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Hyper IgD Syndrome/Mevalonate Aciduria via the MVK 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
11479 MVK 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
11479MVK81479 81479(x2) $890 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.

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).

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

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

  • Megan Piazza, PhD, FACMG

Clinical Features and Genetics

Clinical Features

Hyperimmunoglobulin D syndrome (HIDS) is a disorder characterized by periodic fevers lasting on average 4-6 days and beginning within the first year of life. Fevers may be provoked by vaccination, minor trauma, surgery, or stress and are associated with abdominal pain, rash, nausea, diarrhea, and lymphadenopathy. Symptoms typically resolve following periodic fever bouts, with joint and skin symptoms disappearing slower (Bader-Meunier et al. 2010; Haas and Hoffmann 2006; Houten et al. 1999).

Mevalonate Aciduria (MVA) is another disorder due to mutation in the MVK gene. Symptoms are identical to HIDS, but also include developmental and neurological abnormalities. These symptoms include hyptonia, psychomotor retardation, failure to thrive, ataxia, and congenital malformations such as microcephaly, dolichocephaly, blue sclerae and central cataracts. Currently, biochemical and genetic testing is unable to distinguish between HIDS and MVA with both types having considerable clinical heterogeneity (Bader-Meunier et al. 2010; Haas and Hoffmann 2006; Houten et al. 1999).

Mutations in the MVK gene have recently been shown to be involved in the pathogenesis of disseminated superficial actinic porokeratosis (DSAP) which is characterized by multiple small, annular, anhidrotic, keratotic lesions found on sun-exposed areas of skin. Symptom onset typically occurs during adolescent with complete penetrance for DSAP occurring before the fourth decade of life (Zhang et al. 2012; Lu et al. 2014).

Genetics

HIDS and MVA are inherited in an autosomal recessive manner through mutations in the MVK gene. To date, missense variants are found in all cases of HIDS and MVA with the c.1129G>A (p.Val377Ile) variant being most prevalent. In two large cohort studies, this variant was found in 34% and 80% of patients (Mandey et al. 2006; Bader-Meunier et al. 2011). Small insertions, deletions, splice site alterations, and nonsense mutations have also been reported but are found in compound heterozygous patients with another missense mutation. Gross deletions encompassing the whole MVK gene have not been reported to date. The MVK gene encodes mevalonate kinase which involved in the isoprenoid biosynthesis pathway and catalyzes mevalonate to 5-phosphomevalonate. While the exact molecular mechanism whereby MVK mutations lead to disease is unclear, it has been suggested that impairment of prenylation chains might play a role (Houten et al. 2002).

In one report, DSAP was described as being inherited in an autosomal dominant manner in Chinese patients via mutations in the MVK gene in both de novo and familial cases. This report documented 14 different mutations which occurred throughout the gene with missense, splice site alterations, small insertions, and small deletions occurring in 68%, 26%, 2%, and 4% cases respectively. The reason why HIDS and MVA carriers have not been reported to display DSAP is unknown. Preliminary studies indicate mevalonate kinase has a role in regulation of calcium induced keratinocyte differentiation and protects cells from ultraviolet induced apoptosis (Zhang et al. 2012).

Clinical Sensitivity - Sequencing with CNV PGxome

Analytical sensitivity is estimated at >99% as no gross deletions have been reported in the MVK gene. In patients with biochemical evidence of impaired mevalonate kinase activity and suspected HIDS or MVA, causative mutations were found in 106 of 106 patients (Mandey et al. 2006). A separate study identified two pathogenic variants in 44 of 50 patients with known HIDS or MVA (Bader-Meunier et al. 2010).

Testing Strategy

This test provides full coverage of all coding exons of the MVK 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. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

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 recommended for individuals with periodic fever syndrome with onset before 5 years of age. Common laboratory findings include elevated white blood cell counts, erythrocyte sedimentation rate, C-reactive protein levels, and levels of mevalonic acid in urine . In >85% of cases patients will have elevated IgD levels but levels may appear normal, especially in times between fever bouts (Bader-Meunier et al. 2010). This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in MVK.

Gene

Official Gene Symbol OMIM ID
MVK 251170
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Citations

  • Bader-Meunier B, Florkin B, Sibilia J, Acquaviva C, Hachulla E, Grateau G, Richer O, Farber CM, Fischbach M, Hentgen V, Jego P, Laroche C, Neven B, Lequerré T, Mathian A, Pellier I, Touitou I, Rabier D, Prieur AM, Cuisset L, Quartier P; SOFREMIP (Société Francophone pour la Rhumatologie et les Maladies Inflammatoires en Pédiatrie); CRI (Club Rhumatismes et Inflammations). 2011. Mevalonate Kinase Deficiency: A Survey of 50 Patients. PEDIATRICS 128: e152–e159. PubMed ID: 21708801
  • Haas D, Hoffmann GF. 2006. Mevalonate kinase deficiencies: from mevalonic aciduria to hyperimmunoglobulinemia D syndrome. Orphanet journal of rare diseases 1: 13. PubMed ID: 16722536
  • Houten SM, Kuis W, Duran M, Koning TJ de, Royen-Kerkhof A van, Romeijn GJ, Frenkel J, Dorland L, Barse MM de, Huijbers WA, Rijkers GT, Waterham HR, Wanders RJ, Poll-The BT. 1999. Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome. Nature genetics 22: 175–177. PubMed ID: 10369261
  • Houten SM, Woerden CS van, Wijburg FA, Wanders RJA, Waterham HR. 2003. Carrier frequency of the V377I (1129G>A) MVK mutation, associated with Hyper-IgD and periodic fever syndrome, in the Netherlands. European Journal of Human Genetics 11: 196–200. PubMed ID: 12634869
  • Lu W-S, Zheng X-D, Yao X-H, Zhang L-F, Hu B, Lu Y-J. 2014. Detection of a novel missense mutation in the mevalonate kinase gene in one Chinese family with DSAP. International journal of clinical and experimental pathology 7: 728. PubMed ID: 24551296
  • Mandey SHL, Schneiders MS, Koster J, Waterham HR. 2006. Mutational spectrum and genotype–phenotype correlations in mevalonate kinase deficiency. Human Mutation 27: 796–802. PubMed ID: 16835861
  • Zhang S-Q, Jiang T, Li M, Zhang X, Ren Y-Q, Wei S-C, Sun L-D, Cheng H, Li Y, Yin X-Y, Hu Z-M, Wang Z-Y, Wang ZY, Liu Y, Guo BR, Tang HY, Tang XF, Ding YT, Wang JB, Li P, Wu BY, Wang W, Yuan XF, Hou JS, Ha WW, Wang WJ, Zhai YJ, Wang J, Qian FF, Zhou FS, Chen G, Zuo XB, Zheng XD, Sheng YJ, Gao JP, Liang B, Li P, Zhu J, Xiao FL, Wang PG, Cui Y, Li H, Liu SX, Gao M, Fan X, Shen SK, Zeng M, Sun GQ, Xu Y, Hu JC, He TT, Li YR, Yang HM, Wang J, Yu ZY, Zhang HF, Hu X, Yang K, Wang J, Zhao SX, Zhou YW, Liu JJ, Du WD, Zhang L, Xia K, Yang S, Wang J, Zhang XJ. 2012. Exome sequencing identifies MVK mutations in disseminated superficial actinic porokeratosis. Nature Genetics 44: 1156–1160. PubMed ID: 22983302

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

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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: $
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