The Invitae Periodic Fever Syndromes Panel analyzes six genes that are associated 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.
LPIN2 MEFV MVK NLRP3 PSTPIP1 TNFRSF1A
LPIN2 MEFV MVK NLRP3 PSTPIP1 TNFRSF1A
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.
Periodic fever syndromes are inherited in either an autosomal recessive or autosomal dominant manner, depending on the underlying gene condition:
|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|
|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|
|PSTPIP1||Pyogenic sterile arthritis, pyoderma gangrenosum, acne (PAPA) syndrome||autosomal dominant|
|TNFRSF1A||TNF receptor-associated periodic syndrome (TRAPS)||autosomal dominant|
*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.
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, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.
Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|