Autoinflammatory Syndrome Panel

SEQmethod-seq-icon Our Sequence Analysis is based on a proprietary targeted sequencing method OS-Seq™ and offers panels targeted for genes associated with certain phenotypes. A standard way to analyze NGS data for finding the genetic cause for Mendelian disorders. Results in 21 days. DEL/DUPmethod-dup-icon Targeted Del/Dup (CNV) analysis is used to detect bigger disease causing deletions or duplications from the disease-associated genes. Results in 21 days. PLUSmethod-plus-icon Plus Analysis combines Sequence + Del/Dup (CNV) Analysis providing increased diagnostic yield in certain clinical conditions, where the underlying genetic defect may be detectable by either of the analysis methods. Results in 21 days.

Test code: IM0201

The Blueprint Genetics Autoinflammatory Syndrome Panel is a 25 gene test for genetic diagnostics of patients with clinical suspicion of chronic infantile neurologic cutaneous articular syndrome (CINCA), cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), familial cold autoinflammatory syndrome 2 (FCAS2), hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), Muckle-Wells syndrome (MWS), neonatal-onset multisystem inflammatory disease (NOMID) or tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS).

Inheritance of familial Mediterranean fever (FMF) and hyperimmunoglobulinemia D with periodic fever syndrome (HIDS) is autosomal recessive, while it is autosomal dominant for tumor necrosis factor (TNF) receptor associated periodic syndrome (TRAPS), cryopyrin-associated periodic syndromes (CAPS, including Muckle-Wells syndrome and chronic infantile neurologic cutaneous articular syndrome (CINCA)) and familial cold autoinflammatory syndrome 2 (FCAS2). Inheritance of interferonopathies is either autosomal recessive or autosomal dominant. Clinical utility of this Panel is phenotype specific. For example, it is estimated to be >90% for FMF and circa 80% for HIDS. In addition to autoinflammatory syndromes, this Panel has differential diagnostics power to ELANE-related neutropenias and specifically to interferonopathias caused by inappropriate exposure to IFN due to overstimulation, enhanced sensitivity or defective negative regulation.

About Autoinflammatory Syndrome

Autoinflammatory syndromes are a group of diseases characterized by recurrent episodes of inflammation without evidence of auto-antigen exposure. Episodes can occur periodically or irregularly. Hereditary periodic fevers are typical examples of diseases within this group. In addition to fever and localized inflammation, these diseases may cause other syndrome-specific symptoms, such as arthalgia, myalgia and tender skin lesions for TRAPS, abdominal pain, vomiting and diarrhea for HIDS, urticaria, myalgia, arthalgia for FCAS2 and skin rash, sensorineural hearing loss and general signs of inflammation for CINCA and Muckle-Wells syndrome. FMF is the most common of periodic fever syndromes having a prevalence of 1:250 to 1:1000 in different populations. It is the most common in the eastern coast of Mediterranean. Other syndromes are much rarer. For example a combined prevelance of 1:360 000 is estimated for CAPS. The penetrance of periodic fever syndromes is often low.

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Results in 3-4 weeks.

