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.