PACS2 Gene Curation
- Andrea Oza
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 - 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.
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Clinical Validity Points Total | MODERATE (stopped here, could continue curation to try to reach strong/definitive) Source: see above. |
Clinical Validity Classification 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 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).
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Penetrance Complete (100%) High (≥80%) Moderate (<80% and >20%) Low (≤20%) (list source/PMID) |
Source: |
Age of Onset Congenital Pediatric Adolescent Adulthood Late adulthood (list source/PMID) | Congenital |
Severity | Severe |
Clinical Features | Epilepsy, global developmental delay with or without autism, common cerebellar dysgenesis, and facial dysmorphism Sources: 29656858, 30684285 |
HPO Terms |
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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 |
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Case ID, Curator name, Date, Jira ticket link | D-190506270-BH-3968-P-A (Bahrain case). Andrea Oza 10.18.2023 |