EPG5 – Vici syndrome

Vici syndrome is a rare, multisystem autosomal recessive disorder caused by biallelic mutations in EPG5. Affected individuals present neonatally or in infancy with agenesis of the corpus callosum, oculocutaneous hypopigmentation, congenital cataracts, cardiomyopathy, combined immunodeficiency, profound developmental delay, progressive microcephaly, and failure to thrive. Recessive inheritance and the clinical triad of callosal agenesis, cataracts, and hypopigmentation are highly predictive of underlying EPG5 disruption.

Genetic analyses in a cohort of 50 children from 30 unrelated families identified 39 distinct EPG5 mutations, predominantly truncating and splice‐site alleles, confirming autosomal recessive inheritance (PMID:26917586). Among these, the recurrent founder variant c.1007A>G (p.Gln336Arg) was observed in multiple patients, suggesting a population‐specific allele and supporting strong segregation in consanguineous pedigrees.

The variant spectrum comprises 34 nonsense or frameshift mutations, 4 canonical splice‐site variants, and a minority of missense changes. The founder allele c.1007A>G (p.Gln336Arg) exemplifies a recurrent missense change leading to loss of canonical splicing and absent transcript in severe cases, yet preserved residual expression in attenuated phenotypes.

Functional studies demonstrate that EPG5 deficiency causes a severe block of autophagosome–lysosome fusion in patient fibroblasts and HeLa cells, leading to accumulation of non‐degradative autolysosomes. Knock‐down of the Drosophila epg5 ortholog induces progressive neurodegeneration, and structural analyses show that human EPG5 interacts with GABARAP subfamily proteins via tandem LIR motifs to mediate tethering to late autophagic compartments (PMID:28615637; PMID:33674710).

Phenotypic variability is reported in patients with hypomorphic or intronic splice‐modulating variants, who exhibit primarily neurological features with minimal systemic involvement. These attenuated cases highlight a dosage‐sensitivity model in which residual EPG5 expression correlates with milder disease and extended survival.

Taken together, the cumulative genetic, segregation, and mechanistic data provide strong evidence for a definitive gene–disease relationship between EPG5 and Vici syndrome. EPG5 sequencing should be prioritized in infants with callosal agenesis plus cataracts, hypopigmentation, and cardiomyopathy, facilitating early diagnosis, optimized supportive care, and genetic counseling.

References

• Brain : a journal of neurology • 2016 • EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy PMID:26917586
• Scientific reports • 2017 • Defects in autophagosome-lysosome fusion underlie Vici syndrome, a neurodevelopmental disorder with multisystem involvement PMID:28615637
• Communications biology • 2021 • Insights on autophagosome-lysosome tethering from structural and biochemical characterization of human autophagy factor EPG5 PMID:33674710

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