The Invitae Periodic Fever Syndromes Panel analyzes 12 genes that are associated with periodic fevers and bouts of systemic and localized inflammation that lack an infectious cause. This test is useful for the diagnosis of patients who, based on clinical symptoms or abnormal laboratory findings, are suspected of having a periodic fever syndrome. Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions.
ADA2 ELANE LPIN2 MEFV MVK NLRC4 NLRP12 NLRP3 PSMB8 PSTPIP1 TNFRSF1A TRNT1
ADA2 ELANE LPIN2 MEFV MVK NLRC4 NLRP12 NLRP3 PSMB8 PSTPIP1 TNFRSF1A TRNT1
For a broader analysis of autoinflammatory syndromes with and without periodic fevers please refer to:
|Gene||Disorder||Protein name||Protein symbol|
|ADA2||ADA2 deficiency||cat eye syndrome chromosome region, candidate 1||CECR1|
|ELANE||Elastase deficiency (SCN1), cyclic neutropenia||elastase||ELANE|
|LPIN2||Chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anemia (Majeed syndrome)||lipin 2||LIPIN2|
|MEFV||Familial Mediterranean Fever||pyrin||PYRIN|
|MVK*||Mevalonate kinase deficiency||mevalonate kinase||MVK|
|NLRC4||NLRC4-MAS (macrophage activation syndrome), Familial cold autoinflammatory syndrome 4||NLR family, CARD containing 4||NLRC4|
|NLRP12||Familial cold autoinflammatory syndrome 2||NACHT domain-, leucine-rich repeat-, and PYD-containing protein 12||NALP12|
|NLRP3||Muckle-Wells syndrome, Familial cold autoinflammatory syndrome 1, Neonatal onset multisystem inflammatory disease (NOMID) or chronic infantile neurologic cutaneous and articular syndrome (CINCA)||cryopyrin||cryopyrin|
|PSMB8||CANDLE (chronic atypical neutrophilic dermatitis with lipodystrophy)||proteasome subunit, beta-type 8||PSMB8|
|PSTPIP1||Pyogenic sterile arthritis, pyoderma gangrenosum, acne (PAPA) syndrome||CD2 antigen-binding protein 1||C2BP1|
|TNFRSF1A||TNF receptor-associated periodic syndrome (TRAPS)||tumor necrosis factor receptor 1||TNFR1|
|TRNT1||TRNT1 deficiency||tRNA nucleotidyltransferase, CCA-adding 1||TRNT1|
Periodic fever syndromes are a group of inherited disorders that cause periodic fevers and bouts of autoinflammatory symptoms without an infectious cause. Common inflammatory signs are skin rash, joint pain, and swelling, although localized inflammation can occur at other sites (depending on the underlying genetic cause), such as in the pericardium or heart muscle, meninges, or mucous membranes. Kidney failure, hearing loss, vision problems, and joint contractures are some of the long-term complications that may occur as a result of progressive kidney damage caused by some periodic fever syndromes. The length and frequency of attacks varies between the different underlying genetic conditions and even between patients with the same genetic condition. Most patients have their first attack in childhood, but symptom onset can range from childhood to adulthood. Early diagnosis and treatment is critical for reducing the morbidity and mortality associated with these disorders. Familial Mediterranean fever is the most common of the periodic fever syndromes; patients with this condition typically have recurrent abdominal pain. There may be differences in treatment regimens between the syndromes, and newer, disorder-specific therapies are in clinical trials. Molecular diagnosis is necessary to understand the long-term complications and to tailor appropriate treatments.
The clinical sensitivity of this test is difficult to determine. There is phenotypic overlap between patients with monogenic periodic fever syndromes and those with periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA)—one of the most common periodic fever syndromes. PFAPA may have a sporadic incidence or a complex genetic inheritance pattern (reviewed in PMID: 26457006).
Four common variants in MEFV: c.442G>C (p.Glu148Gln), c.1105C>T (p.Pro369Ser), c.329T>C (p.Leu110Pro), and c.1223G>A (p.Arg408Gln), are not reported in our Primary report as they are classified as Likely Benign. If present, these variants would be listed in our Supplemental report, which is available upon request.
Periodic fever syndromes are inherited in either an autosomal recessive or autosomal dominant manner, depending on the underlying gene condition:
|ADA2||Polyarteritis nodosa and Sneddon syndrome||autosomal recessive|
|ELANE||Cyclic neutropenia||autosomal dominant|
|LPIN2||Chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anemia (Majeed syndrome)||autosomal recessive|
|MEFV||Familial Mediterranean fever||autosomal recessive and rarely autosomal dominant|
|MVK*||Mevalonate kinase deficiency, which includes: hyper IgD syndrome; mevalonic aciduria||autosomal recessive|
|NLRC4||Familial cold autoinflammatory syndrome||autosomal dominant|
|NLRP12||Familial cold autoinflammatory syndrome||autosomal dominant|
|NLRP3||Cryopyrin-associated periodic fever syndrome, which includes: Muckle-Wells syndrome; familial cold autoinflammatory syndrome 1; neonatal onset multisystem inflammatory disease (NOMID), also known as chronic infantile neurologic cutaneous and articular syndrome (CINCA)||autosomal dominant|
|PSMB8||Autoinflammation, lipodystrophy, and dermatosis syndrome (ALDD)||autosomal recessive|
|PSTPIP1||Pyogenic sterile arthritis, pyoderma gangrenosum, acne (PAPA) syndrome||autosomal dominant|
|TNFRSF1A||TNF receptor-associated periodic syndrome (TRAPS)||autosomal dominant|
|TNFRSF11A||Autoinflammatory disease||autosomal dominant|
|TRNT1||Sideroblastic anemia with B-cell deficiency||autosomal recessive|
*This gene is also associated with autosomal dominant porokeratosis, which does not cause periodic fever syndrome.
The prevalence of periodic fever syndromes is dependent on the underlying condition. Formal prevalence estimates have not been determined for many of the monogenic periodic fever syndromes due to their rare nature; however, the prevalence of familial Mediterranean fever, the most common of the periodic fever syndromes, is known to vary greatly based on ethnicity. Reports have suggested a prevalence from 1 in 40,000 in the U.S. to 1 in 250 in other populations (PMID: 16979528).
For considerations for testing please refer to:
For management guidelines please refer to:
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|