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

Abstract

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.

Keywords: PACS1; Schuurs–Hoeijmakers syndrome; c.607C>T; intellectual disability; literature review; red flags.

Figure 1

PACS1 (Phosphofurin acidic cluster sorting protein 1) domains and the location of the p.Arg203Trp variant.

Figure 2

PCR-RFLP analysis of the c.607C>T variant in PACS1. Lane 1: U = uncut; lanes 2–3–4: patients Pt1–Pt3 harboring the heterozygous c.607C>T/p.(Arg203Trp) mutation; lane 5: Ctrl, negative control; lane 6: MW, 100-bp DNA molecular weight marker. The amplified PCR product was cleaved with the endonuclease DpnII. Cleavage in the wild-type allele resulted in two fragments of 145 and 21 bp (undetectable), respectively, whereas the presence of the c.607C>T variant abolished the single site of cleavage, resulting in an uncut 166-bp fragment. Heterozygous patients showed 166-, 145-, and 21-bp (undetectable) fragments.

Figure 3

Chart of the clinical features in our cohort.

Figure 4

Chart of clinical features in all the patients considered.

Figure 5

Sagittal T1-weighted (A,B) and axial T2-weighted (C) MRI images obtained from three different SHMS patients and showing hypoplasia/atrophy of the cerebellar vermis (white arrow); (A), thin and dysmorphic corpus callosum (thick arrowhead) (B), enlarged and asymmetric lateral ventricles (*) (C).

Figure 6

Dysmorphic facial features in six of our patients: down-slanting palpebral fissures, thick eyebrows, ocular hypertelorism, low-set ears, bulbous nose, broad nasal bridge, wide mouth, and thin upper lip.