1
Publications for gene CYP27A1 were changed from 25862734; 26874936; 28623566; 27455001; 29321515 to 25862734; 27455001; 26874936; 29321515; 28623566
Rating Changed from Green List (high evidence) to Green List (high evidence)
Childhood onset hereditary spastic paraplegia v1.3 ATP13A2 Louise Daugherty Added phenotypes Adult-onset lower-limb predominant spastic paraparesis; Spastic paraplegia 78, autosomal recessive, 617225; complicated hereditary spastic paraplegia for gene: ATP13A2
Rating Changed from Green List (high evidence) to Green List (high evidence)
Childhood onset hereditary spastic paraplegia v1.3 ARG1 Louise Daugherty Added phenotypes Progressive spastic tetraplegia; Argininaemia, 207800 for gene: ARG1
Publications for gene ARG1 were changed from 26310552; 23859858; 2365823; 1463019 to 2365823; 23859858; 1463019; 26310552
Rating Changed from Green List (high evidence) to Green List (high evidence)
Childhood onset hereditary spastic paraplegia v1.3 ABCD1 Louise Daugherty Added phenotypes spastic paraparesis; VLCFA accumulation; adrenal failure; Hereditary spastic paraplegia for gene: ABCD1
Publications for gene ABCD1 were changed from 11810273; 27084228; 11739809; 26049658; 23664929 to 23664929; 11739809; 26049658; 27084228; 11810273
Rating Changed from Green List (high evidence) to Green List (high evidence)
Childhood onset hereditary spastic paraplegia v1.3 ZFYVE26 Louise Daugherty Added phenotypes Spastic paraplegia 15, autosomal recessive, 270700 for gene: ZFYVE26
Childhood onset hereditary spastic paraplegia v1.3 WDR45B Louise Daugherty Added phenotypes profound developmental delay, early-onset refractory epilepsy, progressive spastic quadriplegia and contractures, and brain malformations.; Neurodevelopmental disorder with spastic quadriplegia and brain abnormalities with or without seizures, 617977 for gene: WDR45B
Childhood onset hereditary spastic paraplegia v1.3 WASHC5 Louise Daugherty Added phenotypes Spastic paraplegia 8, autosomal dominant, 603563 for gene: WASHC5
Childhood onset hereditary spastic paraplegia v1.3 SPG7 Louise Daugherty Added phenotypes Spastic paraplegia 7, autosomal recessive, 607259 for gene: SPG7
Childhood onset hereditary spastic paraplegia v1.3 SPG21 Louise Daugherty Added phenotypes Spastic Paraplegia, Recessive; Mast syndrome, 248900 for gene: SPG21
Childhood onset hereditary spastic paraplegia v1.3 SPG11 Louise Daugherty Added phenotypes Spastic paraplegia 11, autosomal recessive, 604360 for gene: SPG11
Publications for gene SPG11 were changed from 17322883; 16699786 to 16699786; 17322883
Childhood onset hereditary spastic paraplegia v1.3 SPAST Louise Daugherty Added phenotypes Spastic paraplegia 4, autosomal dominant for gene: SPAST
Childhood onset hereditary spastic paraplegia v1.3 SLC1A4 Louise Daugherty Added phenotypes Spastic tetraplegia, thin corpus callosum, and progressive microcephaly, 616657 for gene: SLC1A4
Publications for gene SLC1A4 were changed from 25930971; 26041762; 29989513; 26138499; 27193218 to 26138499; 25930971; 26041762; 27193218; 29989513
Childhood onset hereditary spastic paraplegia v1.3 SACS Louise Daugherty Added phenotypes Spastic ataxia, Charlevoix-Saguenay type, 270550 for gene: SACS
Childhood onset hereditary spastic paraplegia v1.3 RTN2 Louise Daugherty Added phenotypes Spastic paraplegia 12, autosomal dominant, 604805 for gene: RTN2
Childhood onset hereditary spastic paraplegia v1.3 REEP1 Louise Daugherty Added phenotypes Spastic paraplegia 31, autosomal dominant, 610250 for gene: REEP1
Childhood onset hereditary spastic paraplegia v1.3 PNPLA6 Louise Daugherty Added phenotypes Spastic paraplegia 39, autosomal recessive, 612020 for gene: PNPLA6
Childhood onset hereditary spastic paraplegia v1.3 PLP1 Louise Daugherty Added phenotypes Spastic paraplegia 2, X-linked, 312920 for gene: PLP1
Childhood onset hereditary spastic paraplegia v1.3 NKX6-2 Louise Daugherty Added phenotypes Spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy, 617560 for gene: NKX6-2
Childhood onset hereditary spastic paraplegia v1.3 NIPA1 Louise Daugherty Added phenotypes Spastic paraplegia 6,autosomal dominant, 600363 for gene: NIPA1
Publications for gene NIPA1 were changed from 14508710; 15711826 to 15711826; 14508710
Childhood onset hereditary spastic paraplegia v1.3 L1CAM Louise Daugherty Added phenotypes Hereditary spastic paraplegia; X-linked hydrocephalus, MASA syndrome, 303350 for gene: L1CAM
Childhood onset hereditary spastic paraplegia v1.3 KIF5A Louise Daugherty Added phenotypes Spastic paraplegia 10, autosomal dominant, 604187 for gene: KIF5A
Childhood onset hereditary spastic paraplegia v1.3 KIF1A Louise Daugherty Added phenotypes Spastic paraplegia 30, autosomal recessive, 610357 for gene: KIF1A
Childhood onset hereditary spastic paraplegia v1.3 KIDINS220 Louise Daugherty Added phenotypes Spastic paraplegia, intellectual disability, nystagmus, and obesity 617296 for gene: KIDINS220
Childhood onset hereditary spastic paraplegia v1.3 GBA2 Louise Daugherty Added phenotypes Spastic paraplegia 46, autosomal recessive, 614409 for gene: GBA2
Childhood onset hereditary spastic paraplegia v1.3 FARS2 Louise Daugherty Added phenotypes Spastic paraplegia 77, autosomal recessive, 617046 for gene: FARS2
Publications for gene FARS2 were changed from 29126765; 26553276; 25851414; 30250868 to 26553276; 30250868; 25851414; 29126765
Childhood onset hereditary spastic paraplegia v1.3 FA2H Louise Daugherty Added phenotypes Spastic paraplegia 35, autosomal recessive, 612319 for gene: FA2H
Childhood onset hereditary spastic paraplegia v1.3 ERLIN2 Louise Daugherty Added phenotypes Spastic paraplegia, autosomal dominant; Spastic paraplegia 18, autosomal recessive, 611225; hereditary spastic paraplegia; neurodegeneration for gene: ERLIN2
Publications for gene ERLIN2 were changed from 27824013; 23085305; 21330303; 23109142; 28832565; 23897027; 22554690; 25977983; 23109145; 21796390; 29528531 to 23109145; 22554690; 23085305; 27824013; 29528531; 23109142; 28832565; 21330303; 23897027; 21796390; 25977983
Childhood onset hereditary spastic paraplegia v1.3 DDHD2 Louise Daugherty Added phenotypes Spastic paraplegia 54, autosomal recessive, 615033 for gene: DDHD2
Childhood onset hereditary spastic paraplegia v1.3 DDHD1 Louise Daugherty Added phenotypes Spastic paraplegia 28, autosomal recessive, 609340 for gene: DDHD1
Childhood onset hereditary spastic paraplegia v1.3 CYP7B1 Louise Daugherty Added phenotypes Spastic paraplegia 5A, autosomal recessive, 270800 for gene: CYP7B1
Childhood onset hereditary spastic paraplegia v1.3 CYP2U1 Louise Daugherty Added phenotypes Spastic paraplegia 56, autosomal recessive, 615030 for gene: CYP2U1
Childhood onset hereditary spastic paraplegia v1.3 C19orf12 Louise Daugherty Added phenotypes Spastic paraplegia 43, autosomal recessive, 615043; Neurodegeneration with brain iron accumulation 4, 614298 for gene: C19orf12
Childhood onset hereditary spastic paraplegia v1.3 C12orf65 Louise Daugherty Added phenotypes Spastic paraplegia 55, autosomal recessive, 615035 for gene: C12orf65
Childhood onset hereditary spastic paraplegia v1.3 BSCL2 Louise Daugherty Added phenotypes Silver spastic paraplegia syndrome, 270685 for gene: BSCL2
Publications for gene BSCL2 were changed from 14981520; 13680364 to 13680364; 14981520
Childhood onset hereditary spastic paraplegia v1.3 B4GALNT1 Louise Daugherty Added phenotypes Spastic paraplegia 26, autosomal recessive, 609195 for gene: B4GALNT1
Childhood onset hereditary spastic paraplegia v1.3 ATL1 Louise Daugherty Added phenotypes Spastic paraplegia 3A, autosomal dominant,182600; Spastic Paraplegia, Dominant for gene: ATL1
Childhood onset hereditary spastic paraplegia v1.3 AP4S1 Louise Daugherty Added phenotypes developmental delay; seizures; Spastic paraplegia 52, autosomal recessive, 614067 for gene: AP4S1
Childhood onset hereditary spastic paraplegia v1.3 AP4M1 Louise Daugherty Added phenotypes Spastic paraplegia 50, autosomal recessive, 612936 for gene: AP4M1
Childhood onset hereditary spastic paraplegia v1.3 AP4E1 Louise Daugherty Added phenotypes Spastic paraplegia 51, autosomal recessive, 613744 for gene: AP4E1
Childhood onset hereditary spastic paraplegia v1.3 AP4B1 Louise Daugherty Added phenotypes Spastic paraplegia 47, autosomal recessive, 614066 for gene: AP4B1
Childhood onset hereditary spastic paraplegia v1.3 ALS2 Louise Daugherty Added phenotypes Spastic paralysis, infantile onset ascending, 607225 for gene: ALS2
Childhood onset hereditary spastic paraplegia v1.3 ALDH18A1 Louise Daugherty Added phenotypes Spastic paraplegia 9B, autosomal recessive, 616586; SPG9; Spastic paraplegia 9A, autosomal dominant, 601162; ADCL3 AUTOSOMAL RECESSIVE MENTAL RETARDATION-JOINT HYPERMOBILITY-SKIN LAXITY WITH OR WITHOUT METABOLIC ABNORMALITIES (MRJHSL) SPASTIC PARAPLEGIA 9, AUTOSOMAL DOMINANT; Spastic paraplegia 9B, autosomal recessive CUTIS LAXA, AUTOSOMAL DOMINANT 3 for gene: ALDH18A1
Childhood onset hereditary spastic paraplegia v1.3 AFG3L2 Louise Daugherty Added phenotypes Ataxia, spastic, 5, autosomal recessive; Spastic ataxia 5, autosomal recessive, 614487 for gene: AFG3L2
Childhood onset hereditary spastic paraplegia v1.2 NT5C2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Green; rating was updated from Red to Green on the 'Hereditary spastic paraplegia' panel after curation from Sarah Leigh and advice from Helen Brittain. Plus literature confirms a childhood onset of HSP: In PMID:28884889, 3 family members developed HSP symptoms at under 1 year. In PMID:28327087, two brothers from a Consanguineous Qatari family age 9 and 3 years with complex HSP had an early-onset phenotype. PMID:29123918 describe an infantile-onset form of recessive HSP.
