Submission Details

VPS33A was first reported in relation to mucopolysaccharidosis-like syndrome with congenital heart defects and hematopoietic disorders (also known as mucopolysaccharidosis-plus syndrome, MPSPS), an autosomal recessive condition, in 2017 (Dursun et al, PMID: 27547915; Kondo et al, PMID: 28013294). Individuals with this condition have been reported to have features typically associated with mucopolysaccharidosis, including coarse facial features, skeletal abnormalities, hepatosplenomegaly, respiratory problems, and intellectual disability, along with features not typically found in individuals with MPS, such as heart defects, and renal, and hematopoietic disorders. Most patients die by around 2 years of age. While these patients have elevated urinary glycosaminoglycans (GAGs), typically found in the MPS disorders, the activity of lysosomal enzymes associated with MPS are normal. Other features include increased vacuolation observed in cells, increased lysosomal acidity, and normal endocytic and autophagocytic pathway in fibroblasts (Kondo et al, PMID: 28013294; Kondo et al, PMID: 28013294). Mucopolysaccharidosis-like syndrome with congenital heart defects and hematopoietic disorders (also known as mucopolysaccharidosis-plus syndrome, MPSPS) is the only condition known to have been asserted to be caused by variants in VPS33A.

Only two variants, both of them missense, have been reported in individuals with MPSPS. One of the variants, c.1492C>T (p.Arg498Trp), has been identified in at least 16 probands from the Yakut population of Eastern Siberia and in siblings from Turkey (Dursun et al, 2017, PMID: 27547915; Kondo et al, 2017, PMID: 28013294; Pavlova et al, 2019, PMID: 31070736; Vasilev et al, 2020, PMID: 31936524; Faraguna et al, 2022, PMID: 35327996; Sofronova et al, 2023, PMID: 37628632). The other variant, c.599G>C (p.Arg200Pro), which was identified in homozygous individuals from Poland and the Mediterranean region, appears to cause an attenuated phenotype (Lipinski et al, 2022, PMID: 36232726; Pavlova et al, 2022, PMID: 36153662). To our knowledge, no additional variants have been reported in the literature. The mechanism of pathogenicity appears to be loss of function based on evidence that the variant results in decreased stability of the gene product.

This gene-disease relationship is also supported by experimental evidence. VPS33A is a core subunit of the CORVET (class C core vacuole/endosome tethering) and HOPS (homotypic fusion and vacuole protein sorting) complexes. CORVET and HPOS are intracellular, hexameric, membrane‐tethering, protein complexes involved in the endocytic and autophagocytic pathways pathway. The biochemical function of the protein is consistent with the features of lysosomal disease observed in patients (PMID: 25783203). A natural mouse model, the buff mouse, has been reported but the features do not mimic those found in patients, likely due to an alternative disease mechanism, but this is not considered to be conflicting evidence for the gene-disease relationship.

In summary, there is moderate evidence supporting the relationship between VPS33A and mucopolysaccharidosis-like syndrome with congenital heart defects and hematopoietic disorders (also known as mucopolysaccharidosis-plus syndrome, MPSPS), an autosomal recessive condition. While the evidence is borderline for a definitive classification, the ClinGen Lysosomal Diseases Gene Curation Expert Panel felt that a Moderate classification was more appropriate based on the identification of only two different missense variants in the gene in patients with symptoms of MPSPS. The group notes that there is considerable evidence for the role of the c.1492C>T (p.Arg498Trp) variant in this condition in individuals of Turkic/Yakut ancestry. Classification approved by the ClinGen Lysosomal Diseases GCEP on October 3, 2023).