Periodic Fever Syndromes Panel, Sequencing and Deletion/Duplication

  • Preferred test to confirm a diagnosis of a periodic fever syndrome
  • Predictive diagnostic or carrier testing in individuals with a family history of a periodic fever syndrome
Related Tests

Preferred test when clinical symptoms are suspicious for FMF

Recommended test for a known familial sequence variant previously identified in a family member

Periodic fever syndromes are a varied group of autoinflammatory disorders characterized by recurrent episodes of fever that lack an infectious cause. These syndromes include familial Mediterranean fever (FMF), cyclic neutropenia, tumor necrosis factor receptor associated periodic syndrome (TRAPS), Muckle-Wells syndrome, and Hyper-IgD syndrome (HIDS). Genetic testing can confirm a diagnosis or be used to determine whether individuals with a family history of a periodic fever syndrome may be carriers.

Disease Overview

  • For specific disease descriptions, refer to the Genes Tested table.
  • Attacks often begin with a prodromal phase, with symptoms such as fatigue, malaise, and headache.
  • Inflammatory symptoms (eg, fever, pain, rash) follow the prodromal phase.
  • Symptoms usually resolve spontaneously.
  • Individuals are generally asymptomatic between attacks, though in some severe cases, inflammatory symptoms may not completely resolve between attacks.
  • Depending on the specific syndrome, symptoms may be triggered by exposure to cold or trauma.

Indications for Ordering

  • Use to confirm diagnosis of a periodic fever syndrome in a symptomatic individual
  • Diagnostic or carrier testing in individuals with a family history of a periodic fever syndrome

Prevalence

Varies by condition and ethnicity.

Inheritance

See the Genes Tested table.

Test Description

See the Genes Tested table for genes included in the panel.

Methodology

This test is performed using the following sequence of steps:

  • Selected genomic regions, primarily coding exons and exon-intron boundaries, from the targeted genes are isolated from extracted genomic DNA using a probe-based hybrid capture enrichment workflow.
  • Enriched DNA is sequenced by massively parallel sequencing (MPS), also known as next generation sequencing (NGS), followed by paired-end read alignment and variant calling using a custom bioinformatics pipeline. The pipeline includes an algorithm for detection of large (single exon-level or larger) deletions and duplications.
  • Sanger sequencing is performed as necessary to fill in regions of low coverage and, in certain situations, to confirm variant calls.
  • Large deletion/duplication calls made using MPS are confirmed by an orthogonal exon-level microarray when sample quality and technical conditions allow.

Clinical Sensitivity

Variable, dependent on specific disorder

Analytical Sensitivity

Variant Class Analytical Sensitivity (PPA) Estimatea (%)
and 95% Credibility Region (%)
Analytical Specificity (NPA) (%)

SNVs

>99 (96.9-99.4)

>99.9

Deletions 1-10 bpb

93.8 (84.3-98.2)

>99.9

Insertions 1-10 bpb

94.8 (86.8-98.5)

>99.9

Exon-levelc Deletions

97.8 (90.3-99.8) [2 exons or larger]

62.5 (38.3-82.6) [single exon]

>99.9

Exon-levelc Duplications

83.3 (56.4-96.4) [3 exons or larger]

>99.9

aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived. These values do not apply to testing performed by multiplex ligation-dependent probe amplification (MLPA).

bVariants greater than 10 bp may be detected, but the analytical sensitivity may be reduced.

cIn most cases, a single exon deletion or duplication is less than 450 bp and 3 exons span a genomic region larger than 700 bp.

bp, base pairs; NPA, negative percent agreement; PPA, positive percent agreement; SNVs, single nucleotide variants

Limitations

  • A negative result does not exclude a heritable form of a periodic fever syndrome.
  • Diagnostic errors can occur due to rare sequence variations.
  • Interpretation of this test result may be impacted if the individual has had an allogeneic stem cell transplantation.
  • The following will not be evaluated:
    • Variants outside the coding regions and intron-exon boundaries of the targeted genes
    • Regulatory region and deep intronic variants
    • Breakpoints of large deletions/duplications
  • The following may not be detected:
    • Deletions/duplications/insertions of any size by massively parallel sequencing
    • Large duplications less than three exons in size
    • Noncoding transcripts
    • Low-level somatic variants
    • Certain other variants due to technical limitations in the presence of pseudogenes or repetitive/homologous regions