Childhood onset hereditary spastic paraplegia v1.1 NT5C2 Rebecca Foulger Phenotypes for gene: NT5C2 were changed from Spasticparaplegia45, autosomal recessive 613162 to Spastic paraplegia 45, autosomal recessive, 613162
Childhood onset hereditary spastic paraplegia v1.0 SPAST Arianna Tucci reviewed gene: SPAST: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None
Childhood onset hereditary spastic paraplegia v0.145 SLC2A1 Louise Daugherty Phenotypes for gene: SLC2A1 were changed from paroxysmal choreoathetosis; spastic paraplegia; seizure; Developmental delay to Dystonia 9, 601042; paroxysmal choreoathetosis; spastic paraplegia; seizure; Developmental delay
Childhood onset hereditary spastic paraplegia v0.143 HACE1 Louise Daugherty Phenotypes for gene: HACE1 were changed from psychomotor retardation; Spastic paraplegia; seizure; Spastic paraplegia and psychomotor retardation with or without seizures, 616756 to Spastic paraplegia and psychomotor retardation with or without seizures, 616756; psychomotor retardation; Spastic paraplegia; seizure
Childhood onset hereditary spastic paraplegia v0.141 ZFYVE26 Louise Daugherty Phenotypes for gene: ZFYVE26 were changed from Spastic paraplegia 15, autosomal recessive to Spastic paraplegia 15, autosomal recessive, 270700
Childhood onset hereditary spastic paraplegia v0.140 WDR45B Louise Daugherty Phenotypes for gene: WDR45B were changed from profound developmental delay, early-onset refractory epilepsy, progressive spastic quadriplegia and contractures, and brain malformations. to Neurodevelopmental disorder with spastic quadriplegia and brain abnormalities with or without seizures, 617977; profound developmental delay, early-onset refractory epilepsy, progressive spastic quadriplegia and contractures, and brain malformations.
Childhood onset hereditary spastic paraplegia v0.138 WASHC5 Louise Daugherty Phenotypes for gene: WASHC5 were changed from Spastic paraplegia 8, autosomal dominant to Spastic paraplegia 8, autosomal dominant, 603563
Childhood onset hereditary spastic paraplegia v0.136 SPG7 Louise Daugherty Phenotypes for gene: SPG7 were changed from Spastic paraplegia 7, autosomal recessive to Spastic paraplegia 7, autosomal recessive, 607259
Childhood onset hereditary spastic paraplegia v0.134 SPG21 Louise Daugherty Phenotypes for gene: SPG21 were changed from Spastic Paraplegia, Recessive to Spastic Paraplegia, Recessive; Mast syndrome, 248900
Childhood onset hereditary spastic paraplegia v0.132 SPG11 Louise Daugherty Phenotypes for gene: SPG11 were changed from Spastic paraplegia 11, autosomal recessive to Spastic paraplegia 11, autosomal recessive, 604360
Childhood onset hereditary spastic paraplegia v0.126 SACS Louise Daugherty Phenotypes for gene: SACS were changed from Spastic ataxia, Charlevoix-Saguenay type to Spastic ataxia, Charlevoix-Saguenay type, 270550
Childhood onset hereditary spastic paraplegia v0.124 RTN2 Louise Daugherty Phenotypes for gene: RTN2 were changed from Spastic paraplegia 12, autosomal dominant to Spastic paraplegia 12, autosomal dominant, 604805
Childhood onset hereditary spastic paraplegia v0.123 REEP1 Louise Daugherty Phenotypes for gene: REEP1 were changed from Spastic paraplegia 31, autosomal dominant to Spastic paraplegia 31, autosomal dominant, 610250
Childhood onset hereditary spastic paraplegia v0.119 PNPLA6 Louise Daugherty Phenotypes for gene: PNPLA6 were changed from Spastic paraplegia 39, autosomal recessive to Spastic paraplegia 39, autosomal recessive, 612020
Childhood onset hereditary spastic paraplegia v0.117 PLP1 Louise Daugherty Phenotypes for gene: PLP1 were changed from Spastic paraplegia 2, X-linked to Spastic paraplegia 2, X-linked, 312920
Childhood onset hereditary spastic paraplegia v0.116 NIPA1 Louise Daugherty Phenotypes for gene: NIPA1 were changed from Spasticparaplegia6,autosomaldominant,600363; Spastic paraplegia 6, autosomal dominant to Spastic paraplegia 6,autosomal dominant, 600363
Childhood onset hereditary spastic paraplegia v0.114 L1CAM Louise Daugherty Phenotypes for gene: L1CAM were changed from X-linked hydrocephalus, MASA syndrome,303350; Hereditary spastic paraplegia to X-linked hydrocephalus, MASA syndrome, 303350; Hereditary spastic paraplegia
Childhood onset hereditary spastic paraplegia v0.113 L1CAM Louise Daugherty Phenotypes for gene: L1CAM were changed from X-linked hydrocephalus, MASA syndrome, Hereditary spastic paraplegia to X-linked hydrocephalus, MASA syndrome,303350; Hereditary spastic paraplegia
Childhood onset hereditary spastic paraplegia v0.110 KIF5A Louise Daugherty Phenotypes for gene: KIF5A were changed from Spastic paraplegia 10, autosomal dominant to Spastic paraplegia 10, autosomal dominant, 604187
Childhood onset hereditary spastic paraplegia v0.107 KIF1A Louise Daugherty Phenotypes for gene: KIF1A were changed from Spastic paraplegia 30, autosomal recessive to Spastic paraplegia 30, autosomal recessive, 610357
Childhood onset hereditary spastic paraplegia v0.105 HSPD1 Louise Daugherty Phenotypes for gene: HSPD1 were changed from Spastic paraplegia 13, autosomal dominant; 605280 to Spastic paraplegia 13, autosomal dominant, 605280
Childhood onset hereditary spastic paraplegia v0.104 HSPD1 Louise Daugherty Phenotypes for gene: HSPD1 were changed from Spastic paraplegia 13, autosomal dominant to Spastic paraplegia 13, autosomal dominant; 605280
Childhood onset hereditary spastic paraplegia v0.100 FA2H Louise Daugherty Phenotypes for gene: FA2H were changed from Spastic paraplegia 35, autosomal recessive to Spastic paraplegia 35, autosomal recessive, 612319
Childhood onset hereditary spastic paraplegia v0.99 DDHD2 Louise Daugherty Phenotypes for gene: DDHD2 were changed from Spastic paraplegia 54, autosomal recessive to Spastic paraplegia 54, autosomal recessive, 615033
Childhood onset hereditary spastic paraplegia v0.96 DDHD1 Louise Daugherty Phenotypes for gene: DDHD1 were changed from Spastic paraplegia 28, autosomal recessive, 23176821 to Spastic paraplegia 28, autosomal recessive, 609340
Childhood onset hereditary spastic paraplegia v0.95 DDHD1 Louise Daugherty Phenotypes for gene: DDHD1 were changed from Spastic paraplegia 28, autosomal recessive to Spastic paraplegia 28, autosomal recessive, 23176821
Childhood onset hereditary spastic paraplegia v0.94 CYP7B1 Louise Daugherty Phenotypes for gene: CYP7B1 were changed from Spastic paraplegia 5A, autosomal recessive to Spastic paraplegia 5A, autosomal recessive, 270800
Childhood onset hereditary spastic paraplegia v0.91 CYP2U1 Louise Daugherty Phenotypes for gene: CYP2U1 were changed from Spastic paraplegia 56, autosomal recessive to Spastic paraplegia 56, autosomal recessive, 615030
Childhood onset hereditary spastic paraplegia v0.88 C19orf12 Louise Daugherty Phenotypes for gene: C19orf12 were changed from Neurodegeneration with brain iron accumulation 4, 614298 to Neurodegeneration with brain iron accumulation 4, 614298; Spastic paraplegia 43, autosomal recessive, 615043
Childhood onset hereditary spastic paraplegia v0.83 C12orf65 Louise Daugherty Phenotypes for gene: C12orf65 were changed from Spasticparaplegia55,autosomalrecessive,615035 to Spastic paraplegia 55, autosomal recessive, 615035
Childhood onset hereditary spastic paraplegia v0.82 SLC2A1 Rebecca Foulger Added comment: Comment on mode of inheritance: Updated MOI from biallelic to monoallelic as agreed with Arianna. Although Biallelic MOI is suggested by the Reviewer Chris Buxton on the Hereditary spastic paraplegia panel, PMIDs:27725288, 11136715 and 21832227 show autosomal dominant inheritance for the GLUT1 deficiency (including HSP phenotype).
