PACS gene family-related neurological diseases: limited genotypes and diverse phenotypes

Background: The PACS gene family has been demonstrated to be related to intracellular vesicular trafficking. The phenotypes caused by PACS pathogenic variants included epilepsy, intellectual disability/developmental delay (ID/DD), and malformations such as facial abnormalities.Method: Next-generation sequencing (NGS) was performed to detect causative variants. Detailed information on 7 newly diagnosed and 71 previously reported patients was analyzed.Results: Including newly diagnosed cases in our study, 78 cases of PACS gene family-related neurological diseases were reported, including 25 PACS2-related cases and 53 PACS1-related cases. 71.8% of the patients had seizures. Many types of ASMs (anti-seizure medications) have been reported to be effective, and the most commonly used and effective ASMs were sodium valproate (39.3%, 11/28), oxcarbazepine/carbamazepine (32.1%, 9/28), and levetiracetam (17.9%, 5/28). Almost all patients (77/78) had ID/DD. The patient carrying heterozygous deletion of chr14:105821380-106107443 (286 kb) had a later age of onset of epilepsy and ID/DD, and more severe and refractory seizures were seen. The most common pathogenic missense variants were PACS1 p. Arg203Trp (98% of PACS1-related patients) and PACS2 p. Glu209Lys (92% of PACS2-related patients).Conclusions: We reported the first case of PACS gene family-related neurological disease caused by copy number variants (CNVs) and extended the phenotype spectrum. The clinical phenotypes of PACS heterozygous missense variants were similar; however, the patient with causative CNV presented more severe. The pathogenic variant sites of PACS1 and PACS2 were both quite limited but in different regions. These findings may provide clues for further functional studies of PACS family proteins.
Keywords: PACS1; PACS2; epilepsy; ID/DD