Complement System Disorder Panel

  • bpg-method PLUS
  • bpg-method SEQ
  • bpg-method DEL/DUP

Test code: IM0701

The Blueprint Genetics Complement System Disorder Panel is an 80 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: http://blueprintgenetics.com/faqs/#prenatal

Genes in the Complement System Disorder Panel and their clinical significance
Gene Associated phenotypes Inheritance ClinVar HGMD
ADIPOQ Complement system AD/AR 2 8
ADIPOR1* Complement system AD/AR 4
ADIPOR2 Complement system AD/AR
ARMC4* Ciliary dyskinesia AR 13 15
C1QA C1q deficiency AR 2 7
C1QB C1q deficiency AR 4 7
C1QBP Primary immunodeficiency AD/AR 6
C1QC C1q deficiency AR 4 7
C1R Immunodeficiency AD/AR 14 16
C1S Complement component C1s deficiency AR 4 8
C2* Complement component 2 deficiency AR 4 6
C3 Hemolytic uremic syndrome, atypical, Complement component 3 deficiency AD/AR 5 82
C3AR1 Complement system AD/AR 1 3
C4A* Blood group, Chido/Rodgers system BG 1 5
C4B* Complement component 4B deficiency AR 8
C4BPA Complement system AD/AR 2
C4BPB Complement system AD/AR
C5 Eculizumab, poor response to, Complement component 5 deficiency AD/AR 5 17
C5AR1 Complement system AD/AR
C5AR2 Complement system AD/AR 2
C6 Complement component 6 deficiency AR 7 11
C7 Complement component 7 deficiency AR 14 29
C8A Complement component 8 deficiency AR 2 5
C8B Complement component 8 deficiency AR 7 7
C8G Immunodeficiency AD/AR
C9 Complement component 9 deficiency AR 7 7
CCDC39 Ciliary dyskinesia AR 16 38
CCDC40 Ciliary dyskinesia AR 19 32
CCDC65 Ciliary dyskinesia AR 1
CCDC103 Ciliary dyskinesia AR 3 4
CCDC114 Ciliary dyskinesia AR 6 7
CCNO Ciliary dyskinesia AR 9 9
CD46* Hemolytic uremic syndrome, atypical AD/AR 4 64
CD55 Blood group, Cromer system BG 7 6
CD59 CD59 deficiency AR 3 6
CD93 Complement system AD/AR
CFB Complement factor B deficiency, Hemolytic uremic syndrome, atypical AD/AR 2 21
CFD Complement factor D deficiency AR 2 3
CFH* Hemolytic uremic syndrome, atypical, Complement factor H deficiency AD/AR 17 259
CFI Hemolytic uremic syndrome, atypical, Complement factor I deficiency AD/AR 7 123
CFP Properdin deficiency XL 5 17
CLU Complement system AD/AR 16
COLEC11 3MC syndrome AR 6 10
CR1* Blood group, Knops system BG 1 15
CR2 Common variable immunodeficiency AR 2 5
CRP Complement system AD/AR
DGKE Nephrotic syndrome AR 13 27
DNAAF1 Ciliary dyskinesia AR 9 30
DNAAF2 Ciliary dyskinesia AR 6 3
DNAAF3 Primary ciliary dyskinesia AD/AR 6 3
DNAAF5 Ciliary dyskinesia AR 2 2
DNAH5 Ciliary dyskinesia AR 60 141
DNAH11* Ciliary dyskinesia AR 30 90
DNAI1 Ciliary dyskinesia AR 12 28
DNAI2 Ciliary dyskinesia AR 11 6
DNAL1 Ciliary dyskinesia AR 3 1
DRC1 Primary ciliary dyskinesia AD/AR 3 2
DYX1C1 Ciliary dyskinesia AR 9 11
FCN1 Complement system AD/AR 3
FCN2 Complement system AD/AR
FCN3 Immunodeficiency due to Ficolin 3 deficiency AR 1
HYDIN* Primary ciliary dyskinesia AD/AR 5 15
LRRC6 Ciliary dyskinesia AR 7 16
MASP1 3MC syndrome AR 7 17
MASP2 MASP2 deficiency AR 2
MAT2A* Complement system AD/AR 2
NME8 Ciliary dyskinesia AR 1 5
OFD1 Simpson-Golabi-Behmel syndrome, Retinitis pigmentosa, Orofaciodigital syndrome, Joubert syndrome XL 133 156
PIGA* Multiple congenital anomalies-hypotonia-seizures syndrome XL 23 17
PTX3 Complement system AD/AR
RPGR Retinitis pigmentosa XL 62 202
RSPH1 Ciliary dyskinesia AR 11 10
RSPH4A Ciliary dyskinesia AR 8 21
RSPH9 Ciliary dyskinesia AR 4 11
SERPING1 Angioedema AD/AR 26 535
SPAG1 Primary ciliary dyskinesia AD/AR 13 10
THBD Thrombophilia due to thrombomodulin defect, Hemolytic uremic syndrome, atypical AD 5 21
VSIG4 Complement system XL 1
VTN Complement system AD/AR
ZMYND10 Ciliary dyskinesia AR 6 16

*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.

Gene Genomic location HG19 HGVS RefSeq RS-number
OFD1 ChrX:13773245 c.1130-22_1130-19delAATT NM_003611.2 rs312262865
OFD1 ChrX:13768358 c.935+706A>G NM_003611.2 rs730880283
THBD Chr20:23030292 c.-151G>T NM_000361.2 rs16984852

The strengths of this test include:

  • Blueprint Genetics is one of the few laboratories worldwide with CAP and ISO-15189 accreditation for NGS panels and CLIA certification
  • Superior sequencing quality
  • Careful selection of genes based on current literature, our experience and the most current mutation databases
  • Transparent and easy access to quality and performance data at the patient level that are accessible via our Nucleus portal
  • Transparent and reproducible analytical validation for each panel (see Test performance section; for complete details, see our Analytic Validation)
  • Sequencing and high resolution del/dup analysis available in one test
  • Inclusion of non-coding disease causing variants where clinically indicated (please see individual Panel descriptions)
  • Interpretation of variants following ACMG variant classification guidelines
  • Comprehensive clinical statement co-written by a PhD geneticist and a clinician specialist

 

This test does not detect the following:

  • Complex inversions
  • Gene conversions
  • Balanced translocations
  • Mitochondrial DNA variants
  • Variants in regulatory or non-coding regions of the gene unless otherwise indicated (please see Non-coding disease causing variants covered by the panel). This mean for instance intronic variants locating deeper than 15 nucleotides from the exon-intron boundary.

 

This test may not reliably detect the following:

  • Low level mosaicism
  • Stretches of mononucleotide repeats
  • Indels larger than 50bp
  • Single exon deletions or duplications
  • Variants within pseudogene regions/duplicated segments
  • Disorders caused by long repetitive sequences (e.g. trinucleotide repeat expansions)

 

The sensitivity of this test may be reduced if DNA is extracted by a laboratory other than Blueprint Genetics.

For additional information, please refer to the Test performance section and see our Analytic Validation.

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

SEQ 81479
DEL/DUP 81479


ICD codes

Commonly used ICD-10 codes when ordering the Complement System Disorder Panel

ICD-10 Disease
D84.1 Defects in the complement system
D58.8 Atypical 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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