Childhood onset hereditary spastic paraplegia

Gene: ATL1

Green List (high evidence)

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.

Created: 13 Oct 2025, 8:43 p.m. | Last Modified: 13 Oct 2025, 8:43 p.m.

Panel Version: 8.20

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/)

Created: 13 Oct 2025, 8:35 p.m. | Last Modified: 14 Oct 2025, 9:46 a.m.

Panel Version: 8.20

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Spastic paraplegia 3A, autosomal dominant, OMIM:182600; hereditary spastic paraplegia 3A, MONDO:0008437

Publications

• 18446315
• 22378671
• 24473461
• 25193411
• 26888483
• 34808209
• 35925862
• 37927245
• 39003427

Green List (high evidence)

Several reports of biallelic predicted loss of function variants associated with a recessive form (parents are asymptomatic)

Created: 8 May 2025, 4:05 p.m. | Last Modified: 8 May 2025, 4:05 p.m.

Panel Version: 8.1

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Publications

• 24473461
• 26888483
• 37927245
• 39003427

Green List (high evidence)

Childhood onset but rare cases of adult onset reported.

Created: 3 May 2019, 4:27 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Publications

• 11685207
• 15517445

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

I don't know

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.

Created: 9 May 2019, 4:54 p.m.

Green List (high evidence)

Victoria: Also childhood onset HSP. On Current HSP paneland Sheffields HSP panel

Created: 28 Apr 2019, 4:16 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Spastic paraplegia 3A, 182600, autosomal dominant; Spastic Paraplegia, Dominant, Neuropathy, hereditary sensory, type ID, 613708

Spastic paraplegia 3A, childhood onset

Created: 14 Jan 2019, 4:16 p.m.