Genes Tested

Gene MIM Number Disorder Inheritance Age of Onset Clinical Symptoms

ELANE

130130

Cyclic neutropenia

AD

Infancy

Fever and malaise

Mouth ulcers

Cyclic neutropenia

Chronic and severe infections

Severe congenital neutropenia 1

AD

Infancy

Fever

Inflammation of gums and skin

Decreased levels of neutrophils

Chronic and severe infections

LPIN2

605519

Majeed syndrome

AR

Before 2 years

Recurrent fever episodes

Chronic recurrent multifocal osteomyelitis (CRMO)

Congenital dyserythropoietic anemia

Sweet syndrome—painful bumps and blisters

Contractures

Growth retardation

MEFV

608107

Familial Mediterranean fever (FMF)

AR and AD

Typically before 10 years for AR FMF

Milder/AD forms may not present until adulthood

Recurrent fever episodes

Painful inflammation in abdomen, chest, and joints

Erysipelas-like rash on lower legs

608068 Acute febrile neutrophilic dermatosis AD Childhood

Recurrent fever

Acute onset of painful skin lesions

Arthralgia and myalgia

MVK

251170

Porokeratosis 3

AD

Between 3rd-4th decade of life

Annular skin plaques surrounded by distinctive keratotic rim

Fluctuate seasonally

Hyper-IgD syndrome (HIDS)

AR

Infancy

Periodic high fevers

Abdominal and joint pain

Headache

Skin lesions

Hepatomegaly and/or splenomegaly

Elevated immunoglobulin D

Mevalonic aciduria

AR

Infancy

Hepatosplenomegaly

Abdominal and joint pain

Skin rashes

Failure to thrive

Developmental delay and progressive ataxia

Progressive vision problems

NLRP12

609648

Familial cold autoinflammatory syndrome 2 (FCAS2)

AD

First year of life to middle age

Episodic and recurrent rash

Urticaria

Arthralgia

Myalgia

Abdominal and/or thoracic pain

NLRP3

606416

Familial cold autoinflammatory syndrome 1 (FCAS1)

AD

Before age 10

Recurrent episodes of nonpruritic urticaria rash

Episodes triggered by exposure to cold

Low-grade fever and malaise

Sweating, headaches, and nausea

Keratoendotheliitis fugax hereditaria

AD

Between ages 4-12 years

Periodic inflammation of corneal endothelium

Redness of the eye, pain, and photophobia

Blurry vision

Muckle-Wells syndrome

AD

Infancy to early childhood

Recurrent rashes

Intermittent fevers

Joint pain

Recurrent conjunctivitis

Progressive hearing loss

Amyloidosis

Neonatal onset multisystem inflammatory disease (NOMID)/CINCA syndrome

AD

Infancy

Skin rash typically present at birth

Chronic meningitis

Headaches, seizures, and vomiting

Intellectual disability and developmental delay

Hearing and vision loss

Joint inflammation and cartilage overgrowth

Short stature

Contractures

Deafness, autosomal dominant 34, with or without inflammation

AD

Childhood

Postlingual sensorineural hearing loss

Episodic urticaria

Periodic fever

Renal amyloidosis

NOD2

605956

Blau syndrome

AD

Early childhood; usually before age 4

Granulomatous dermatitis

Arthritis

Uveitis

Nephritis; chronic kidney failure

PSTPIP1

606347

Pyogenic sterile arthritis, pyoderma gangrenosum, and acne

AD

Childhood

Pyogenic arthritis

Pyoderma gangrenosum

Severe cystic acne

TNFAIP3

191163

Autoinflammatory syndrome, familial, Behcet-like

AD

First or second decade of life

Mucosal ulcers (particularly in oral and genital areas)

Skin rash

Uveitis

Polyarthritis

TNFRSF1A

191190

Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) (aka periodic fever, familial)

AD

Childhood

Recurrent fever

Sterile peritonitis/pleuritis

Abdominal pain

Myalgia

Leukocytosis

Elevated erythrocyte sedimentation rate

AD, autosomal dominant; AR, autosomal recessive

Additional Resources