Optic neuropathy

Gene: SPG7

Green List (high evidence)

Comment on list classification: There is limited evidence that monoallelic SPG7 variants can cause dominant optic atrophy. The majority of patients reported in literature harbour biallelic SPG7 mutations, with heterozygous carriers being unaffected. Biallelic mutations are known to cause Spastic paraplegia 7, with optic atrophy as a common feature. The evidence for dominant inheritance is controversial (e.g, PMID: 31854126 deep intronic SPG7 variant detectable only by WGS; possible digenic inheritance with variants in other spasticity-related genes / SPG7-interacting genes - emerging evidence for AFG3L2 in particular - PMID: 23065789, 33598982, 33774748; recurring variants are too common in the population to be associated with dominant disease). Based on the available evidence, MOI should be changed to BIALLELIC, autosomal or pseudoautosomal at the next GMS update. Expert review will be requested regarding the monoallelic cases.

Created: 8 Jan 2026, 4:50 p.m. | Last Modified: 11 Feb 2026, 10:30 a.m.

Panel Version: 5.44

PMID: 37983191 Bell et al., 2024
5 cases with heterozygous SPG7 variants and progressive vision loss, several also had previous diagnoses of peripheral neuropathy (e.g., Guillain-Barré Syndrome). Seq method: WES (1 case) or optic atrophy panel (4 cases).
Variants identified: p.Ala759Thr, p.Gln447Ter, p.Ala510Val (3 cases). Age of onset range: 8-48 yrs old.
SPG7: c.1529C>T, p.Ala510Val has MAF = 0.007265 in gnomAD v4.1.0 (European population), with 44 total homozygotes reported;
SPG7: c.2275G>A, p.Ala759Thr has MAF = 0.0009866 in gnomAD v4 (European), no homozygotes reported.
SPG7 c.1339C>T, p.Gln447Ter has 1 allele recorded in gnomAD v4.

PMID: 33841295 Charif et al., 2021
Identified 6 individuals with heterozygous SPG7 variants and 5 families with biallelic SPG7 variants. Heterozygous cases presented with isolated optic atrophy, while individuals with biallelic SPG7 variants had a syndromic presentation with optic atrophy as a feature. Seq method: isolated optic neuropathy panel.

PMID: 32548275 Charif et al., 2020
7 families with isolated optic atrophy, with heterozygous SPG7 variants. Only 1 family with evidence of segregation with disease, unaffected family members not genotyped. Seq method: targeted optic atrophy panel - exonic sequences of 22 genes, including SPG7 and AFG3L2.

PMID: 24466038 Wedding et al., 2014
Report of 4 patients from 2 Norwegian families with biallelic variants in SPG7. Individuals presented with a combination of progressive external ophthalmoplegia and spastic paraplegia.
Family A (consanguineous) - 2 affected siblings, homozygous for SPG7 c.2102A>C, p.H 701P - heterozygous in unaffected subjects.
Family B (no consanguinity) - compound het for c.2102A>C, p.H 701P and c.1454_1462del
Immunohistochemical studies in skeletal muscle showed mosaic deficiency predominantly affecting respiratory complex I, but also complexes III and IV.

PMID: 24727571 Pfeffer et al., 2014:
Cohort of 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. All individuals with SPG7 were noted to have features of optic atrophy.
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 pedigree - variant not reported in gnomAD v4.1.0, absent in unaffected family members.

SPG7 is associated with Spastic paraplegia 7, autosomal recessive, OMIM:607259 (accessed 8th Jan 2026). Entry for Spastic paraplegia 7 in GeneReviews (https://www.ncbi.nlm.nih.gov/books/NBK1107/) mentions that the possibility of autosomal dominant inheritance remains controversial. SPG7 link to SPG7-related spastic paraplegia (biallelic_autosomal) is classified as definitive on the Gene2Phenotype Eye disorders panel.

Created: 8 Jan 2026, 4:14 p.m. | Last Modified: 8 Jan 2026, 5 p.m.

Panel Version: 5.38

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Spastic paraplegia 7, autosomal recessive, OMIM:607259; hereditary spastic paraplegia 7, MONDO:0011803

Publications

• 23065789
• 24466038
• 24727571
• 32548275
• 33841295
• 37983191

The mode of inheritance of this gene has been updated to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.

Created: 30 Jan 2023, 1:02 p.m. | Last Modified: 30 Jan 2023, 1:02 p.m.

Panel Version: 3.7

Green List (high evidence)

New papers (32548275; 33841295) describing SPG7 as a cause of autosomal dominant optic atrophy - update of inheritance needed.

Created: 3 Aug 2022, 3:44 p.m. | Last Modified: 3 Aug 2022, 3:44 p.m.

Panel Version: 2.70

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Phenotypes
Dominnat optic atrophy

Publications

• 32548275
• 33841295

Variants in this GENE are reported as part of current diagnostic practice

Based on the expert review from Penny Clouston (Oxford) and recent literature the MOI should be changed from "BIALLELIC, autosomal or pseudoautosomal" to "BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal".

Created: 9 Aug 2022, 8:05 a.m. | Last Modified: 9 Aug 2022, 8:05 a.m.

Panel Version: 2.72

Comment on publications: New publications added

Created: 9 Aug 2022, 8:03 a.m. | Last Modified: 9 Aug 2022, 8:03 a.m.

Panel Version: 2.71

Comment on list classification: Promoted from amber to green. There are >3 unrelated cases with different variants reported. It is associated with a phenotype in OMIM but not in Gene2Phenotype. Based on this evidence and the expert review, the gene has been given a green rating.

Created: 22 Mar 2019, 3:14 p.m.

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Green List (high evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
SPASTIC PARAPLEGIA 7, AUTOSOMAL RECESSIVE, 607259

Variants in this GENE are reported as part of current diagnostic practice

Comment on list classification: OA is a very minor part in only 1 of the OMIM families. Neurological presentation predominates here so unlikely to be recruited under OA, and risk of inappropriate unrelated predictive information being generated.

Created: 11 Sep 2016, 9:18 a.m.

Comment on list classification: Spastic paraplegia 7, autosomal recessive includes optic atrophy, and is green on the version 1.0 HSP panel.

Created: 7 Sep 2016, 9:47 a.m.