Rare anaemia

Gene: VPS4A

Green List (high evidence)

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

Created: 4 Mar 2022, 10:03 a.m. | Last Modified: 4 Mar 2022, 10:03 a.m.

Panel Version: 1.38

Comment on list classification: New gene added by Evan Reid (University of Cambridge). At least 5 different variants reported in 10 unrelated individuals with a comparable phenotype, including haemolytic anaemia in 7/10 cases. Pathogenicity is supported by functional data.

There is enough evidence to promote this gene to Green at the next GMS panel update (added 'for-review' tag)

Created: 3 Feb 2021, 11:13 a.m. | Last Modified: 3 Feb 2021, 11:13 a.m.

Panel Version: 1.13

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

Panel Version: 1.11

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

Created: 3 Feb 2021, 11:10 a.m. | Last Modified: 3 Feb 2021, 11:10 a.m.

Panel Version: 1.10

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

Phenotypes
CIMDAG syndrome

Publications

• 33186545
• 33186543
• 33460484

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

Green List (high evidence)

Multiple families (now 10) described with a consistent phenotype (termed CIMDAG as an acronym for the major features). This includes congenital anaemia in most cases, in some cases this is of a dyserythropoeitic type. All have de novo heterozygous missense mutations of VPS4A, with a distinct mutational hotspot (R284) in many families. Mechanism is likely dominant negative. Haplo-insufficiency of VPS4A is tolerated and present in general population databases, so loss of function mutations likely do not cause this disease.
Sources: Literature, Research

Created: 2 Feb 2021, 9:26 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
developmental delay; intellectual disability; cerebellar hypoplasia; pontine hypoplasia; thin corpus callosum; microcephaly; growth retardation; congenital anaemia; dyserythropeoitic anaemia; dystonia; congenital cataracts; deafness

Publications

• (PMID: 33186545
• 33186543
• 33460484)

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments