Early onset or syndromic epilepsy
Gene: PACS2
Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: John Taylor and Helen Lord. Suggested gene rating: Green.Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.
Panel Version: 1.189
AD EIEE66 - Olson et al, 2018 - 14 unrelated children 98 months to 16 years with EIEE66 - most had onset of seizures in the first few days/weeks of life (focal motor and some had accompanying autonomic, tonic and generalised tonic-clonic seizures, seizures tend to attenuate with time). De novo het missense mutation E209K identified in all. In vitro functional expression studies showed that the PACS2 E290K variant interacted to a greater extent with the client proteins SIRT1, HDAC1 and TRPV1 compared to wt. These findings suggest that the mutation reduces the ability of the predicted autpregulatory domain to modulate the interaction beween the PACS2 and client proteins which may disturb cellular function - may be consistent with dom-neg effect.Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.
Panel Version: 1.188
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Epileptic encephalopathy, early infantile, 618067
Publications
Comment when marking as ready: Associated with relevant phenotype in OMIM and as possible Gen2Phen gene. Single de novo variant reported in at least 14 unrelated cases variants (PMID 29656858), together with previous reports of haploinsufficiency encompassing the PACS2 gene (PMID 28867141).Created: 17 Sep 2018, 11:26 a.m.
14 unrelated patients reported with variants in this gene and EE.Created: 18 Aug 2018, 8:50 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Epileptic encephalopathy, early infantile, 66, MIM#618067
Publications
PMID 29656858 is a collaborative study reporting on 14 subjects, all with a recurrent de novo PACS2 missense variant [NM_018026.2:c.607C>T or p.(Arg203Trp)]. The phenotype is characterized by epilepsy (universal feature - neonatal or ealy infantile onset), global DD/ID (universal feature), variable cerebellar dysgenesis. A few had additional autistic features or ASD. Based on the available data, epilepsy may resolve in early childhood, so older individuals might be ascertained due to their DD/ID. There appear to be no consistent facial features. //
PMID 22488736 which is cited in the previous report, describes an individual with a minimal - 0.305 Mb - deletion encompassing PACS2 and 5 other genes. This individual presented with DD/ID and epilepsy. The authors review the cases with 14q32.3 deletions reported in the literature, although most deletions are poorly characterized or much larger and - as a result - less relevant.Created: 16 Aug 2018, 3:53 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Phenotypes
Epileptic encephalopathy, early infantile, 66, 618067
Publications
Source Wessex and West Midlands GLH was added to PACS2.
Source NHS GMS was added to PACS2.
Konstantinos Varvagiannis: PMID 29656858 is a collaborati
Gene: pacs2 has been classified as Green List (High Evidence).
Gene: pacs2 has been classified as Green List (High Evidence).
Publications for gene: PACS2 were set to 29656858; 22488736
Phenotypes for gene: PACS2 were changed from Global developmental delay; Intellectual disability; Seizures; Abnormality of the cerebrum to Epileptic encephalopathy, early infantile, 66, 618067
PACS2 was added to Genetic Epilepsy Syndromes panel. Sources: Literature
PACS2 was created by Konstantinos Varvagiannis