PACS2 was first reported in relation to autosomal dominant developmental and epileptic encephalopathy in 2018 (Olsen et al., PMID: 29656858). PACS2 encodes a multifunctional sorting protein involved in nuclear gene expression and pathway traffic regulation. Clinical features in affected individuals include neonatal/early-infantile-onset epilepsy, hypotonia, global developmental delay, intellectual disability, autism or autistic behavior, cerebellar dysgenesis, and facial dysmorphism. Other less common features include distal limb abnormalities, ocular abnormalities, and cardiac defects. Two missense variants that have been reported in 14 probands in 5 publications (PMIDs: 29656858, 30684285, 34894068, 35770754, 36645641) are included in this curation. Of note, 13 of 14 probands had the recurrent PACS2 p.Glu209Lys variant. Most variants are de novo. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The recurrent p.Glu209Lys variant reduces the ability of the predicted autoregulatory domain to modulate the interaction between PACS2 and client proteins, which may be consistent with a dominant-negative effect (PMID: 29656858).
This gene-disease relationship is also supported by experimental evidence, including biochemical function and protein interaction studies. The paralog PACS1 is involved in a neurodevelopmental disorder with overlapping features (Schuurs-Hoeijmakers syndrome), and PACS1 and PACS2 proteins interact with WDR37 (PMID: 34642815), which is also implicated in a neurodevelopmental disorder.
In summary, there is definitive evidence supporting the relationship between PACS2 and autosomal dominant developmental and epileptic encephalopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on May 1, 2024 (SOP 10).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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