Bilateral congenital or childhood onset cataracts

Gene: VPS4A

The rating of this gene has been updated following NHS Genomic Medicine Service approval.

Created: 8 Mar 2022, 9:09 a.m. | Last Modified: 8 Mar 2022, 9:09 a.m.

Panel Version: 2.98

Green List (high evidence)

Comment on mode of inheritance: Setting MOI to 'Monoallelic' as only one biallelic case reported to date, and patients with biallelic variants would still be picked up by the Genomics England pipeline.

Created: 3 Feb 2021, 11:29 a.m. | Last Modified: 3 Feb 2021, 11:29 a.m.

Panel Version: 2.62

Comment on list classification: At least 5 different variants reported in 10 unrelated individuals with a comparable phenotype, including congenital/early-onset cataracts in 6/10 cases. Pathogenicity is supported by functional data.

There are sufficient cases to promote this gene to Green at the next GMS panel update (added 'for-review' tag)

Created: 3 Feb 2021, 11:23 a.m. | Last Modified: 3 Feb 2021, 11:23 a.m.

Panel Version: 2.61

Gene currently not associated with any phenotype in OMIM (last edited: 20/12/2019) or Gene2Phenotype.

- PMID: 33186545 (2020) - Six unrelated individuals with de novo missense variants (c.850A>T, c.850A>G, c.616G>A) affecting the ATPase domain of VPS4A. Clinical features include severe DD and profound ID (6/6), hypotonia (5/6), microcephaly (6/6), dystonia (5/6), congenital cataracts (4/5), epilepsy (3/6), anaemia (3/6 - dyserythropoietic in 2), and structural brain abnormalities including cerebellar hypoplasia (5/6) or severe cerebral atrophy (1/6). Some functional data indicating a dominant-negative effect.

- PMID: 33186543 (2020) - Three unrelated individuals with congenital dyserythropoietic anaemia, severe neurodevelopmental delay, and dystonia. Two patients harboured different de novo variants (c.850A>T, c.608G>A) in the ATPase domain, while the third had a homozygous alteration (c.83C>T) occurring in the N-terminal microtubule interacting and trafficking domain of VPS4A. The first two individuals congenital microcephaly with brain MRI showing white matter and cerebral volume loss, thin corpus callosum, and ponto-cerebellar atrophy. One individual also displayed a seizure disorder and congenital cataracts. The case with the biallelic variant presented with a milder hematologic phenotype and had macrocephaly (rather than microcephaly) and delayed white matter myelination. Functional studies support pathogenicity.

- PMID: 33460484 (2021) - One child with a a severe neurodevelopmental disorder and congenital haemolytic anaemia but no overt sign of dyserythropoiesis, associated with a de novo variant (c.850A>T) in VPS4A. Other features include microcephaly (-2.5 SD), choreodystonic movements, and bilateral cataract. Brain MRI showed cerebral atrophy, thin dysplastic corpus callosum, basal ganglia atrophy, brainstem hypoplasia, cerebellar hypoplasia and dysplasia
Sources: Expert Review

Created: 3 Feb 2021, 11:20 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
CIMDAG syndrome

Publications

• 33186545
• 33186543
• 33460484