Hyper IgD Syndrome/Mevalonate Aciduria via the MVK Gene

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).

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).

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).

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).