Content Comparison

Inheritance

Autosomal dominant

Prevalence

 <1 / 1 000 000

Source: Orphanet

Rapid or full curation?

•  Rapid
•  Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

ClinGen: None / GenCC: Strong (Invitae); Limited (Ambry) / BabySeq: None /

Clinical Validity Scoring Notes and points

Variant/Case Evidence: De novo LOF variant with NMD

• c.577_579delTCC, p.Ser193del - Absent gnomAD v4, in frame deletion.

  • De novo in individual 985.382, per table S4 patient is a male with severe ID, not walking, nonverbal, with brain imaging showing atrophy, ventriculomegaly, decreased white matter and thin CC (MRI), central hypotonia and spasticity (PMID: 25356899, 2014) =

• • 1.5 points

• De novo missense variants in 6 probands

• (PMID: 33186545, 2020)

  • c.850A>T (p.Arg284Trp) - absent gnomAD v4 and de novo in probands 1, 3, 4, and 5 (1x4 = 4 points)

    • cultured fibroblasts showed significantly enlarged endosomal organelles fig 2 J-L (+0.5)

  • c.850A>G (p.Arg284Gly) - absent gnomAD and de novo in proband 2 (1 point)

    • cultured fibroblasts showed significantly enlarged endosomal organelles fig 2 J-L, and had atypical ESCRT-III protein IST1 accumulates on endosomes (+0.5)

  • c.616G>A (p.

• • Glu206Lys) - absent gnomAD and de novo in proband 6 (1 point)

• De novo missense variants in 2 probands (PMID: 33186543) = 1.2 points

  • c.850A>T (p.Arg284Trp), Same variant as above but different proband, no author overlap. 1 POINT

  • c.608G>A (p.Gly203Glu) - Absent gnomad v4. 1 POINT

  • They also report a homozygous variant Ala28Val, but this is not part of the curation. Phenotype is similar, perhaps biallelic LOF variants cause a similar disorder.

• De novo missense variant in 1 proband (PMID: 33460484)

• • c.850 A> T (p.R284W) recurrent variant

Segregation Evidence: N/A

Case/Control Evidence: N/A

Experimental Evidence: N/A

• Human neuron iPSC cells expressing VPS4A-p.Arg284Trp or -p.Arg284Gly mutants showed no detectable exogenous VPS4A by immunoblotting, and only very sparse expression (<1% of cells) was observed by immunofluorescence, compared to wt VPS4A cell lines. Propose dominant negative effect. Cell culture model = 1 POINT

• In yeast, Glu228Gln mutation induced a dominant negative vacuolar protein sorting defect(PMID 11563910 - this is per OMIM, I couldnt access the full text). Protein interaction 1 POINT

Source: PMID: 25356899; 33186545, 33186543, 33460484,

• 11563910

Clinical Validity Points Total

712.9 points5

Source:

Clinical Validity Classification

ModerateDefinitive

Source: PMID: 25356899; 33186545, 33186543, 33460484,

• 11563910

Molecular Mechanism

Loss of functionUnknown, proposed dominant negative (PMID: 33186545, 11563910)

Penetrance

(list source/PMID)

High to Complete

Source:

Age of Onset

(list source/PMID)

Neonatal (Orphanet)

Severity

Moderate to Severe

Clinical Features

Severely impaired psychomotor development and hematologic abnormalities apparent from early infancy. Affected individuals show poor overall growth with microcephaly, impaired intellectual development, poor or absent speech, poor eye contact, and motor problems, such as inability to walk, hypotonia, and spasticity. Brain imaging typically shows cerebral and cerebellar atrophy, thin corpus callosum, and delayed myelination.

Eye involvement - congenital cataract, retinal dystrophy

Epilepsy

Hepatosplenomegaly

Sensorineural deafness

Growth retardation

Sources: PMID: 33186545, 33186543

HPO Terms

https://hpo.jax.org/app/

developmental delay, microcephaly, hypotonia, spasticity, cerebral atrophy

Gene SOPs & Notes

 LINK if SOP is a long document. Short notes if it is easy to digest. eg. Last known truncating variant

Curation Summary

The VPS4A gene is associated with autosomal dominant CIMDAG (cerebellar hypoplasia-intellectual disability-congenital microcephaly-dystonia-anemia-growth retardation) syndrome (PMID: 25356899, 33186545, 33186543, 33460484). This is a rare syndrome characterized by severely impaired psychomotor development and hematologic abnormalities apparent from early infancy. Affected individuals show poor overall growth with microcephaly, impaired intellectual development, poor or absent speech, poor eye contact, and motor problems, such as inability to walk, hypotonia, and spasticity. Brain imaging typically shows cerebral and cerebellar atrophy, thin corpus callosum, and delayed myelination. Additional features include eye involvement (congenital cataract, retinal dystrophy), hepatosplenomegaly, and sensorineural deafness (PMID: 33186545, 33186543). The molecular mechanism is proposed to be dominant-negative (PMID: 33186545, 11563910).

Case ID, Curator name, Date, Jira ticket link

Grant Fischer - 12/12/2024