VPS35L – Ritscher-Schinzel Syndrome

VPS35L encodes a core subunit of the Retriever complex, recently implicated in Ritscher-Schinzel syndrome (RSS) after WASHC5 and CCDC22. Initial reports described a sibling pair with severe RSS, and subsequent studies have expanded the genotype–phenotype correlation to include additional unrelated patients. RSS due to biallelic VPS35L variants follows an autosomal recessive inheritance pattern with evidence of segregation in an affected sibling pair. Functional assays across patient-derived cells and animal models support a loss-of-function mechanism, consistent with human phenotypes.

Genetic Evidence

Five affected individuals (three unrelated probands and a previously reported sibling pair) harbor biallelic VPS35L variants (autosomal recessive) (PMID:36113987)(PMID:31712251). Segregation analysis demonstrated concordant inheritance of compound heterozygous alleles in a sibship of two affected children (PMID:31712251). Reported variants include frameshift and missense classes, e.g. c.1097dup (p.Cys366TrpfsTer28) (PMID:31712251), indicative of loss-of-function alleles. No recurrent or founder variants have been identified to date.

Clinical Spectrum

Patients present with classic RSS features—cranio-cerebello-cardiac malformations—plus novel complications exclusive to VPS35L deficiency: hypercholesterolaemia (HP:0003124), hypogammaglobulinaemia (HP:0004313), intestinal lymphangiectasia (HP:0002593) and proteinuria (HP:0000093) (PMID:36113987). Phenotypic severity ranges from mild to severe, correlating with residual VPS35L protein levels in patient cells.

Functional Evidence

Cellular analyses show VPS35L ablation reduces cell surface LDL receptor and LRP1 levels, impairing LDL uptake and linking Retriever dysfunction to hypercholesterolaemia (PMID:36113987). In vitro, VPS35L knockout cells exhibit impaired autophagy under both nutrient-rich and starvation conditions, consistent with Retriever complex loss (PMID:31712251). Vps35l–/– mice display early embryonic lethality between E7.5 and E10.5, underscoring VPS35L’s essential developmental role (PMID:31712251).

Conflicting Evidence

To date, no studies have refuted the VPS35L–RSS association or proposed alternative phenotypes. Clinical findings are consistent across independent cohorts.

Conclusion

The collective genetic and functional data support a moderate clinical validity for VPS35L in RSS, establishing a distinct allelic series and mechanistic underpinning of Retriever complex deficiency. Key take-home: Biallelic VPS35L variants cause a unique RSS subtype with multisystem involvement and hypercholesterolaemia, informing molecular diagnosis and targeted management.

References

• Journal of medical genetics • 2023 • Clinical diversity and molecular mechanism of VPS35L-associated Ritscher-Schinzel syndrome. PMID:36113987
• Journal of medical genetics • 2020 • Biallelic VPS35L pathogenic variants cause 3C/Ritscher-Schinzel-like syndrome through dysfunction of retriever complex. PMID:31712251

Evidence Based Scoring (AI generated)