Optic Atrophy

Gene: AFG3L2

Green List (high evidence)

- The ADOA variants mostly are located within or close to the ATPase/AAA domain, while those in the proteolytic domain mostly cause dominant spinocerebellar ataxia type 28 (SCA28) or recessive spastic ataxia with epilepsy (SPAX5) (PMIDs: 32219868, 32600459).

- PMID: 32219868: Different missense variants reported in 9 families with optic atrophy, AD or de novo. Two additional families had compound het variants that fit recessive inheritance pattern. One additional family had severe syndromic optic neuropathy in one compound het individual while family members carrying only one variant had a pure optic atrophy phenotype.

- PMID: 32600459: 1 family with AD optic atrophy. Functional studies using patient fibroblasts showed a missense variant destabilises the long isoforms of OPA1 protein and led to mitochondrial fragmentation.

- PMID: 32548275: 7 missense variants reported in 8 families with AD or sporadic optic atrophy.

Created: 29 Jul 2020, 7:40 a.m. | Last Modified: 29 Jul 2020, 7:40 a.m.

Panel Version: 0.108

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Autosomal dominant optic atrophy; Autosomal recessive spastic ataxia 5, MIM#614487; Autosomal dominant spinocerebellar ataxia 28, MIM#610246

Publications

• 32219868
• 32600459
• 32548275

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

Green List (high evidence)

Comment when marking as ready: Please note OA has only been associated with a specific variant in this gene, R468C. The variant is de novo in some of the families, suggesting a hotspot rather than founder effect.

Created: 15 Apr 2020, 11:18 p.m. | Last Modified: 15 Apr 2020, 11:18 p.m.

Panel Version: 0.77

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Optic atrophy 12, MIM# 618977

Green List (high evidence)

Recurrent missense, R468C, variant associated with OA - reported in 3 families.

PMID: 29181157; Colavito 2017; R468C reported in a patient with isolated OA
PMID: 26539208; Charif 2015: R468C reported in a family with OA and mild ID
PMID: 30252181; Magri 2018: Reported a patient with early-onset optic atrophy with spastic ataxia. Patient harboured de novo R468C and het frameshift in SPG7. Functional analysis of R468C in yeast showed abolished AFG3L2 function.

PMID: 30389403; Mancini 2019: Mouse model harbouring a different missense results in adult-onset ataxia and no vision loss

Created: 15 Apr 2020, 1:36 a.m. | Last Modified: 15 Apr 2020, 1:38 a.m.

Panel Version: 0.60

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

Phenotypes
Spastic ataxia 5, autosomal recessive (MIM#614487); Spinocerebellar ataxia 28 (MIM#610246)

Publications

• 29181157
• 26539208
• 30252181
• 30389403