Original Article Investigation of an inherited PCGF2: p.Pro65Leu mutation causing Turnpenny-Fry syndrome

Background: Turnpenny-Fry syndrome (TPFS) has recently been defined as an uncommon monogenic disease and is characterized by global developmental delay (GDD), intellectualdisability (ID), facial dysmorphology, and skeletal abnormality. PCGF2 is the only known causative gene for TPFS, which is a component of polycomb repressive complex 1 (PRC1). PRC1 is a multi-protein complex controlling the knockdown of gene expression. Methods: The present study included the clinical evaluation of a 2.5-year-old boy with GDD and ID using cerebral MRI and the genetic testing with whole-exome sequencing. Additionally, the in silico molecular dynamic (MD) simulation was carried out on the identified variant. Results: A recurrent missense variant, namely PCGF2: c.194C > T (p.Pro65Leu), was identified and suggested to be inherited from a mosaic father based on Sanger sequencing validation. MD results suggested a deleterious effect on the intramolecular structural flexibility and stability of PCGF2 protein by this variant. Conclusion: Our results indicated that PCGF2: p.Pro65Leu might be a hotspot for GDD and highlighted the effect of this variant on protein function.