VPS35L-related Ritscher-Schinzel syndrome: Expanding genotype-phenotype correlations.

INTRODUCTION

Ritscher-Schinzel syndrome (RTSC; 3C syndrome) is a rare syndromic neurodevelopmental disorder resulting from defects in endosomal recycling. Biallelic variants in VPS35L, encoding a core component of the Retriever complex, have only recently been implicated in RTSC.

METHODS

Trio-based-whole exome sequencing was performed in a male infant with classical RTSC features. Variant pathogenicity was assessed using population databases, multiple in-silico predictors, structural modeling, and splicing analyses. Segregation analysis was performed in the parents.

RESULTS

A novel homozygous VPS35L variant (NM_020314.7: c.881T > C; p.(Phe294Ser)) affecting a highly conserved residue was identified. The variant is absent from population databases and is predicted to be deleterious. Structural modeling and stability calculations indicate a marked destabilizing effect, whereas splicing predictions do not support a major effect of nucleotide change on canonical splice site usage. Clinically, the patient exhibited cerebellar, craniofacial, skeletal, and cardiac anomalies with severe postnatal growth retardation.

CONCLUSIONS

This patient provides additional evidence supporting the pathogenic role of VPS35L in RTSC and expands the emerging molecular and clinical spectrum of VPS35L-related disorder, highlighting the value of detailed genotype-phenotype correlation in ultra-rare syndromes.