DNA icon

Mucopolysaccharidosis-Plus Syndrome via the VPS33A Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
13325 VPS33A 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
13325VPS33A81479 81479,81479 $890 Order Options and Pricing

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing backbone).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing backbone).

Turnaround Time

18 days on average for standard orders or 13 days on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • Jana Paderova, PhD

Clinical Features and Genetics

Clinical Features

Lysosomal storage disorders (LSDs) are inborn errors of metabolism that result in the gradual accumulation of substrate inside the lysosome, which ultimately leads to cell death (Platt et al. 2018. PubMed ID: 30275475). Classically, LSDs result from a biochemical deficiency of key lysosomal proteins such as hydrolases, which breakdown complex macromolecules into amino acids, monosaccharides, and free fatty acids, and permeases, which facilitate transport of macromolecules across the limiting membrane of the lysosome. Molecular defects in non-lysosomal proteins that are important for lysosomal function can also result in disease (Platt et al. 2018. PubMed ID: 30275469). For example, molecular defects in vesicular trafficking pathways related to lysosome biogenesis and function are emerging as a new subgroup of LSDs (Akizu et al. 2015. PubMed ID: 25848753; Ebrahimi-Fakhari et al. 2016. PubMed ID: 26715604; Edvardson et al. 2015. PubMed ID: 26307567; Hirst et al. 2015. PubMed ID: 26085577).

Mucopolysaccharidosis-plus syndrome (MPS-PS) is an ultra-rare disorder caused by molecular defects in non-lysosomal proteins that are important for lysosomal function. The only affected populations described so far in the literature include children of Turkish and Yukutian ethnic origin (Dursun et al. 2017. PubMed ID: 27547915; Kondo et al. 2017. PubMed ID: 28013294; Pavlova et al. 2019. PubMed ID: 31070736) with an estimated incidence of 1 in 12-15,000 live births and an estimated carrier frequency of 1 in 110 in the Yakut population (Kondo et al. 2017. PubMed ID: 28013294; Vasilev et al. 2020. PubMed ID: 31936524). MPS-PS presents with clinical features that overlap the mucopolysaccharidoses (MPS) group of LSDs as well as additional features. Major clinical features of MPS-PS that overlap with MPS disorders include coarse facial features, short neck, failure to thrive, joint contraction and/or stiffness, dysostosis multiplex, hepatosplenomegaly, and delayed psychomotor and speech development. Other major clinical features include hypogammaglobulinemia, recurrent respiratory infections, severe broncho-pulmonary complications, proteinuria, cardiovascular findings such as congenital heart defects, hypertrophic cardiomyopathy, and heart failure, as well as hematological findings including anemia, thrombocytopenia, and leukopenia. Less common clinical features of patients affected by MPS-PS include coagulation defects, hypopigmentation of the retina, optic atrophy, retinopathy, nystagmus, nephromegaly, nephrotic syndrome with renal impairment, and sepsis. Similar to MPS disorders, increased urinary excretion of the glycosaminoglycans dermatan sulfate and heparin sulfate is detected in patients affected by MPS-PS. However, unlike patients with MPS disorders, patients with MPS-PS have no detectable enzyme deficiencies. The clinical presentation of MPS-PS is severe and progressive. Most patients present with breathing problems and joint stiffness at the age of 2-6 months, and die before 2 years of age secondary to heart failure, acute respiratory distress syndrome, and/or renal failure (Vasilev et al. 2020. PubMed ID: 31936524).

While there are currently no treatments reported for MPS-PS, patients and their families may benefit from a molecular diagnosis for prognostic information, symptom management, and reproductive planning.

Genetics

The only pathogenic variant in VPS33A identified to date is a missense variant, c.1492C>T (p.Arg498Trp), reported in the homozygous state in ~20 unrelated Turkish and Yakutian patients, consistent with autosomal recessive inheritance (Vasilev et al. 2020. PubMed ID: 31936524). This variant is very rare, having been reported in only 0.003% of European (non-Finnish) alleles in the gnomAD public population database (gnomAD), but is estimated to occur in up to 0.9% of alleles in the Yakut population (Kondo et al. 2017. PubMed ID: 28013294; Vasilev et al. 2020. PubMed ID: 31936524). It is likely, but not certain, that the c.1492C>T (p.Arg498Trp) variant is a founder variant in the Yakut population, a genetic and geographic isolate with nomadic Turkic origins (Keyser et al. 2015. PubMed ID: 25487336).

The VPS33A (vacuolar protein-sorting-associated protein 33A) gene encodes a core subunit of the HOPS (homotypic fusion and vacuole protein sorting) and CORVET (class c core vacuole/endosome tethering) protein complexes, both of which are highly conserved eukaryotic protein complexes that regulate endocytic trafficking. Specifically, HOPS is involved with early endosomal membrane tethering and fusion, while CORVET plays a similar role in endo-lysosomal trafficking. Both complexes are built on the foundation of the class c core complex (VPS-C), composed of the VPS11, VPS16, VPS18, and VPS33A subunits, with additional unique subunits that confer specificity. The VPS33A subunit helps to organize HOPS and CORVET complexes for tethering function, and binds syntaxin family SNAREs (soluble N-ethylmale-imide-sensitive factor-attachment protein receptors) to facilitate SNARE complex assembly ahead of membrane fusion (Bowman et al. 2019. PubMed ID: 30945407). 

