Complement System Disorder 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: IM0701

The Blueprint Genetics Complement System Disorder Panel is an 82 gene test for genetic diagnostics of patients with clinical suspicion of atypical hemolytic uremic syndrome (aHUS) or defects in the complement system.

Compelement deficiencies are a heterogenous group of diseases. This Panel covers comprehensively genes associated with autosomal recessive, autosomal dominant as well as X-linked forms of complement deficiencies. The clinical utility of this Panel varies among deficiencies and is estimated to be for example >80% for atypical hemolytic uremic syndrome. In addition to complement system disorders, this Panel have differential diagnostics power to other diseases such as primary ciliary dyskinesia, that is characterized by recurrent respiratory infections. This Panel is included in the comprehensive Primary Immunodeficiency Panel.

About Complement System Disorder

The complement system disorders are a group of primary immunodeficiencies resulting in absent or suboptimal function of complement system proteins. In general, deficiencies of the classical and alternative complement pathways are rather rare, while deficiencies of the proteins in the mannose-binding lectin (MBL) pathway are more common and affects up to 5-25% of individuals. Altogether, complement system deficiensies are estimated to comprise 5-10% of all primary immunodeficiensies. C2-deficiency is the most common classical pathway complement deficiency in many populations and its prevalence is estimated to be 1:10 000. There are two main categories of complement system disorders, originating from mutations in genes encoding proteins either inhibiting or activating the complement system and thus resulting overactive or underactive responses, respectively. Complement system disorders predispose patients to (Neisserial) infections, atypical hemolytic uremic syndrome, age-related macular degeneration, systemic lupus erythematosus SLE and preeclampsia.

Availability

Results in 3-4 weeks. We do not offer a maternal cell contamination (MCC) test at the moment. We offer prenatal testing only for cases where the maternal cell contamination studies (MCC) are done by a local genetic laboratory. Read more.

