Novel PUF60 variant suggesting an interaction between Verheij and Cornelia de Lange syndrome: phenotype description and review of the literature

Abstract

Verheij syndrome [VRJS; OMIM 615583] is a rare autosomal dominant neurodevelopmental disorder characterized by distinct clinical features, including growth retardation, intellectual disability, cardiac, and renal anomalies. VRJS is caused by deletions of chromosome 8q24.3 or pathogenic variants in the PUF60 gene. Recently, pathogenic PUF60 variants have been reported in some individuals with VRJS, contributing to the variability in the clinical presentation and severity of the condition. PUF60 encodes a protein involved in regulating gene expression and cellular growth. In this report, we describe a new case of VRJS with developmental delay, cardiac-, and renal abnormalities, caused by a heterozygous pathogenic PUF60 variant. Surprisingly, DNA methylation analysis revealed a pattern resembling the Cornelia de Lange syndrome (CdLS) episignature, suggesting a potential connection between PUF60 and CdLS-related genes. This case report further delineates the clinical and molecular spectrum of VRJS and supports further research to validate the interaction between VRJS and CdLS.

Fig. 1. Confirmed episignature for our case.

A Hierarchical clustering and B multidimensional scaling plots demonstrate the clustering of our case (shown in red) with the CdLS cases (marked in blue), which is distinct from controls (individuals without CdLS or VRJS; shown in green) c The methylation variant pathogenicity (MVP) score range from 0 to 1. Scores. Scores approaching 1 indicate a high likelihood of a methylation pattern characteristic of the target syndrome (CdLS), while scores close to 0 indicating a methylation profile similar to controls. Our case is showing an high MVP score, suggesting the presence of the CdLS episignature.