Childhood onset hereditary spastic paraplegia v0.80 BSCL2 Louise Daugherty Phenotypes for gene: BSCL2 were changed from Silver spastic paraplegia syndrome, to Silver spastic paraplegia syndrome, 270685
Childhood onset hereditary spastic paraplegia v0.79 SLC2A1 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Green following review on the 'Hereditary spastic paraplegia' panel. Age of onset of Spastic paraplegia in patients from PMID:27725288 includes 'Infancy, 3 yr, 4 yr, 10 yr, not examined).
Childhood onset hereditary spastic paraplegia v0.77 B4GALNT1 Louise Daugherty Phenotypes for gene: B4GALNT1 were changed from Spastic paraplegia 26, autosomal recessive to Spastic paraplegia 26, autosomal recessive, 609195
Childhood onset hereditary spastic paraplegia v0.77 B4GALNT1 Louise Daugherty Phenotypes for gene: B4GALNT1 were changed from Spastic paraplegia 26, autosomal recessive to Spastic paraplegia 26, autosomal recessive, 609195
Childhood onset hereditary spastic paraplegia v0.76 ATL1 Louise Daugherty Phenotypes for gene: ATL1 were changed from Spastic paraplegia 3A, autosomal dominant; Spastic paraplegia 3A, autosomal dominant,; Spastic Paraplegia, Dominant to Spastic paraplegia 3A, autosomal dominant,182600; Spastic Paraplegia, Dominant
Childhood onset hereditary spastic paraplegia v0.73 AP4S1 Louise Daugherty Phenotypes for gene: AP4S1 were changed from seizures; developmental delay; Spastic paraplegia 52, autosomal recessive to seizures; developmental delay; Spastic paraplegia 52, autosomal recessive, 614067
Childhood onset hereditary spastic paraplegia v0.71 AP4M1 Louise Daugherty Phenotypes for gene: AP4M1 were changed from Spastic paraplegia 50, autosomal recessive to Spastic paraplegia 50, autosomal recessive, 612936
Childhood onset hereditary spastic paraplegia v0.70 AP4E1 Louise Daugherty Phenotypes for gene: AP4E1 were changed from Spastic paraplegia 51, autosomal recessive to Spastic paraplegia 51, autosomal recessive, 613744
Childhood onset hereditary spastic paraplegia v0.67 AP4B1 Louise Daugherty Phenotypes for gene: AP4B1 were changed from Spastic paraplegia 47, autosomal recessive to Spastic paraplegia 47, autosomal recessive, 614066
Childhood onset hereditary spastic paraplegia v0.66 ALS2 Louise Daugherty Phenotypes for gene: ALS2 were changed from 607225 to Spastic paralysis, infantile onset ascending, 607225
Childhood onset hereditary spastic paraplegia v0.65 ALDH18A1 Louise Daugherty Phenotypes for gene: ALDH18A1 were changed from ADCL3 AUTOSOMAL RECESSIVE MENTAL RETARDATION-JOINT HYPERMOBILITY-SKIN LAXITY WITH OR WITHOUT METABOLIC ABNORMALITIES (MRJHSL) SPASTIC PARAPLEGIA 9, AUTOSOMAL DOMINANT; SPG9; Spastic paraplegia 9B, autosomal recessive CUTIS LAXA, AUTOSOMAL DOMINANT 3; Spastic paraplegia 9A, autosomal dominant to ADCL3 AUTOSOMAL RECESSIVE MENTAL RETARDATION-JOINT HYPERMOBILITY-SKIN LAXITY WITH OR WITHOUT METABOLIC ABNORMALITIES (MRJHSL) SPASTIC PARAPLEGIA 9, AUTOSOMAL DOMINANT; SPG9; Spastic paraplegia 9B, autosomal recessive CUTIS LAXA, AUTOSOMAL DOMINANT 3; Spastic paraplegia 9A, autosomal dominant, 601162; Spastic paraplegia 9B, autosomal recessive, 616586
Childhood onset hereditary spastic paraplegia v0.63 AFG3L2 Louise Daugherty Phenotypes for gene: AFG3L2 were changed from Spastic ataxia 5, autosomal recessive; Ataxia, spastic, 5, autosomal recessive to Spastic ataxia 5, autosomal recessive, 614487; Ataxia, spastic, 5, autosomal recessive
Childhood onset hereditary spastic paraplegia v0.61 ERLIN1 Rebecca Foulger Phenotypes for gene: ERLIN1 were changed from Hereditary spastic paraplegia - childhood onset to Hereditary spastic paraplegia; Spastic paraplegia 62, 615681
Childhood onset hereditary spastic paraplegia v0.60 ERLIN1 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Green following review on the Hereditary spastic paraplegia panel.
Childhood onset hereditary spastic paraplegia v0.59 HACE1 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green following review on the Hereditary spastic paraplegia panel.
Childhood onset hereditary spastic paraplegia v0.58 CYP27A1 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Amber to Green following review on the Hereditary spastic paraplegia panel.
Childhood onset hereditary spastic paraplegia v0.57 GBA2 Louise Daugherty Phenotypes for gene: GBA2 were changed from Spastic paraplegia 46, autosomal recessive to Spastic paraplegia 46, autosomal recessive, 614409
Childhood onset hereditary spastic paraplegia v0.54 RAB3GAP2 Rebecca Foulger Added comment: Comment on list classification: Kept rating as Red following review on the Hereditary spastic paraplegia panel.
Childhood onset hereditary spastic paraplegia v0.53 LYST Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Amber following review on the Hereditary spastic paraplegia panel.
Childhood onset hereditary spastic paraplegia v0.52 LYST Rebecca Foulger Phenotypes for gene: LYST were changed from spastic paraplegia to spastic paraplegia; Chediak-Higashi syndrome, 214500
Childhood onset hereditary spastic paraplegia v0.50 KLC4 Rebecca Foulger Added comment: Comment on list classification: Kept rating as Red following review on the Hereditary spastic paraplegia panel.
Childhood onset hereditary spastic paraplegia v0.49 KLC4 Rebecca Foulger Phenotypes for gene: KLC4 were changed from spastic paraplegia to spastic paraplegia; progressive complicated spastic paraplegia
Childhood onset hereditary spastic paraplegia v0.48 KDM5C Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Amber following review on the Hereditary spastic paraplegia panel.
Childhood onset hereditary spastic paraplegia v0.47 KDM5C Rebecca Foulger Phenotypes for gene: KDM5C were changed from Intellectual disability; progressive spasticity; epilepsy; hypothyroidism; developmental delay to Mental retardation, X-linked, syndromic, Claes-Jensen type, 300534; Intellectual disability; progressive spasticity; epilepsy; hypothyroidism; developmental delay
Childhood onset hereditary spastic paraplegia v0.46 HACE1 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Amber following review on the Hereditary spastic paraplegia panel.
Childhood onset hereditary spastic paraplegia v0.45 HACE1 Rebecca Foulger Phenotypes for gene: HACE1 were changed from psychomotor retardation; Spastic paraplegia; seizure to psychomotor retardation; Spastic paraplegia; seizure; Spastic paraplegia and psychomotor retardation with or without seizures, 616756
Childhood onset hereditary spastic paraplegia v0.44 ERLIN1 Rebecca Foulger Phenotypes for gene: ERLIN1 were changed from Hereditary spastic paraplegia to Hereditary spastic paraplegia - childhood onset
Childhood onset hereditary spastic paraplegia v0.43 DARS Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Amber following review on the Hereditary spastic paraplegia panel.
Childhood onset hereditary spastic paraplegia v0.42 DARS Rebecca Foulger Phenotypes for gene: DARS were changed from leg spasticity; Brain stem and spinal cord Hypomyelination to Brain stem and spinal cord Hypomyelination; leg spasticity; Hypomyelination with brainstem and spinal cord involvement and leg spasticity, 615281
Childhood onset hereditary spastic paraplegia v0.41 CYP27A1 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Amber following review on the Hereditary spastic paraplegia panel.
