PCGF2 – Turnpenny-Fry syndrome

Turnpenny-Fry syndrome is an autosomal dominant neurodevelopmental disorder caused by heterozygous mutations in PCGF2, which encodes a core component of polycomb repressive complex 1 (PRC1). Affected individuals present with global developmental delay, intellectual disability, characteristic craniofacial dysmorphism, and variable skeletal anomalies. Since the initial report in 2018, the clinical spectrum has expanded to include immune dysregulation and malignancy. The syndrome is universally associated with missense substitutions at the highly conserved Pro65 residue of PCGF2.

Genetic evidence includes 13 unrelated probands harboring de novo Pro65 substitutions and one additional patient with a novel heterozygous variant, totaling 14 cases supporting causality. The recurrent c.194C>T (p.Pro65Leu) variant has been observed in 12 de novo occurrences and one inherited from a mosaic parent ([PMID:30343942], [PMID:36105049], [PMID:38283775], [PMID:34750959]). Variant spectrum is restricted to missense changes at Pro65, with no reported truncating or splice variants.

Segregation data show predominantly de novo occurrence with one case of parental mosaicism and no evidence of transmission among fully affected relatives ([PMID:36105049]). This pattern is consistent with an autosomal dominant mechanism and a dominant-negative effect rather than haploinsufficiency.

Functional studies demonstrate that Pro65 substitutions disrupt intramolecular loop flexibility, impair histone H2A monoubiquitination by PRC1, and sequester complex components into non-functional assemblies. Structural modeling and MD simulations predict decreased stability of PCGF2 and altered PRC1 topology, corroborated by in vitro enzymatic assays ([PMID:30343942], [PMID:36105049], [PMID:31093962]).

The phenotype is remarkably consistent across patients, with universal global developmental delay and intellectual disability (HP:0001249, HP:0001263). Skeletal, cardiovascular, and facial anomalies are common, and T-cell acute lymphoblastic leukemia has been reported in one patient ([PMID:38283775]).

Overall, the association of PCGF2 with Turnpenny-Fry syndrome is classified as Definitive based on replication in multiple independent families, a recurrent mutational hotspot, and concordant functional evidence. Genetic testing for Pro65 substitutions enables precise diagnosis, informs recurrence risk counseling, and guides surveillance for comorbidities. Key take-home: PCGF2 missense variants at Pro65 cause a clinically recognizable autosomal dominant syndrome amenable to molecular diagnosis.

References

• American journal of human genetics • 2018 • Missense Mutations of the Pro65 Residue of PCGF2 Cause a Recognizable Syndrome Associated with Craniofacial, Neurological, Cardiovascular, and Skeletal Features PMID:30343942
• American journal of medical genetics. Part A • 2022 • A new case of Turnpenny-Fry syndrome. PMID:34750959
• American journal of translational research • 2022 • Investigation of an inherited PCGF2: p.Pro65Leu mutation causing Turnpenny-Fry syndrome. PMID:36105049
• Cureus • 2024 • Acute Lymphoblastic Leukemia in a Pediatric Patient With Turnpenny-Fry Syndrome. PMID:38283775
• FEBS letters • 2019 • Topology and enzymatic properties of a canonical Polycomb repressive complex 1 isoform. PMID:31093962

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