VAC14 – Yunis-Varon syndrome

Yunis-Varon syndrome (YVS) is a severe autosomal recessive disorder characterized by skeletal anomalies, dysmorphism, global developmental delay and intracytoplasmic vacuolation in brain and other tissues. Pathogenic variants in FIG4 have been the only reported genetic cause of YVS, but recent data implicate VAC14, which encodes a scaffold protein in the PIKfyve–VAC14–FIG4 complex essential for PtdIns(3,5)P2 synthesis. Exome sequencing of a female neonate with a YVS phenotype and normal FIG4 sequencing identified biallelic rare coding variants in VAC14, including the LoF variant c.923T>A (p.Leu308Ter) (PMID:28635952). No additional family segregation data were reported.

Patient fibroblasts exhibited a characteristic vacuolation phenotype recapitulating PtdIns(3,5)P2 deficiency that was ameliorated in a dose-dependent manner by ML-SA1, a pharmacological activator of the lysosomal PtdIns(3,5)P2 effector TRPML1 (PMID:28635952). This rescue supports a loss-of-function mechanism via impaired PIKfyve–VAC14–FIG4 complex assembly and downstream PI(3,5)P2 signalling. While only a single VAC14‐related YVS case is described, functional concordance with known complex biology strengthens the association. Further studies are needed to identify additional unrelated probands and assess phenotypic variability.

Key Take-home: Biallelic VAC14 mutations cause Yunis-Varon syndrome through loss of scaffold function leading to impaired PI(3,5)P2 synthesis, offering a potential avenue for targeted therapeutic activation of TRPML1.

References

• European journal of human genetics • 2017 • Yunis-Varón syndrome caused by biallelic VAC14 mutations PMID:28635952

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