Childhood onset hereditary spastic paraplegia v0.40 CYP27A1 Rebecca Foulger Phenotypes for gene: CYP27A1 were changed from progressive lower extremity spasticity,often disproportionate to any degree of weakness to Cerebrotendinous xanthomatosis, 213700; progressive lower extremity spasticity,often disproportionate to any degree of weakness
Childhood onset hereditary spastic paraplegia v0.38 ATP13A2 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Green following review on the Hereditary spastic paraplegia panel. Note that this gene may not be appropriate for a childhood onset panel.
Childhood onset hereditary spastic paraplegia v0.36 ATP13A2 Rebecca Foulger Phenotypes for gene: ATP13A2 were changed from Adult-onset lower-limb predominant spastic paraparesis to Adult-onset lower-limb predominant spastic paraparesis; Spastic paraplegia 78, autosomal recessive, 617225; complicated hereditary spastic paraplegia
Childhood onset hereditary spastic paraplegia v0.35 ARG1 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Green following review on the Hereditary spastic paraplegia panel.
Childhood onset hereditary spastic paraplegia v0.33 ARG1 Rebecca Foulger Phenotypes for gene: ARG1 were changed from Argininaemia; Progressive spastic tetraplegia to Argininaemia, 207800; Progressive spastic tetraplegia
Childhood onset hereditary spastic paraplegia v0.31 ABCD1 Rebecca Foulger Phenotypes for gene: ABCD1 were changed from adrenal failure; VLCFA accumulation; Hereditary spastic paraplegia to adrenal failure; VLCFA accumulation; Hereditary spastic paraplegia; spastic paraparesis
Childhood onset hereditary spastic paraplegia v0.30 ABCD1 Rebecca Foulger Added comment: Comment on list classification: Updated rating from Red to Green following review on the Hereditary spastic paraplegia panel.
Childhood onset hereditary spastic paraplegia v0.28 TBP_CAG Louise Daugherty STR: TBP_CAG was added
STR: TBP_CAG was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list
STR tags were added to STR: TBP_CAG.
Mode of inheritance for STR: TBP_CAG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for STR: TBP_CAG were set to Spinocerebellar ataxia 17 607136
Review for STR: TBP_CAG was set to GREEN
Added comment: Source PanelApp panels : Hereditary spastic paraplegia Version 1.141
Sources: Expert list
Childhood onset hereditary spastic paraplegia v0.26 PPP2R2B_CAG Louise Daugherty STR: PPP2R2B_CAG was added
STR: PPP2R2B_CAG was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list
STR tags were added to STR: PPP2R2B_CAG.
Mode of inheritance for STR: PPP2R2B_CAG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for STR: PPP2R2B_CAG were set to Spinocerebellar ataxia 12 604326
Review for STR: PPP2R2B_CAG was set to GREEN
Added comment: Source PanelApp panels : Hereditary spastic paraplegia Version 1.141
Sources: Expert list
Childhood onset hereditary spastic paraplegia v0.24 HTT_CAG Louise Daugherty STR: HTT_CAG was added
STR: HTT_CAG was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list
STR tags were added to STR: HTT_CAG.
Mode of inheritance for STR: HTT_CAG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for STR: HTT_CAG were set to Huntington disease 143100
Review for STR: HTT_CAG was set to GREEN
Added comment: Source PanelApp panels : Hereditary spastic paraplegia Version 1.141
Sources: Expert list
Childhood onset hereditary spastic paraplegia v0.22 FXN_GAA Louise Daugherty STR: FXN_GAA was added
STR: FXN_GAA was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list
STR tags were added to STR: FXN_GAA.
Mode of inheritance for STR: FXN_GAA was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for STR: FXN_GAA were set to Friedreich ataxia 229300
Review for STR: FXN_GAA was set to GREEN
Added comment: Source PanelApp panels : Hereditary spastic paraplegia Version 1.141
Sources: Expert list
Childhood onset hereditary spastic paraplegia v0.20 CACNA1A_CAG Louise Daugherty STR: CACNA1A_CAG was added
STR: CACNA1A_CAG was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list
STR tags were added to STR: CACNA1A_CAG.
Mode of inheritance for STR: CACNA1A_CAG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for STR: CACNA1A_CAG were set to Spinocerebellar ataxia 6 183086
Review for STR: CACNA1A_CAG was set to GREEN
Added comment: Source PanelApp panels : Hereditary spastic paraplegia Version 1.141
Sources: Expert list
Childhood onset hereditary spastic paraplegia v0.18 ATXN7_CAG Louise Daugherty STR: ATXN7_CAG was added
STR: ATXN7_CAG was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list
STR tags were added to STR: ATXN7_CAG.
Mode of inheritance for STR: ATXN7_CAG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for STR: ATXN7_CAG were set to Spinocerebellar ataxia 7 164500
Review for STR: ATXN7_CAG was set to GREEN
Added comment: Source PanelApp panels : Hereditary spastic paraplegia Version 1.141
Sources: Expert list
Childhood onset hereditary spastic paraplegia v0.16 ATXN3_CAG Louise Daugherty STR: ATXN3_CAG was added
STR: ATXN3_CAG was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list
STR tags were added to STR: ATXN3_CAG.
Mode of inheritance for STR: ATXN3_CAG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for STR: ATXN3_CAG were set to Machado-Joseph disease 109150
Review for STR: ATXN3_CAG was set to GREEN
Added comment: Source PanelApp panels : Hereditary spastic paraplegia Version 1.141
Sources: Expert list
Childhood onset hereditary spastic paraplegia v0.14 ATXN2_CAG Louise Daugherty STR: ATXN2_CAG was added
STR: ATXN2_CAG was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list
STR tags were added to STR: ATXN2_CAG.
Mode of inheritance for STR: ATXN2_CAG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for STR: ATXN2_CAG were set to Spinocerebellar ataxia 2 183090
Review for STR: ATXN2_CAG was set to GREEN
Added comment: Source PanelApp panels : Hereditary spastic paraplegia Version 1.141
Sources: Expert list
Childhood onset hereditary spastic paraplegia v0.12 ATXN10_ATTCT Louise Daugherty STR: ATXN10_ATTCT was added
STR: ATXN10_ATTCT was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list
STR tags were added to STR: ATXN10_ATTCT.
Mode of inheritance for STR: ATXN10_ATTCT was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for STR: ATXN10_ATTCT were set to Spinocerebellar ataxia 10 603516
Review for STR: ATXN10_ATTCT was set to GREEN
Added comment: Source PanelApp panels : Hereditary spastic paraplegia Version 1.141
Sources: Expert list
Childhood onset hereditary spastic paraplegia v0.10 ATXN1_CAG Louise Daugherty STR: ATXN1_CAG was added
STR: ATXN1_CAG was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list
STR tags were added to STR: ATXN1_CAG.
Mode of inheritance for STR: ATXN1_CAG was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for STR: ATXN1_CAG were set to Spinocerebellar ataxia 1 164400
Review for STR: ATXN1_CAG was set to GREEN
Added comment: Source PanelApp panels : Hereditary spastic paraplegia Version 1.141
Sources: Expert list
Childhood onset hereditary spastic paraplegia v0.6 ZFYVE27 Sarah Leigh gene: ZFYVE27 was added
gene: ZFYVE27 was added to Hereditary spastic paraplegia - childhood onset. Sources: Radboud University Medical Center, Nijmegen,Expert list,Expert Review Red,Illumina TruGenome Clinical Sequencing Services
Mode of inheritance for gene: ZFYVE27 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ZFYVE27 were set to Mannan AU (2006)
Phenotypes for gene: ZFYVE27 were set to Spastic paraplegia 33, autosomal dominant
Childhood onset hereditary spastic paraplegia v0.6 ZFYVE26 Sarah Leigh gene: ZFYVE26 was added
gene: ZFYVE26 was added to Hereditary spastic paraplegia - childhood onset. Sources: Radboud University Medical Center, Nijmegen,UKGTN,Expert list,Expert Review Green,Illumina TruGenome Clinical Sequencing Services
Mode of inheritance for gene: ZFYVE26 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ZFYVE26 were set to Hanein et al. (2008)
Phenotypes for gene: ZFYVE26 were set to Spastic paraplegia 15, autosomal recessive
Childhood onset hereditary spastic paraplegia v0.6 ZEB2 Sarah Leigh gene: ZEB2 was added
gene: ZEB2 was added to Hereditary spastic paraplegia - childhood onset. Sources: UKGTN,Expert Review Red
Mode of inheritance for gene: ZEB2 was set to
Childhood onset hereditary spastic paraplegia v0.6 WDR48 Sarah Leigh gene: WDR48 was added
gene: WDR48 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list,Expert Review Red
Mode of inheritance for gene: WDR48 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WDR48 were set to Novarino et al. (2014)
Childhood onset hereditary spastic paraplegia v0.6 WDR45B Sarah Leigh gene: WDR45B was added
gene: WDR45B was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review Green,Literature
Mode of inheritance for gene: WDR45B was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: WDR45B were set to 21937992; 28503735
Phenotypes for gene: WDR45B were set to profound developmental delay, early-onset refractory epilepsy, progressive spastic quadriplegia and contractures, and brain malformations.
