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Intellectual disability

Gene: VPS4A

Amber List (moderate evidence)

VPS4A (vacuolar protein sorting 4 homolog A)
EnsemblGeneIds (GRCh38): ENSG00000132612
EnsemblGeneIds (GRCh37): ENSG00000132612
OMIM: 609982, Gene2Phenotype
VPS4A is in 5 panels

2 reviews

Arina Puzriakova (Genomics England Curator)

Green List (high evidence)

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 severe-to-profound ID/DD. 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, 11:06 a.m. | Last Modified: 3 Feb 2021, 11:06 a.m.
Panel Version: 3.756
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 a.m. | Last Modified: 3 Feb 2021, 11 a.m.
Panel Version: 3.755
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, 10:54 a.m. | Last Modified: 3 Feb 2021, 10:54 a.m.
Panel Version: 3.754

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

Phenotypes
CIMDAG syndrome

Publications

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

Evan Reid (University of Cambridge)

Green List (high evidence)

Multiple families (now 10) described with a consistent phenotype (termed CIMDAG as an acronym for the major features). 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, 9:23 a.m. | Last Modified: 2 Feb 2021, 9:23 a.m.
Panel Version: 3.751

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

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

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Amber
Phenotypes
  • CIMDAG syndrome
Tags
for-review
OMIM
609982
Clinvar variants
Variants in VPS4A
Penetrance
Complete
Publications
Mode of Pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Panels with this gene

History Filter Activity

9 Feb 2021, Gel status: 2

Set Phenotypes

Arina Puzriakova (Genomics England Curator)

Phenotypes for gene: VPS4A were changed from developmental delay; intellectual disability; cerebellar hypoplasia; pontine hypoplasia; thin corpus callosum; microcephaly; growth retardation; congenital anaemia; dyserythropeoitic anaemia; dystonia; congenital cataracts; deafness to CIMDAG syndrome

3 Feb 2021, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: vps4a has been classified as Amber List (Moderate Evidence).

3 Feb 2021, Gel status: 2

Set mode of inheritance

Arina Puzriakova (Genomics England Curator)

Mode of inheritance for gene: VPS4A was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

3 Feb 2021, Gel status: 2

Added Tag

Ivone Leong (Genomics England Curator)

Tag for-review tag was added to gene: VPS4A.

3 Feb 2021, Gel status: 2

Entity classified by Genomics England curator

Ivone Leong (Genomics England Curator)

Gene: vps4a has been classified as Amber List (Moderate Evidence).

3 Feb 2021, Gel status: 0

Set publications

Ivone Leong (Genomics England Curator)

Publications for gene: VPS4A were set to (PMID: 33186545; 33186543; 33460484)

2 Feb 2021, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes, Set penetrance, Set mode of pathogenicity

Evan Reid (University of Cambridge)

gene: VPS4A was added gene: VPS4A was added to Intellectual disability. Sources: Literature,Research Mode of inheritance for gene: VPS4A was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: VPS4A were set to (PMID: 33186545; 33186543; 33460484) Phenotypes for gene: VPS4A were set to developmental delay; intellectual disability; cerebellar hypoplasia; pontine hypoplasia; thin corpus callosum; microcephaly; growth retardation; congenital anaemia; dyserythropeoitic anaemia; dystonia; congenital cataracts; deafness Penetrance for gene: VPS4A were set to Complete Mode of pathogenicity for gene: VPS4A was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: VPS4A was set to GREEN