Expanding the Clinical Spectrum Associated with the Recurrent Arg203Trp Variant in PACS1: An Italian Cohort Study

Background/Objectives: Schuurs–Hoeijmakers syndrome (SHMS), also known as PACS1 neurodevelopmental disorder, is a rare condition characterized by intellectual disability, distinctive craniofacial abnormalities, and congenital malformations. SHMS has already been associated with variants in the PACS1 gene in 63 patients. In this study, we describe 10 new Italian SHMS patients all harboring the common de novo p.(Arg203Trp) variant. Methods: The 10 patients we studied were evaluated by clinical geneticists and child neurologists and a detailed description of clinical features was recorded. Data were then coded using the Human Phenotype Ontology (HPO) terms. The recurrent p.(Arg203Trp) variant in PACS1 was identified by clinical exome sequencing or whole exome sequencing in trio using standard methodologies. To facilitate mutation identification, we designed a new PCR-RFLP strategy adopting the endonuclease DpnII. Results: We define a detailed clinical phenotyping in patients with intellectual disability and facial characteristics (thick eyebrows, down-slanting palpebral fissures, ocular hypertelorism, low-set ears, a thin upper lip, and a wide mouth) that can help clinicians form a more efficient diagnosis of SHMS even through neuroimaging and neuropsychological evaluation. Conclusions: Our series of 10 newly affected Italian children highlights specific clinical features that may help clinicians recognize and better manage this syndrome, contributing to precision medicine approaches in medical genetics.