Childhood onset hereditary spastic paraplegia v0.6 WASHC5 Sarah Leigh gene: WASHC5 was added
gene: WASHC5 was added to Hereditary spastic paraplegia - childhood onset. Sources: Radboud University Medical Center, Nijmegen,UKGTN,Expert list,Expert Review Green,Illumina TruGenome Clinical Sequencing Services
Mode of inheritance for gene: WASHC5 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: WASHC5 were set to Valdmanis et al. (2007)
Phenotypes for gene: WASHC5 were set to Spastic paraplegia 8, autosomal dominant
Childhood onset hereditary spastic paraplegia v0.6 VPS37A Sarah Leigh gene: VPS37A was added
gene: VPS37A was added to Hereditary spastic paraplegia - childhood onset. Sources: Radboud University Medical Center, Nijmegen,Expert list,Expert Review Red
Mode of inheritance for gene: VPS37A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS37A were set to Zivony-Elboum et al. (2012)
Phenotypes for gene: VPS37A were set to Spastic paraplegia 53, autosomal recessive
Childhood onset hereditary spastic paraplegia v0.6 VAMP1 Sarah Leigh gene: VAMP1 was added
gene: VAMP1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Radboud University Medical Center, Nijmegen,Expert Review Red
Mode of inheritance for gene: VAMP1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: VAMP1 were set to 22958904
Phenotypes for gene: VAMP1 were set to Spastic ataxia 1, autosomal dominant, 108600
Childhood onset hereditary spastic paraplegia v0.6 USP8 Sarah Leigh gene: USP8 was added
gene: USP8 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list,Expert Review Red
Mode of inheritance for gene: USP8 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: USP8 were set to Novarino et al. (2014)
Childhood onset hereditary spastic paraplegia v0.6 TUBB4A Sarah Leigh gene: TUBB4A was added
gene: TUBB4A was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review,Expert Review Green
Mode of inheritance for gene: TUBB4A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: TUBB4A were set to Dystonia 4, torsion, autosomal dominant 128101; ataxia; Leukodystrophy, hypomyelinating, 6 612438
Childhood onset hereditary spastic paraplegia v0.6 TFG Sarah Leigh gene: TFG was added
gene: TFG was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list,Expert Review Red
Mode of inheritance for gene: TFG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TFG were set to Beetz et al. (2013)
Childhood onset hereditary spastic paraplegia v0.6 TECPR2 Sarah Leigh gene: TECPR2 was added
gene: TECPR2 was added to Hereditary spastic paraplegia - childhood onset. Sources: Radboud University Medical Center, Nijmegen,Expert list,Expert Review Red
Mode of inheritance for gene: TECPR2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TECPR2 were set to 23176824; 26542466
Phenotypes for gene: TECPR2 were set to Spastic paraplegia 49, autosomal recessive, 615031
Childhood onset hereditary spastic paraplegia v0.6 SPG7 Sarah Leigh gene: SPG7 was added
gene: SPG7 was added to Hereditary spastic paraplegia - childhood onset. Sources: Radboud University Medical Center, Nijmegen,UKGTN,Expert list,Expert Review Green,Illumina TruGenome Clinical Sequencing Services
Mode of inheritance for gene: SPG7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPG7 were set to Casari et al (1998)
Phenotypes for gene: SPG7 were set to Spastic paraplegia 7, autosomal recessive
Childhood onset hereditary spastic paraplegia v0.6 SPG21 Sarah Leigh gene: SPG21 was added
gene: SPG21 was added to Hereditary spastic paraplegia - childhood onset. Sources: UKGTN,Expert list,Expert Review Green,Illumina TruGenome Clinical Sequencing Services
Mode of inheritance for gene: SPG21 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPG21 were set to Simpson et al. (2003)
Phenotypes for gene: SPG21 were set to Spastic Paraplegia, Recessive
Childhood onset hereditary spastic paraplegia v0.6 SPG11 Sarah Leigh gene: SPG11 was added
gene: SPG11 was added to Hereditary spastic paraplegia - childhood onset. Sources: Radboud University Medical Center, Nijmegen,UKGTN,Expert list,Expert Review Green,Illumina TruGenome Clinical Sequencing Services
Mode of inheritance for gene: SPG11 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPG11 were set to Stevanin et al. (2007)
Phenotypes for gene: SPG11 were set to Spastic paraplegia 11, autosomal recessive
Childhood onset hereditary spastic paraplegia v0.6 SPAST Sarah Leigh gene: SPAST was added
gene: SPAST was added to Hereditary spastic paraplegia - childhood onset. Sources: UKGTN,Radboud University Medical Center, Nijmegen,Expert list,Expert Review Green,Eligibility statement prior genetic testing,Illumina TruGenome Clinical Sequencing Services
Mode of inheritance for gene: SPAST was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SPAST were set to Hazan et al (1999)
Phenotypes for gene: SPAST were set to Spastic paraplegia 4, autosomal dominant
Childhood onset hereditary spastic paraplegia v0.6 SPART Sarah Leigh gene: SPART was added
gene: SPART was added to Hereditary spastic paraplegia - childhood onset. Sources: UKGTN,Expert list,Expert Review Green
Mode of inheritance for gene: SPART was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SPART were set to Patel et al. (2002
Childhood onset hereditary spastic paraplegia v0.6 SLC33A1 Sarah Leigh gene: SLC33A1 was added
gene: SLC33A1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Radboud University Medical Center, Nijmegen,UKGTN,Expert list,Expert Review Red,Illumina TruGenome Clinical Sequencing Services
Mode of inheritance for gene: SLC33A1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: SLC33A1 were set to Lin et al. (2008)
Phenotypes for gene: SLC33A1 were set to Spastic paraplegia 42, autosomal dominant,
Childhood onset hereditary spastic paraplegia v0.6 SLC2A1 Sarah Leigh gene: SLC2A1 was added
gene: SLC2A1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review Red,Literature
Mode of inheritance for gene: SLC2A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC2A1 were set to 21832227; 18606970; 11136715
Phenotypes for gene: SLC2A1 were set to paroxysmal choreoathetosis; spastic paraplegia; seizure; Developmental delay
Childhood onset hereditary spastic paraplegia v0.6 SLC25A46 Sarah Leigh gene: SLC25A46 was added
gene: SLC25A46 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review Green,Literature
Mode of inheritance for gene: SLC25A46 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC25A46 were set to 28369803; 26168012
Phenotypes for gene: SLC25A46 were set to Neuropathy, hereditary motor and sensory, type VIB, 616505
Childhood onset hereditary spastic paraplegia v0.6 SLC1A4 Sarah Leigh gene: SLC1A4 was added
gene: SLC1A4 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review,Expert Review Green
Mode of inheritance for gene: SLC1A4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SLC1A4 were set to 25930971; 26041762; 29989513; 26138499; 27193218
Phenotypes for gene: SLC1A4 were set to Spastic tetraplegia, thin corpus callosum, and progressive microcephaly, 616657
Childhood onset hereditary spastic paraplegia v0.6 SLC16A2 Sarah Leigh gene: SLC16A2 was added
gene: SLC16A2 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list,Expert Review Green
Mode of inheritance for gene: SLC16A2 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: SLC16A2 were set to Friesema et al. (2003)
Childhood onset hereditary spastic paraplegia v0.6 SERAC1 Sarah Leigh gene: SERAC1 was added
gene: SERAC1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Other,Expert Review Green
Mode of inheritance for gene: SERAC1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SERAC1 were set to 27186703; 28482397; 27604308; 28778788; 29205472; 22683713; 16527507
Phenotypes for gene: SERAC1 were set to MEGDEL syndrome; MEGDHEL syndrome; 3-MEthylGlutaconic aciduria, Dystonia-Deafness, Hepatopathy, Encephalopathy, Leigh-like syndrome; 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome, 614739
Childhood onset hereditary spastic paraplegia v0.6 SACS Sarah Leigh gene: SACS was added
gene: SACS was added to Hereditary spastic paraplegia - childhood onset. Sources: Radboud University Medical Center, Nijmegen,UKGTN,Expert Review Green
Mode of inheritance for gene: SACS was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: SACS were set to Spastic ataxia, Charlevoix-Saguenay type
Childhood onset hereditary spastic paraplegia v0.6 RTN2 Sarah Leigh gene: RTN2 was added
gene: RTN2 was added to Hereditary spastic paraplegia - childhood onset. Sources: Radboud University Medical Center, Nijmegen,Expert list,Expert Review Green,Illumina TruGenome Clinical Sequencing Services
Mode of inheritance for gene: RTN2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: RTN2 were set to Montenegro et al. (2012)
Phenotypes for gene: RTN2 were set to Spastic paraplegia 12, autosomal dominant
Childhood onset hereditary spastic paraplegia v0.6 REEP2 Sarah Leigh gene: REEP2 was added
gene: REEP2 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review Amber,Other,Literature
Mode of inheritance for gene: REEP2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: REEP2 were set to 24388663
Phenotypes for gene: REEP2 were set to ?Spastic paraplegia 72, autosomal recessive, 615625; ?Spastic paraplegia 72, autosomal dominant,615625
Childhood onset hereditary spastic paraplegia v0.6 REEP1 Sarah Leigh gene: REEP1 was added
gene: REEP1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Radboud University Medical Center, Nijmegen,UKGTN,Expert list,Expert Review Green,Illumina TruGenome Clinical Sequencing Services