Genes in the Autoinflammatory Syndrome Panel and their clinical significance
GeneAssociated phenotypesInheritanceClinVarHGMD
ACP5Spondyloenchondrodysplasia with immune dysregulationAR1024
ADARDyschromatosis symmetrica hereditaria, Aicardi-Goutières syndromeAD/AR16202
CARD14PsoriasisAD930
DDX58Singleton-Merten syndromeAD27
ELANENeutropeniaAD30213
IFIH1Singleton-Merten syndromeAD1017
IL1RNOsteomyelitis, sterile multifocal, with periostitis and pustulosisAR516
IL36RNPustular psoriasis, generalizedAR819
ISG15Immunodeficiency, with basal ganglia calcificationAR33
LPIN2Majeed syndromeAR810
MEFVFamilial Mediterranean feverAD/AR24177
MVKMevalonic aciduria, Hyper-IgD syndromeAR27168
NLRP3Neonatal onset multisystem inflammatory disease (NOMID), Muckle-Wells syndrome, Chronic infantile neurologic cutaneous articular (CINCA) syndromeAD15125
NLRP12Familial cold autoinflammatory syndromeAD39
NOD2Blau syndrome, Sarcoidosis, early-onsetAD/AR1093
PLCG2Familial cold autoinflammatory syndrome 3 (PLAID), Autoinflammation, antibody deficiency, and immune dysregulation syndrome (APLAID)AD48
PSMB8Nakajo-Nishimura syndrome, Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome, Autoinflammation, lipodystrophy, and dermatosis syndrome, Joint contractures, muscular atrophy, microcytic anemia, and panniculitis-induced lipodystrophy syndromeAR410
PSTPIP1Pyogenic sterile arthritis, pyoderma gangrenosum, and acneAD525
RNASEH2AAicardi-Goutières syndromeAR1221
RNASEH2BAicardi-Goutières syndromeAR539
RNASEH2CAicardi-Goutières syndromeAR414
SAMHD1Aicardi-Goutières syndromeAR2248
TMEM173STING-associated vasculopathy, infantile-onsent (SAVI)AD37
TNFRSF1APeriodic fever (TNF receptor-associated periodic syndrome)AD18101
TREX1Vasculopathy, retinal, with cerebral leukodystrophy, Chilblain lupus, Aicardi-Goutières syndromeAD/AR2465

Gene, refers to HGNC approved gene symbol; Inheritance to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL); ClinVar, refers to a number of variants in the gene classified as pathogenic or likely pathogenic in ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/); HGMD, refers to a number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD, http://www.hgmd.cf.ac.uk/ac/). The list of associated (gene specific) phenotypes are generated from CDG (http://research.nhgri.nih.gov/CGD/) or Orphanet (http://www.orpha.net/) databases.

Blueprint Genetics offers a comprehensive autoinflammatory syndrome panel that covers classical genes associated with Blau syndrome, chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE), chronic infantile neurologic cutaneous articular syndrome (CINCA), congenital neutropenia, cryopyrin-associated periodic syndromes (CAPS), cyclic neutropenia, deficiency of interleukin 1 receptor antagonist, deficiency of interleukin 36 receptor antagonist, familial Mediterranean fever (FMF), familial cold autoinflammatory syndrome 2 (FCAS2), hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), Muckle-Wells syndrome (MWS), neonatal-onset multisystem inflammatory disease (NOMID), pediatric granulomatous arthritis, pyogenic arthritis, pyoderma gangrenosum and acne syndrome and tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS). The genes are carefully selected based on the existing scientific evidence, our experience and most current mutation databases. Candidate genes are excluded from this first-line diagnostic test. The test does not recognise balanced translocations or complex inversions, and it may not detect low-level mosaicism. The test should not be used for analysis of sequence repeats or for diagnosis of disorders caused by mutations in the mitochondrial DNA.

Please see our latest validation report showing sensitivity and specificity for SNPs and indels, sequencing depth, % of the nucleotides reached at least 15x coverage etc. If the Panel is not present in the report, data will be published when the Panel becomes available for ordering. Analytical validation is a continuous process at Blueprint Genetics. Our mission is to improve the quality of the sequencing process and each modification is followed by our standardized validation process. All the Panels available for ordering have sensitivity and specificity higher than > 0.99 to detect single nucleotide polymorphisms and a high sensitivity for indels ranging 1-19 bp. The diagnostic yield varies substantially depending on the used assay, referring healthcare professional, hospital and country. Blueprint Genetics’ Plus Analysis (Seq+Del/Dup) maximizes the chance to find molecular genetic diagnosis for your patient although Sequence Analysis or Del/Dup Analysis may be cost-effective first line test if your patient’s phenotype is suggestive for a specific mutation profile. Detection limit for Del/Dup analysis varies through the genome from one to six exon Del/Dups depending on exon size, sequencing coverage and sequence content.

