Optic neuropathy

Gene: ATAD3A

Comment on list classification: Promoted gene from Red to Amber based on the available literature. As not every patient with a monoallelic variant in this gene presented with optic atrophy, this gene has been rated Amber until further evidence is available.

PMID: 27640307 describes 5 patients from 5 unrelated families with the same de novo variant (c.1582 C>T, R528W). 3/5 patients have optic atrophy and 2/5 have hypertrophic cardiomyopathy (HCM). The authors have suggested that R528W exerts a dominant negative effect.

Three patients from 2 additional families have biallelic variants (1 compound heterozygous and 1 biallelic deletion of ATAD3B and ATAD3A). These 3 patients did not have optic atrophy nor HCM, but had congenital cataracts.

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.

PMID: 31727539 describes a consanguineous family with 4 affected individuals with biallelic variant (c.1217T>G, L406R). 3/4 had congenital cataracts and 4/4 had HCM. No one had optic atrophy.

Created: 24 Aug 2020, 3:07 p.m. | Last Modified: 24 Aug 2020, 3:07 p.m.

Panel Version: 2.24

Comment on mode of inheritance: Changed MOI from Both monoallelic and biallelic to Monoallelic only as it is patients with the Monoallelic form had optic atrophy (PMID: 27640307). Patients with biallelic variants had congenital cataract.

Created: 14 Jul 2020, 10:14 a.m. | Last Modified: 14 Jul 2020, 10:14 a.m.

Panel Version: 2.18

Green List (high evidence)

Please note gene causes both a mono-allelic and a bi-allelic disorder. Optic atrophy reported in individuals with the recurrent de novo missense p.Arg528Trp only at this stage. The de novo status of this variant suggests it is functionally important in the pathogenesis of optic atrophy.

Created: 16 Apr 2020, 12:22 a.m. | Last Modified: 16 Apr 2020, 12:22 a.m.

Panel Version: 2.3

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Harel-Yoon syndrome, MIM#617183

Publications

• 27640307
• 28652416

Red List (low evidence)

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Harel-Yoon syndrome: optic atrophy, peripheral neuropathy, delayed psychomotor development, intellectual disability, spastic paraplegia (HAYOS), 617183

Publications

• 27640307