Mode of inheritance for gene: REEP1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: REEP1 were set to Zuchner et al. (2006)
Phenotypes for gene: REEP1 were set to Spastic paraplegia 31, autosomal dominant
Childhood onset hereditary spastic paraplegia v0.6 RAB3GAP2 Sarah Leigh gene: RAB3GAP2 was added
gene: RAB3GAP2 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review Red,Literature
Mode of inheritance for gene: RAB3GAP2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: RAB3GAP2 were set to 24482476
Phenotypes for gene: RAB3GAP2 were set to spastic paraplegia
Childhood onset hereditary spastic paraplegia v0.6 PSEN1 Sarah Leigh gene: PSEN1 was added
gene: PSEN1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Radboud University Medical Center, Nijmegen,Expert Review Red
Mode of inheritance for gene: PSEN1 was set to
Phenotypes for gene: PSEN1 were set to Alzheimer disease, type 3, with spastic paraparesis and unusual plaques; Alzheimer disease, type 3, with spastic paraparesis and apraxia
Childhood onset hereditary spastic paraplegia v0.6 POLR3A Sarah Leigh gene: POLR3A was added
gene: POLR3A was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review Green,Literature
Mode of inheritance for gene: POLR3A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: POLR3A were set to 21855841; 25655951
Phenotypes for gene: POLR3A were set to Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism; Autosomal Recessive Ataxia
Childhood onset hereditary spastic paraplegia v0.6 PNPLA6 Sarah Leigh gene: PNPLA6 was added
gene: PNPLA6 was added to Hereditary spastic paraplegia - childhood onset. Sources: Radboud University Medical Center, Nijmegen,Expert list,Expert Review Green,Illumina TruGenome Clinical Sequencing Services
Mode of inheritance for gene: PNPLA6 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PNPLA6 were set to Rainier et al. (2008)
Phenotypes for gene: PNPLA6 were set to Spastic paraplegia 39, autosomal recessive
Childhood onset hereditary spastic paraplegia v0.6 PLP1 Sarah Leigh gene: PLP1 was added
gene: PLP1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Radboud University Medical Center, Nijmegen,UKGTN,Expert list,Expert Review Green
Mode of inheritance for gene: PLP1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: PLP1 were set to Saugier-Veber et al (1994)
Phenotypes for gene: PLP1 were set to Spastic paraplegia 2, X-linked
Childhood onset hereditary spastic paraplegia v0.6 PGAP1 Sarah Leigh gene: PGAP1 was added
gene: PGAP1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list,Expert Review Red
Mode of inheritance for gene: PGAP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PGAP1 were set to Novarino et al. (2014)
Childhood onset hereditary spastic paraplegia v0.6 PCDH12 Sarah Leigh gene: PCDH12 was added
gene: PCDH12 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review
Mode of inheritance for gene: PCDH12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PCDH12 were set to 27164683
Phenotypes for gene: PCDH12 were set to microcephaly; epilepsy; midbrain abnormalities; intellectual disability; hypothalamic abnormalities; perithalamic hyperechogenicity; periventricular hyperechogenicity
Childhood onset hereditary spastic paraplegia v0.6 OPA3 Sarah Leigh gene: OPA3 was added
gene: OPA3 was added to Hereditary spastic paraplegia - childhood onset. Sources: Other,Expert Review Green,Literature
Mode of inheritance for gene: OPA3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: OPA3 were set to 25201222; 11668429; 20301646; 24944951; 25657044
Phenotypes for gene: OPA3 were set to 3-methylglutaconic aciduria, type III, 258501; Costeff syndrome
Childhood onset hereditary spastic paraplegia v0.6 NT5C2 Sarah Leigh gene: NT5C2 was added
gene: NT5C2 was added to Hereditary spastic paraplegia - childhood onset. Sources: Radboud University Medical Center, Nijmegen,Expert list,Expert Review Red
Mode of inheritance for gene: NT5C2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NT5C2 were set to 29123918; 28884889; 24482476; 28327087
Phenotypes for gene: NT5C2 were set to Spasticparaplegia45, autosomal recessive 613162
Childhood onset hereditary spastic paraplegia v0.6 NKX6-2 Sarah Leigh gene: NKX6-2 was added
gene: NKX6-2 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review Green,Literature
Mode of inheritance for gene: NKX6-2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NKX6-2 were set to 15601927; 28575651
Phenotypes for gene: NKX6-2 were set to Spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy, 617560
Childhood onset hereditary spastic paraplegia v0.6 NIPA1 Sarah Leigh gene: NIPA1 was added
gene: NIPA1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Radboud University Medical Center, Nijmegen,UKGTN,Expert list,Expert Review Green,Illumina TruGenome Clinical Sequencing Services
Mode of inheritance for gene: NIPA1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: NIPA1 were set to Rainier et al. (2003)
Phenotypes for gene: NIPA1 were set to Spasticparaplegia6,autosomaldominant,600363; Spastic paraplegia 6, autosomal dominant
Childhood onset hereditary spastic paraplegia v0.6 MTPAP Sarah Leigh gene: MTPAP was added
gene: MTPAP was added to Hereditary spastic paraplegia - childhood onset. Sources: Radboud University Medical Center, Nijmegen,UKGTN,Expert Review Red
Mode of inheritance for gene: MTPAP was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: MTPAP were set to Spastic ataxia 4, autosomal recessive; Ataxia, spastic, 4
Childhood onset hereditary spastic paraplegia v0.6 MARS2 Sarah Leigh gene: MARS2 was added
gene: MARS2 was added to Hereditary spastic paraplegia - childhood onset. Sources: Radboud University Medical Center, Nijmegen,Expert Review Red
Mode of inheritance for gene: MARS2 was set to
Phenotypes for gene: MARS2 were set to Spastic ataxia 3, autosomal recessive
Childhood onset hereditary spastic paraplegia v0.6 MARS Sarah Leigh gene: MARS was added
gene: MARS was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list,Expert Review Red
Mode of inheritance for gene: MARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MARS were set to Novarino et al. (2014)
Childhood onset hereditary spastic paraplegia v0.6 MAG Sarah Leigh gene: MAG was added
gene: MAG was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review Amber,Literature
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
Childhood onset hereditary spastic paraplegia v0.6 LYST Sarah Leigh gene: LYST was added
gene: LYST was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review Red,Literature
Mode of inheritance for gene: LYST was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: LYST were set to 24521565
Phenotypes for gene: LYST were set to spastic paraplegia
Childhood onset hereditary spastic paraplegia v0.6 L1CAM Sarah Leigh gene: L1CAM was added
gene: L1CAM was added to Hereditary spastic paraplegia - childhood onset. Sources: UKGTN,Expert list,Expert Review Green
Mode of inheritance for gene: L1CAM was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: L1CAM were set to PMID: 7920659
Phenotypes for gene: L1CAM were set to X-linked hydrocephalus, MASA syndrome, Hereditary spastic paraplegia
Childhood onset hereditary spastic paraplegia v0.6 KLC4 Sarah Leigh gene: KLC4 was added
gene: KLC4 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review Red,Literature
Mode of inheritance for gene: KLC4 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: KLC4 were set to 26423925
Phenotypes for gene: KLC4 were set to spastic paraplegia
Childhood onset hereditary spastic paraplegia v0.6 KIF5A Sarah Leigh gene: KIF5A was added
gene: KIF5A was added to Hereditary spastic paraplegia - childhood onset. Sources: Radboud University Medical Center, Nijmegen,UKGTN,Expert list,Expert Review Green,Illumina TruGenome Clinical Sequencing Services
Mode of inheritance for gene: KIF5A was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: KIF5A were set to Reid et al. (2002)
Phenotypes for gene: KIF5A were set to Spastic paraplegia 10, autosomal dominant
Childhood onset hereditary spastic paraplegia v0.6 KIF1C Sarah Leigh gene: KIF1C was added
gene: KIF1C was added to Hereditary spastic paraplegia - childhood onset. Sources: Radboud University Medical Center, Nijmegen,Expert list,Expert Review Red
Mode of inheritance for gene: KIF1C was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF1C were set to 17273843; 24482476; 24319291
Phenotypes for gene: KIF1C were set to Spastic ataxia 2,autosomal recessive
Childhood onset hereditary spastic paraplegia v0.6 KIF1A Sarah Leigh gene: KIF1A was added
gene: KIF1A was added to Hereditary spastic paraplegia - childhood onset. Sources: Radboud University Medical Center, Nijmegen,Expert list,Expert Review Green,Illumina TruGenome Clinical Sequencing Services
Mode of inheritance for gene: KIF1A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: KIF1A were set to Erlich et al. (2011)
Phenotypes for gene: KIF1A were set to Spastic paraplegia 30, autosomal recessive
Childhood onset hereditary spastic paraplegia v0.6 KIDINS220 Sarah Leigh gene: KIDINS220 was added
gene: KIDINS220 was added to Hereditary spastic paraplegia - childhood onset. Sources: Other,Expert Review Green
Mode of inheritance for gene: KIDINS220 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes for gene: KIDINS220 were set to Spastic paraplegia, intellectual disability, nystagmus, and obesity 617296
Childhood onset hereditary spastic paraplegia v0.6 KDM5C Sarah Leigh gene: KDM5C was added
gene: KDM5C was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review Red,Literature
Mode of inheritance for gene: KDM5C was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: KDM5C were set to 26919706; 15586325; 10982473