The sequencing data generated in our laboratory is analyzed with our proprietary data analysis and annotation pipeline, integrating state-of-the art algorithms and industry-standard software solutions. Incorporation of rigorous quality control steps throughout the workflow of the pipeline ensures the consistency, validity and accuracy of results. The highest relevance in the reported variants is achieved through elimination of false positive findings based on variability data for thousands of publicly available human reference sequences and validation against our in-house curated mutation database as well as the most current and relevant human mutation databases. Reference databases currently used are the 1000 Genomes Project (http://www.1000genomes.org), the NHLBI GO Exome Sequencing Project (ESP; http://evs.gs.washington.edu/EVS), the Exome Aggregation Consortium (ExAC; http://exac.broadinstitute.org), ClinVar database of genotype-phenotype associations (http://www.ncbi.nlm.nih.gov/clinvar) and the Human Gene Mutation Database (http://www.hgmd.cf.ac.uk). The consequence of variants in coding and splice regions are estimated using the following in silico variant prediction tools: SIFT (http://sift.jcvi.org), Polyphen (http://genetics.bwh.harvard.edu/pph2/), and Mutation Taster (http://www.mutationtaster.org).

Through our online ordering and statement reporting system, Nucleus, the customer can access specific details of the analysis of the patient. This includes coverage and quality specifications and other relevant information on the analysis. This represents our mission to build fully transparent diagnostics where the customer gains easy access to crucial details of the analysis process.

In addition to our cutting-edge patented sequencing technology and proprietary bioinformatics pipeline, we also provide the customers with the best-informed clinical report on the market. Clinical interpretation requires fundamental clinical and genetic understanding. At Blueprint Genetics our geneticists and clinicians, who together evaluate the results from the sequence analysis pipeline in the context of phenotype information provided in the requisition form, prepare the clinical statement. Our goal is to provide clinically meaningful statements that are understandable for all medical professionals, even without training in genetics.

Variants reported in the statement are always classified using the Blueprint Genetics Variant Classification Scheme modified from the ACMG guidelines (Richards et al. 2015), which has been developed by evaluating existing literature, databases and with thousands of clinical cases analyzed in our laboratory. Variant classification forms the corner stone of clinical interpretation and following patient management decisions. Our statement also includes allele frequencies in reference populations and in silico predictions. We also provide PubMed IDs to the articles or submission numbers to public databases that have been used in the interpretation of the detected variants. In our conclusion, we summarize all the existing information and provide our rationale for the classification of the variant.

A final component of the analysis is the Sanger confirmation of the variants classified as likely pathogenic or pathogenic. This does not only bring confidence to the results obtained by our NGS solution but establishes the mutation specific test for family members. Sanger sequencing is also used occasionally with other variants reported in the statement. In the case of variant of uncertain significance (VUS) we do not recommend risk stratification based on the genetic finding. Furthermore, in the case VUS we do not recommend use of genetic information in patient management or genetic counseling. For some cases Blueprint Genetics offers a special free of charge service to investigate the role of identified VUS.

We constantly follow genetic literature adapting new relevant information and findings to our diagnostics. Relevant novel discoveries can be rapidly translated and adopted into our diagnostics without delay. These processes ensure that our diagnostic panels and clinical statements remain the most up-to-date on the market.

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ICD & CPT codes

CPT codes

SEQ81479
DEL/DUP81479


ICD codes

Commonly used ICD-10 codes when ordering the Autoinflammatory Syndrome Panel

ICD-10Disease
E85.0Familial Mediterranean fever (FMF)
E85.0Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS)
E85.0Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS)
E85.0Muckle-Wells syndrome (MWS)
E85.0Familial cold autoinflammatory syndrome 2 (FCAS2)
E85.0Cryopyrin-associated periodic syndromes (CAPS)
E85.0Chronic infantile neurologic cutaneous articular syndrome (CINCA)

Accepted sample types

  • EDTA blood, min. 1 ml
  • Purified DNA, min. 5μg
  • Saliva (Oragene DNA OG-500 kit)

Label the sample tube with your patient’s name, date of birth and the date of sample collection.

Note that we do not accept DNA samples isolated from formalin-fixed paraffin-embedded (FFPE) tissue.