Skip to end of metadata
Go to start of metadata

You are viewing an old version of this content. View the current version.

Compare with Current View Version History

Version 1 Current »

Gene-disease assertions not curated here (add link or write note):

Disease

PACS2-related developmental and epileptic encephalopathy

Inheritance

Autosomal dominant

Prevalence

 Unknown

Source: orphanet

Rapid or full curation?

  • Rapid
  • Full

ClinGen / GenCC / BabySeq / HGMD / OMIM

ClinGen - none. GenCC - Strong (Invitae) and Moderate (Ambry). BabySeq - none. HGMD - primarily missense associated with autism or neurodevelopmental disorder.

Clinical Validity Scoring Notes and points

Olson et al 2018 PMID: 29656858 - Missense variant c.625G>A p.E209K reported as a recurrent de novo variant using trio WES. Variant was found in 12 individuals de novo. Variant is absent gAD but has low REVEL score 0.228. PACS2 encodes multifunctional sorting protein involved in nuclear gene expression and pathway traffic regulation. In vitro functional studies demonstrated that the recurrent variant reduces the ability of the predicted autoregulatory domain to mudlate the interaction between PACS2 and client proteins which may disturb cellular function. Scored 12x0.5 = 6 variant points.

Zang 2022 PMID: 36188273 - PACS2 E209K protein exhibited slower turnover rate relative to WT upon cycloheximide treatment in 293T cells (Fig 2B), and this longer half life suggests disruption in proteostasis. It has an enhanced association with 14-3-3epsilon in 293T cells (fig 3). PACS-2 E209K increased susceptibility to staurosporine-induced apoptosis in HCT 116 cells (fig 4). 1 POINT PROTEIN INTERACTION AND 0.5 POINT FUNCTIONAL ALTERATION NON-PATIENT CELLS 1.5 POINTS

Wilfert 2021 PMID: 34312540 c.83G>A p.W28* reported here. See supplement table 22. Variant found in this autism spectrum cohort. Unclear whether this is de novo. Not scoring.

Dentici 2019 PMID: 30684285 - c.631G>A p.E211K (absent gAD, low REVEL score 0.19) reported in a boy with developmental and epileptic encephalopathy. The variant was de novo via WES. Clinical phenotype included epilepsy, abnormal brain MRI, global DD, Intellectual disability. Distinctive facial gestalt (synophrs, high arched and sparse eybrows, long eyelashes, low-set and posteriorly rotated ears, broad nasal tip, smooth philtrum, thin and everted upper lip vermilion, widely spaced teeth. 0.5 variant points

WANG 2020 PMID: 33004838 c.1151delC p.(Pro384Leufs*55 - NMD+ in supplement data 5, rare severe variant.

Clinical Validity Points Total

MODERATE (stopped here, could continue curation to try to reach strong/definitive)

Source: see above.

Clinical Validity Classification

 Classifications (pts)

Definitive (12pts)

Strong (12pts)

Moderate (7-11pts)

Limited (0.1-6pts)

No genetic evidence

Refuted

Disputed

MODERATE (stopped here, could continue curation to try to reach strong/definitive)

Source: see above.

Molecular Mechanism

 Mechanisms

Loss of function

Gain of function

Dominant negative

Unknown

Other

Unknown, but LOF is not likely. Only two LOF variants reported in HGMD (see Wilfert and Wang in Clinical Validity notes above).

Penetrance

 options

Complete (100%)

High (≥80%)

Moderate  (<80% and >20%)

Low (≤20%)

(list source/PMID)

Source:

Age of Onset

 options

Congenital

Pediatric

Adolescent

Adulthood

Late adulthood

(list source/PMID)

Congenital

Severity

 Options

Embryonic lethal - presence of a pathogenic variant or variants is not compatible with life. The penetrance must be complete.
Severe - presence of a pathogenic variant or variant(s) results in significantly reduced fitness. The penetrance must be complete or high.
Moderate - significant morbidity or mortality due to clinical features, but fitness may not be reduced, or penetrance is reduced.
Mild - Presence of a variant or variant(s) is not associated with reduced fitness, no significant morbidity or mortality, and/or penetrance is low.
None - presence of a variant results in no phenotype. An example is recessive disorders in which no phenotype is reported in carriers.

Severe

Clinical Features

Epilepsy, global developmental delay with or without autism, common cerebellar dysgenesis, and facial dysmorphism

Sources: 29656858, 30684285

HPO Terms

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

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

 Examples

- The @GENE@ is associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Variable expression or severity:
The severity and expressivity of the disorder is highly variable, even within families.
- If multiple conditions associated with the gene:
It has also been associated with @inheritance pattern@ @condition@, which is characterized by @clinical features@ (PMIDs).

- Limited evidence gene: The PCNA gene has been reported in individuals with early onset autosomal recessive ataxia (PMID: 33426167, 24911150), however, evidence supporting this gene-dIsease relationship is limited

Case ID, Curator name, Date, Jira ticket link

D-190506270-BH-3968-P-A (Bahrain case). Andrea Oza 10.18.2023

  • No labels