Phenotypes for gene: KDM5C were set to Intellectual disability; progressive spasticity; epilepsy; hypothyroidism; developmental delay
Childhood onset hereditary spastic paraplegia v0.6 IBA57 Sarah Leigh gene: IBA57 was added
gene: IBA57 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review Amber,Literature
Mode of inheritance for gene: IBA57 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: IBA57 were set to 30258207; 25609768
Phenotypes for gene: IBA57 were set to ?Spastic paraplegia 74, autosomal recessive, 616451
Childhood onset hereditary spastic paraplegia v0.6 HSPD1 Sarah Leigh gene: HSPD1 was added
gene: HSPD1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Radboud University Medical Center, Nijmegen,UKGTN,Expert list,Expert Review Green,Illumina TruGenome Clinical Sequencing Services
Mode of inheritance for gene: HSPD1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: HSPD1 were set to Hansen et al. (2002)
Phenotypes for gene: HSPD1 were set to Spastic paraplegia 13, autosomal dominant
Childhood onset hereditary spastic paraplegia v0.6 HACE1 Sarah Leigh gene: HACE1 was added
gene: HACE1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review Red,Literature
Mode of inheritance for gene: HACE1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: HACE1 were set to 26437029; 26424145
Phenotypes for gene: HACE1 were set to psychomotor retardation; Spastic paraplegia; seizure
Childhood onset hereditary spastic paraplegia v0.6 GJC2 Sarah Leigh gene: GJC2 was added
gene: GJC2 was added to Hereditary spastic paraplegia - childhood onset. Sources: Radboud University Medical Center, Nijmegen,UKGTN,Expert list,Expert Review Red
Mode of inheritance for gene: GJC2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GJC2 were set to Orthmann-Murphy et al. (2009)
Phenotypes for gene: GJC2 were set to Spastic paraplegia 44, autosomal recessive
Childhood onset hereditary spastic paraplegia v0.6 GCH1 Sarah Leigh gene: GCH1 was added
gene: GCH1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review Amber,Literature
Mode of inheritance for gene: GCH1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: GCH1 were set to 21935284; 24509643
Phenotypes for gene: GCH1 were set to progressive spastic paraplegia; Spastic paraplegia; Dystonia, DOPA-responsive, with or without hyperphenylalaninemia, 128230; Dystonia
Childhood onset hereditary spastic paraplegia v0.6 GBA2 Sarah Leigh gene: GBA2 was added
gene: GBA2 was added to Hereditary spastic paraplegia - childhood onset. Sources: Radboud University Medical Center, Nijmegen,UKGTN,Expert list,Expert Review Green
Mode of inheritance for gene: GBA2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: GBA2 were set to Martin et al. (2013)
Phenotypes for gene: GBA2 were set to Spastic paraplegia 46, autosomal recessive
Childhood onset hereditary spastic paraplegia v0.6 GAD1 Sarah Leigh gene: GAD1 was added
gene: GAD1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Radboud University Medical Center, Nijmegen,Expert Review Red
Mode of inheritance for gene: GAD1 was set to
Phenotypes for gene: GAD1 were set to Cerebralpalsy,spasticquadriplegic,1,603513
Childhood onset hereditary spastic paraplegia v0.6 FARS2 Sarah Leigh gene: FARS2 was added
gene: FARS2 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review Green,Literature
Mode of inheritance for gene: FARS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FARS2 were set to 29126765; 26553276; 25851414; 30250868
Phenotypes for gene: FARS2 were set to Spastic paraplegia 77, autosomal recessive, 617046
Childhood onset hereditary spastic paraplegia v0.6 FA2H Sarah Leigh gene: FA2H was added
gene: FA2H was added to Hereditary spastic paraplegia - childhood onset. Sources: Radboud University Medical Center, Nijmegen,UKGTN,Expert list,Expert Review Green
Mode of inheritance for gene: FA2H was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FA2H were set to Edvardson et al. (2008)
Phenotypes for gene: FA2H were set to Spastic paraplegia 35, autosomal recessive
Childhood onset hereditary spastic paraplegia v0.6 ERLIN2 Sarah Leigh gene: ERLIN2 was added
gene: ERLIN2 was added to Hereditary spastic paraplegia - childhood onset. Sources: Radboud University Medical Center, Nijmegen,Expert list,Expert Review Green
Mode of inheritance for gene: ERLIN2 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Publications for gene: ERLIN2 were set to 27824013; 23085305; 21330303; 23109142; 28832565; 23897027; 22554690; 25977983; 23109145; 21796390; 29528531
Phenotypes for gene: ERLIN2 were set to Spastic paraplegia 18, autosomal recessive, 611225; neurodegeneration; hereditary spastic paraplegia; Spastic paraplegia, autosomal dominant
Childhood onset hereditary spastic paraplegia v0.6 ERLIN1 Sarah Leigh gene: ERLIN1 was added
gene: ERLIN1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Other,Expert Review Red
Mode of inheritance for gene: ERLIN1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ERLIN1 were set to 24482476
Phenotypes for gene: ERLIN1 were set to Hereditary spastic paraplegia
Childhood onset hereditary spastic paraplegia v0.6 ENTPD1 Sarah Leigh gene: ENTPD1 was added
gene: ENTPD1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Radboud University Medical Center, Nijmegen,Expert list,Expert Review Red
Mode of inheritance for gene: ENTPD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ENTPD1 were set to Novarino et al. (2014)
Phenotypes for gene: ENTPD1 were set to Spasticparaplegia64,615683
Childhood onset hereditary spastic paraplegia v0.6 DSTYK Sarah Leigh gene: DSTYK was added
gene: DSTYK was added to Hereditary spastic paraplegia - childhood onset. Sources: Other
Mode of inheritance for gene: DSTYK was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DSTYK were set to 28157540
Phenotypes for gene: DSTYK were set to Spastic paraplegia 23, 270750
Childhood onset hereditary spastic paraplegia v0.6 DDHD2 Sarah Leigh gene: DDHD2 was added
gene: DDHD2 was added to Hereditary spastic paraplegia - childhood onset. Sources: Radboud University Medical Center, Nijmegen,Expert list,Expert Review Green
Mode of inheritance for gene: DDHD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DDHD2 were set to Schuurs-Hoeijmakers et al. (2012)
Phenotypes for gene: DDHD2 were set to Spastic paraplegia 54, autosomal recessive
Childhood onset hereditary spastic paraplegia v0.6 DDHD1 Sarah Leigh gene: DDHD1 was added
gene: DDHD1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Radboud University Medical Center, Nijmegen,Expert list,Expert Review Green
Mode of inheritance for gene: DDHD1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DDHD1 were set to Tesson et al. (2012)
Phenotypes for gene: DDHD1 were set to Spastic paraplegia 28, autosomal recessive
Childhood onset hereditary spastic paraplegia v0.6 DARS Sarah Leigh gene: DARS was added
gene: DARS was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review Red,Literature
Mode of inheritance for gene: DARS was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: DARS were set to 25527264; 23643384
Phenotypes for gene: DARS were set to leg spasticity; Brain stem and spinal cord Hypomyelination
Childhood onset hereditary spastic paraplegia v0.6 CYP7B1 Sarah Leigh gene: CYP7B1 was added
gene: CYP7B1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Radboud University Medical Center, Nijmegen,UKGTN,Expert list,Expert Review Green,Illumina TruGenome Clinical Sequencing Services
Mode of inheritance for gene: CYP7B1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CYP7B1 were set to Tsaousidou et al. (2008) i
Phenotypes for gene: CYP7B1 were set to Spastic paraplegia 5A, autosomal recessive
Childhood onset hereditary spastic paraplegia v0.6 CYP2U1 Sarah Leigh gene: CYP2U1 was added
gene: CYP2U1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Radboud University Medical Center, Nijmegen,Expert list,Expert Review Green
Mode of inheritance for gene: CYP2U1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CYP2U1 were set to Tesson et al. (2012)
Phenotypes for gene: CYP2U1 were set to Spastic paraplegia 56, autosomal recessive
Childhood onset hereditary spastic paraplegia v0.6 CYP27A1 Sarah Leigh gene: CYP27A1 was added
gene: CYP27A1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review Red,Literature
Mode of inheritance for gene: CYP27A1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: CYP27A1 were set to 25862734
Phenotypes for gene: CYP27A1 were set to progressive lower extremity spasticity,often disproportionate to any degree of weakness
Childhood onset hereditary spastic paraplegia v0.6 CDK16 Sarah Leigh gene: CDK16 was added
gene: CDK16 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review Amber,Literature
Mode of inheritance for gene: CDK16 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: CDK16 were set to 25644381; 26350204
Phenotypes for gene: CDK16 were set to Intellectual disability and spastic paraplegia
Childhood onset hereditary spastic paraplegia v0.6 CCT5 Sarah Leigh gene: CCT5 was added
gene: CCT5 was added to Hereditary spastic paraplegia - childhood onset. Sources: Radboud University Medical Center, Nijmegen,Expert Review Red,Illumina TruGenome Clinical Sequencing Services
Mode of inheritance for gene: CCT5 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CCT5 were set to Neuropathy, hereditary sensory, with spastic paraplegia; Sensory Neuropathy with Spastic Paraplegia
Childhood onset hereditary spastic paraplegia v0.6 CAPN1 Sarah Leigh gene: CAPN1 was added
gene: CAPN1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list,Expert Review Green