Genes in the Complement System Disorder Panel and their clinical significance
GeneAssociated phenotypesInheritanceClinVarHGMD
ADIPOQComplement systemAD/AR122
ADIPOR1*Complement systemAD/AR4
ADIPOR2Complement systemAD/AR2
ARMC4*Ciliary dyskinesiaAR1215
C1QAC1q deficiencyAR18
C1QBC1q deficiencyAR17
C1QBPPrimary immunodeficiencyAD/AR
C1QCC1q deficiencyAR37
C1RImmunodeficiencyAD/AR715
C1SComplement component C1s deficiencyAR48
C2*Complement component 2 deficiencyAR47
C3Hemolytic uremic syndrome, atypical, Complement component 3 deficiencyAD/AR486
C3AR1Complement systemAD/AR13
C4A*Blood group, Chido/Rodgers systemBG18
C4B*Complement component 4B deficiencyAR9
C4BPAComplement systemAD/AR5
C4BPBComplement systemAD/AR
C5Eculizumab, poor response to, Complement component 5 deficiencyAD/AR520
C5AR1Complement systemAD/AR
C5AR2Complement systemAD/AR4
C6Complement component 6 deficiencyAR610
C7Complement component 7 deficiencyAR1130
C8AComplement component 8 deficiencyAR24
C8BComplement component 8 deficiencyAR77
C8GImmunodeficiencyAD/AR
C9Complement component 9 deficiencyAR67
CCDC39Ciliary dyskinesiaAR1338
CCDC40Ciliary dyskinesiaAR1531
CCDC65Ciliary dyskinesiaAR21
CCDC103Ciliary dyskinesiaAR24
CCDC114Ciliary dyskinesiaAR57
CCNOCiliary dyskinesiaAR79
CD46*Hemolytic uremic syndrome, atypicalAD/AR262
CD55Blood group, Cromer systemBG1
CD59CD59 deficiencyAR36
CD93Complement systemAD/AR
CFBComplement factor B deficiency, Hemolytic uremic syndrome, atypicalAD/AR224
CFDComplement factor D deficiencyAR23
CFH*Hemolytic uremic syndrome, atypical, Complement factor H deficiencyAD/AR15260
CFHR1*Hemolytic uremic syndrome, atypicalAD/AR/Digenic29
CFHR3*Hemolytic uremic syndrome, atypicalAD/AR/Digenic14
CFIHemolytic uremic syndrome, atypical, Complement factor I deficiencyAD/AR6118
CFPProperdin deficiencyXL516
CLUComplement systemAD/AR20
COLEC113MC syndromeAR66
CR1*Blood group, Knops systemBG129
CR2Common variable immunodeficiencyAR27
CRPComplement systemAD/AR
DGKENephrotic syndromeAR1021
DNAAF1Ciliary dyskinesiaAR828
DNAAF2Ciliary dyskinesiaAR43
DNAAF3Primary ciliary dyskinesiaAD/AR33
DNAAF5Ciliary dyskinesiaAR22
DNAH5Ciliary dyskinesiaAR36135
DNAH11*Ciliary dyskinesiaAR2590
DNAI1Ciliary dyskinesiaAR1028
DNAI2Ciliary dyskinesiaAR76
DNAL1Ciliary dyskinesiaAR31
DRC1Primary ciliary dyskinesiaAD/AR32
DYX1C1Ciliary dyskinesiaAR617
FCN1Complement systemAD/AR4
FCN2Complement systemAD/AR7
FCN3Immunodeficiency due to Ficolin 3 deficiencyAR1
HYDIN*Primary ciliary dyskinesiaAD/AR313
LRRC6Ciliary dyskinesiaAR814
MASP13MC syndromeAR714
MASP2MASP2 deficiencyAR18
MAT2A*Complement systemAD/AR2
NME8Ciliary dyskinesiaAR16
OFD1Simpson-Golabi-Behmel syndrome, Retinitis pigmentosa, Orofaciodigital syndrome, Joubert syndromeXL129148
PIGA*Multiple congenital anomalies-hypotonia-seizures syndromeXL1914
PTX3Complement systemAD/AR
RPGRRetinitis pigmentosaXL41184
RSPH1Ciliary dyskinesiaAR910
RSPH4ACiliary dyskinesiaAR721
RSPH9Ciliary dyskinesiaAR211
SERPING1AngioedemaAD/AR15513
SPAG1Primary ciliary dyskinesiaAD/AR710
THBDThrombophilia due to thrombomodulin defect, Hemolytic uremic syndrome, atypicalAD527
VSIG4Complement systemXL1
VTNComplement systemAD/AR
ZMYND10Ciliary dyskinesiaAR616
  • * Some regions of the gene are duplicated in the genome leading to limited sensitivity within the regions. Thus, low-quality variants are filtered out from the duplicated regions and only high-quality variants confirmed by other methods are reported out. Read more.

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 Complement System Disorder Panel that covers classical genes associated with atypical hemolytic uremic syndrome (aHUS), defects in the complement system and primary ciliary dyskinesia. 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.

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. Average sensitivity and specificity in Blueprint NGS Panels is 99.3% and 99.9% for detecting SNPs. Sensitivity to for indels vary depending on the size of the alteration: 1-10bps (96.0%), 11-20 bps (88.4%) and 21-30 bps (66.7%). The longest detected indel was 46 bps by sequence analysis. Detection limit for Del/Dup (CNV) analysis varies through the genome depending on exon size, sequencing coverage and sequence content. The sensitivity is 71.5% for single exon deletions and duplications and 99% for three exons’ deletions and duplications. We have validated the assays for different starting materials including EDTA-blood, isolated DNA (no FFPE) and saliva that all provide high-quality results. 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.

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 Complement System Disorder Panel

ICD-10Disease
D84.1Defects in the complement system
D58.8Atypical hemolytic uremic syndrome (aHUS)

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.

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