Functional studies in multiple model systems suggest that the VPS33A gene is intolerant to loss-of-function variation. Originally discovered in genetic screens carried out in Saccharomyces cerevisiae to identify genetic mutants that interfere with protein sorting to the yeast vacuole (lysosome in humans), vps33a null variation resulted in severe endocytic trafficking defects (Robinson et al. 1988. PubMed ID: 3062374; Banta et al. 1988. PubMed ID: 3049619). While vps33a null variation in yeast was ultimately viable, loss-of-function in the vps-33.1 gene, which encodes the Vps33a protein in Caenorhabditis elegans, resulted in maternal-effect embryonic lethality (Akbar et al. 2009. PubMed ID: 19158398). Consistent with this finding, complete loss-of-function of the carnation (car) gene, which encodes the Vps33A protein in Drosophila melanogaster, is lethal during larval development (Gengyo-Ando et al. 2016. PubMed ID: 27558849). VPS33A has been cited as a conditionally essential gene for growth of human tissue culture cells (Online Gene Essentiality, ogee.medgenius.info). Only 24% of expected loss-of-function variants in the VPS33A gene were observed in the gnomAD public population database, suggesting this gene is under strong selection against loss-of-function (O/E = 0.24 90% CI [0.14-0.44], gnomAD).

The buff (bf) mouse model harbors a spontaneous point mutation in Vps33a (VPS33A (D251E)) resulting in coat hypopigmentation, prolonged bleeding times, progressive motor deficits, and neuronal cell loss. This has been described as a Hermansky-Pudlak syndrome-like phenotype (Suzuki et al. 2003. PubMed ID: 12538872; Chintala et al. 2009. PubMed ID: 19254700). Interestingly, many MPS-PS clinical features overlap with Hermansky-Pudlak syndrome, including vision problems, issues with blood clotting, respiratory complications including pulmonary fibrosis, and kidney failure (Huizing et al. 2017. PubMed ID: 20301464). Structural studies suggest the buff mutation VPS33A (D251E) destabilizes protein folding by disrupting a normal interaction with nearby residue I256 (Graham et al. 2013. PubMed ID: 23901104). A heterozygous missense variant at this residue, I256L, has been reported in a patient with Hermansky-Pudlak syndrome (Suzuki et al. 2003. PubMed ID: 12538872), although it is not clear at this time whether this substitution is sufficient for disease.

Clinical Sensitivity - Sequencing with CNV PGxome

Clinical sensitivity is difficult to estimate because only a small number of patients with MPS-PS have been reported. Due to rarity of MPS-PS, as well as phenotypic overlap with lysosomal storage disorders, immunodeficiency disorders, and hereditary causes of developmental delay, clinical sensitivity may be low. Analytical sensitivity should be high because all pathogenic variants reported to date are detectable by sequencing.

Testing Strategy

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the VPS33A gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing.

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).

Indications for Test

This test is suitable for patients with an infancy-onset syndromic presentation including failure to thrive, coarse facial features, joint stiffness, skeletal abnormalities, recurrent respiratory infections, and respiratory distress. This test may be especially suitable for a patient presenting with an MPS-like disorder in the absence of lysosomal enzyme deficiencies upon biochemical testing. Due to high genetic heterogeneity of lysosomal storage disorders, immunodeficiency disorders, and hereditary causes of developmental delay, VPS33A could be included as part of a larger sequencing panel or genome test. Targeted testing is indicated for family members of patients who have known pathogenic variants in VPS33A. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in VPS33A.

Gene

Official Gene Symbol OMIM ID
VPS33A 610034
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Mucopolysaccharidosis-plus syndrome AR 617303

Related Test

Name
Lysosomal Storage Disorders Panel

Citations

  • Akbar et al. 2009. PubMed ID: 19158398
  • Akizu et al. 2015. PubMed ID: 25848753
  • Banta et al. 1988. PubMed ID: 3049619
  • Bowman et al. 2019. PubMed ID: 30945407
  • Chintala et al. 2009. PubMed ID: 19254700
  • Dursun et al. 2017. PubMed ID: 27547915
  • Ebrahimi-Fakhari et al. 2016. PubMed ID: 26715604
  • Edvardson et al. 2015. PubMed ID: 26307567
  • Gengyo-Ando et al. 2016. PubMed ID: 27558849
  • Graham et al. 2013. PubMed ID: 23901104
  • Hirst et al. 2015. PubMed ID: 26085577
  • Huizing et al. 2017. PubMed ID: 20301464
  • Keyser et al. 2015. PubMed ID: 25487336
  • Kondo et al. 2017. PubMed ID: 28013294
  • Online Gene Essentiality (OGEE).
  • Pavlova et al. 2019. PubMed ID: 31070736
  • Platt et al. 2018. PubMed ID: 30275475
  • Robinson et al. 1988. PubMed ID: 3062374
  • Suzuki et al. 2003. PubMed ID: 12538872
  • Vasilev et al. 2020. PubMed ID: 31936524

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

loading Loading... ×

ORDER OPTIONS

View Ordering Instructions

1) Select Test Method (Backbone)


1) Select Test Type


2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

No Additional Test Options are available for this test.

Note: acceptable specimen types are whole blood and DNA from whole blood only.
Total Price: $
×
Copy Text to Clipboard
×