Mode of inheritance for gene: CAPN1 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: CAPN1 were set to Spastic paraplegia 76 autosomal recessive, 616907
Childhood onset hereditary spastic paraplegia v0.6 C19orf12 Sarah Leigh gene: C19orf12 was added
gene: C19orf12 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list,Expert Review Green
Mode of inheritance for gene: C19orf12 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C19orf12 were set to Landoure (2013)
Childhood onset hereditary spastic paraplegia v0.6 C12orf65 Sarah Leigh gene: C12orf65 was added
gene: C12orf65 was added to Hereditary spastic paraplegia - childhood onset. Sources: Radboud University Medical Center, Nijmegen,Expert list,Expert Review Green
Mode of inheritance for gene: C12orf65 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: C12orf65 were set to Shimazaki et al. (2012)
Phenotypes for gene: C12orf65 were set to Spasticparaplegia55,autosomalrecessive,615035
Childhood onset hereditary spastic paraplegia v0.6 BSCL2 Sarah Leigh gene: BSCL2 was added
gene: BSCL2 was added to Hereditary spastic paraplegia - childhood onset. Sources: Radboud University Medical Center, Nijmegen,UKGTN,Expert list,Expert Review Green
Mode of inheritance for gene: BSCL2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: BSCL2 were set to Windpassinger et al. (2004)
Phenotypes for gene: BSCL2 were set to Silver spastic paraplegia syndrome,
Childhood onset hereditary spastic paraplegia v0.6 B4GALNT1 Sarah Leigh gene: B4GALNT1 was added
gene: B4GALNT1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Radboud University Medical Center, Nijmegen,Expert list,Expert Review Green
Mode of inheritance for gene: B4GALNT1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: B4GALNT1 were set to Boukhris et al. (2013)
Phenotypes for gene: B4GALNT1 were set to Spastic paraplegia 26, autosomal recessive
Childhood onset hereditary spastic paraplegia v0.6 ATP13A2 Sarah Leigh gene: ATP13A2 was added
gene: ATP13A2 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review Red,Literature
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 Adult-onset lower-limb predominant spastic paraparesis
Childhood onset hereditary spastic paraplegia v0.6 ATL1 Sarah Leigh gene: ATL1 was added
gene: ATL1 was added to Hereditary spastic paraplegia - childhood onset. Sources: UKGTN,Radboud University Medical Center, Nijmegen,Expert list,Expert Review Green,Eligibility statement prior genetic testing,Illumina TruGenome Clinical Sequencing Services
Mode of inheritance for gene: ATL1 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications for gene: ATL1 were set to PMID: 11685207
Phenotypes for gene: ATL1 were set to Spastic paraplegia 3A, autosomal dominant; Spastic paraplegia 3A, autosomal dominant,; Spastic Paraplegia, Dominant
Childhood onset hereditary spastic paraplegia v0.6 ARSI Sarah Leigh gene: ARSI was added
gene: ARSI was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list,Expert Review Red
Mode of inheritance for gene: ARSI was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ARSI were set to Novarino et al. (2014)
Childhood onset hereditary spastic paraplegia v0.6 ARL6IP1 Sarah Leigh gene: ARL6IP1 was added
gene: ARL6IP1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list,Expert Review Red
Mode of inheritance for gene: ARL6IP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ARL6IP1 were set to Novarino et al. (2014)
Childhood onset hereditary spastic paraplegia v0.6 ARG1 Sarah Leigh gene: ARG1 was added
gene: ARG1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review Red,Literature
Mode of inheritance for gene: ARG1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ARG1 were set to 23859858; 26310552
Phenotypes for gene: ARG1 were set to Argininaemia; Progressive spastic tetraplegia
Childhood onset hereditary spastic paraplegia v0.6 AP5Z1 Sarah Leigh gene: AP5Z1 was added
gene: AP5Z1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Radboud University Medical Center, Nijmegen,Expert list,Expert Review Red,Illumina TruGenome Clinical Sequencing Services
Mode of inheritance for gene: AP5Z1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AP5Z1 were set to Slabicki et al. (2010) i
Phenotypes for gene: AP5Z1 were set to Spastic paraplegia 48, autosomal recessive; Spastic Paraplegia, Recessive
Childhood onset hereditary spastic paraplegia v0.6 AP4S1 Sarah Leigh gene: AP4S1 was added
gene: AP4S1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Radboud University Medical Center, Nijmegen,Expert list,Expert Review Green
Mode of inheritance for gene: AP4S1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AP4S1 were set to Abou Jamra et al. (2011)
Phenotypes for gene: AP4S1 were set to seizures; developmental delay; Spastic paraplegia 52, autosomal recessive
Childhood onset hereditary spastic paraplegia v0.6 AP4M1 Sarah Leigh gene: AP4M1 was added
gene: AP4M1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Radboud University Medical Center, Nijmegen,Expert list,Expert Review Green
Mode of inheritance for gene: AP4M1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AP4M1 were set to Verkerk et al. (2009)
Phenotypes for gene: AP4M1 were set to Spastic paraplegia 50, autosomal recessive
Childhood onset hereditary spastic paraplegia v0.6 AP4E1 Sarah Leigh gene: AP4E1 was added
gene: AP4E1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Radboud University Medical Center, Nijmegen,Expert list,Expert Review Green
Mode of inheritance for gene: AP4E1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AP4E1 were set to Moreno-De-Luca et al. (2011)
Phenotypes for gene: AP4E1 were set to Spastic paraplegia 51, autosomal recessive
Childhood onset hereditary spastic paraplegia v0.6 AP4B1 Sarah Leigh gene: AP4B1 was added
gene: AP4B1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Radboud University Medical Center, Nijmegen,Expert list,Expert Review Green
Mode of inheritance for gene: AP4B1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AP4B1 were set to Abou Jamra et al. (2011) i
Phenotypes for gene: AP4B1 were set to Spastic paraplegia 47, autosomal recessive
Childhood onset hereditary spastic paraplegia v0.6 AMPD2 Sarah Leigh gene: AMPD2 was added
gene: AMPD2 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list,Expert Review Red
Mode of inheritance for gene: AMPD2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AMPD2 were set to Novarino et al. (2014)
Phenotypes for gene: AMPD2 were set to Pontocerebellar hypolplasia (biallelic); Hereditary Spastic Paraplegia?
Childhood onset hereditary spastic paraplegia v0.6 ALS2 Sarah Leigh gene: ALS2 was added
gene: ALS2 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list,Expert Review Green
Mode of inheritance for gene: ALS2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ALS2 were set to 12145748
Phenotypes for gene: ALS2 were set to 607225
Childhood onset hereditary spastic paraplegia v0.6 ALDH18A1 Sarah Leigh gene: ALDH18A1 was added
gene: ALDH18A1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Other,Expert Review Green,Literature
Mode of inheritance for gene: ALDH18A1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: ALDH18A1 were set to ADCL3 AUTOSOMAL RECESSIVE MENTAL RETARDATION-JOINT HYPERMOBILITY-SKIN LAXITY WITH OR WITHOUT METABOLIC ABNORMALITIES (MRJHSL) SPASTIC PARAPLEGIA 9, AUTOSOMAL DOMINANT; SPG9; Spastic paraplegia 9B, autosomal recessive CUTIS LAXA, AUTOSOMAL DOMINANT 3; Spastic paraplegia 9A, autosomal dominant
Childhood onset hereditary spastic paraplegia v0.6 AIMP1 Sarah Leigh gene: AIMP1 was added
gene: AIMP1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert list,Expert Review Green
Mode of inheritance for gene: AIMP1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: AIMP1 were set to 21092922
Phenotypes for gene: AIMP1 were set to 260600
Childhood onset hereditary spastic paraplegia v0.6 AFG3L2 Sarah Leigh gene: AFG3L2 was added
gene: AFG3L2 was added to Hereditary spastic paraplegia - childhood onset. Sources: Radboud University Medical Center, Nijmegen,UKGTN,Expert Review Green
Mode of inheritance for gene: AFG3L2 was set to BIALLELIC, autosomal or pseudoautosomal
Phenotypes for gene: AFG3L2 were set to Spastic ataxia 5, autosomal recessive; Ataxia, spastic, 5, autosomal recessive
Childhood onset hereditary spastic paraplegia v0.6 ADAR Sarah Leigh gene: ADAR was added
gene: ADAR was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review,Expert Review Green
Mode of inheritance for gene: ADAR was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ADAR were set to 25243380
Phenotypes for gene: ADAR were set to Aicardi-Goutieres syndrome 6, 615010
Childhood onset hereditary spastic paraplegia v0.6 ABCD1 Sarah Leigh gene: ABCD1 was added
gene: ABCD1 was added to Hereditary spastic paraplegia - childhood onset. Sources: Expert Review Red,Literature
Mode of inheritance for gene: ABCD1 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Phenotypes for gene: ABCD1 were set to adrenal failure; VLCFA accumulation; Hereditary spastic paraplegia
Childhood onset hereditary spastic paraplegia v0.5 Louise Daugherty List of related panels changed from Childhood onset hereditary spastic paraplegia; GMS R61 to Childhood onset hereditary spastic paraplegia
Childhood onset hereditary spastic paraplegia v0.2 Ellen McDonagh List of related panels changed from to Childhood onset hereditary spastic paraplegia; GMS R61
Childhood onset hereditary spastic paraplegia v0.0 Ellen McDonagh Added Panel Hereditary spastic paraplegia - childhood onset
Set panel types to: GMS Rare Disease Virtual