. DEFECTS OF INNATE IMMUNITY .

Complement System Deficiencies panel [38 genes]

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Defects in complement system components increase susceptibility to infection and autoimmune disorders, whereas defects in complement regulatory proteins may lead to serious disorders due to unrestricted activation. The clinical expression of genetically determined deficiencies of the complement system is variable and depends on the role of the deficient component in normal host defence and inflammation. Clinical features are diverse, but cluster into features that align with the known functions of complement: prevention of infection, disposal of apoptotic cells and immune complexes, and protection of endothelial surfaces.

Clinical features

  • Infections, disseminated, recurrent
  • Inflammation
  • Onset: infancy to adulthood

Prevalence

  • ~1-10% of PIDs
  • 0.03% in the general population

Service benefits and management

  • Accurate diagnosis & prognosis
  • Complications management
  • Targeted treatment
  • Vaccination against encapsulated bacteria
  • Antibiotics
  • Antiinflammatory  therapy

C1QA, C1QB, C1QC, C1R, C1S, C2, C3, C4A, C4B, C5, C6, C7, C8A, C8B, C8G, C9, CD46, CD55, CD59, CFB, CFD, CFH, CFHR1, CFHR2, CFHR3, CFHR4, CFHR5, CFI, CFP, DGKE, F12, FCN3, G6PD, MASP1, MASP2, MBL2, SERPING1, THBD

Panels included

Atypical Haemolytic Uremic Syndrome (aHUS) - 13 genes
Hereditary Angioedema (HAE) - 2 genes
Disseminated Neisserial Infections - 9 genes
SLE-like Syndrome - 8 genes
Pyogenic Infections, Recurrent - 6 genes

Gene-related phenotypes

Gene Phenotype MIM MOI
C1QA C1q deficiency 613652 AR
C1QB C1q deficiency 613652 AR
C1QC C1q deficiency 613652 AR
C1R Ehlers-Danlos syndrome, periodontal type, 1 130080 AR | AD
C1S C1s deficiency | Ehlers-Danlos syndrome, periodontal type, 2 613783 | 617174 AR | AD
C2 C2 deficiency | Macular degeneration, age-related, 14, reduced risk of 217000 | 615489 AR | AD
C3 C3 deficiency | Hemolytic uremic syndrome, atypical 5, susceptibility to 613779 | 612925 AR | AD
C4A C4a deficiency 614380 AR | AD
C4B C4b deficiency 614379 AR
C5 C5 deficiency 609536 AR
C6 C6 deficiency 612446 AR
C7 C7 deficiency 610102 AR
C8A C8 deficiency, type I 613790 AR
C8B C8 deficiency, type II 613789 AR
C8G C8 deficiency - -
C9 C9 deficiency 613825 AR
CD46 Hemolytic uremic syndrome, atypical 2, susceptibility to 612922 AR | AD
CD55 Complement hyperactivation, angiopathic thrombosis, and protein-losing enteropathy 226300 AR
CD59 Hemolytic anemia, CD59-mediated, with or without immune-mediated polyneuropathy 612300 AR
CFB Hemolytic uremic syndrome, atypical, 4, susceptibility to | Complement factor B deficiency 612924 | 615561 AD
CFD Complement factor D deficiency 613912 AR
CFH Complement factor H deficiency | Hemolytic uremic syndrome, atypical, 1, susceptibility to | Macular degeneration, age-related, 4 | Basal laminar drusen 609814 | 235400 | 610698 | 126700 AD | AR
CFHR1 Hemolytic uremic syndrome, atypical, susceptibility to | Macular degeneration, age-related, reduced risk of 235400 | 603075 AD | AR
CFHR2 Hemolytic uremic syndrome - AD
CFHR3 Hemolytic uremic syndrome, atypical, susceptibility to | Macular degeneration, age-related, reduced risk of 235400 | 603075 AD | AR
CFHR4 Hemolytic uremic syndrome - AD | AR
CFHR5 Nephropathy due to CFHR5 deficiency 614809 AD | AR
CFI Complement factor I deficiency | Hemolytic uremic syndrome, atypical, 3, susceptibility to | Macular degeneration, age-related, 13, susceptibility to 610984 | 612923 | 615439 AD | AR
CFP Properdin deficiency, X-linked 312060 XLR
DGKE Nephrotic syndrome, type 7 | Hemolytic uremic syndrome, atypical, 7, susceptibility to 615008 AR
G6PD Hemolytic anemia, G6PD deficient (favism) 300908 AR
F12 Factor XII deficiency | Angioedema, hereditary, type III 234000 | 610618 AD
FCN3 Immunodeficiency due to ficolin 3 deficiency 613860 AR
MASP1 3MC syndrome 1 257920 AR
MASP2 MASP2 deficiency 613791 AR
MBL2 Chronic infections, due to MBL deficiency 614372 AD
SERPING1 Angioedema, hereditary, types I and II | Complement component 4, partial deficiency of 106100 | 120790 AR | AD
THBD Thrombophilia due to thrombomodulin defect | Hemolytic uremic syndrome, atypical, 6, susceptibility to 614486 | 612926 AD | Mu

(*) MIM: OMIM (Online Mendelian Inheritance in Man) identifier code; MOI: mode of inheritance; AD: autosomal dominant inheritance; AR: autosomal recessive inheritance; XL: X-linked inheritance; XLR: X-linked recessive inheritance; XLD: X-linked dominant inheritance; Mu: multifactorial inheritance; SMu: somatic mutation.

References

  1. Grumach AS, Kirschfink M. Are complement deficiencies really rare? Overview on prevalence, clinical importance and modern diagnostic approach. Mol Immunol. 2014;61(2):110-117. doi:10.1016/j.molimm.2014.06.030
  2. IUIS Scientific Committee. Primary Immunodeficiency Diseases. Vol 118. (Rezaei N, Aghamohammadi A, Notarangelo LD, eds.). Berlin, Heidelberg: Springer Berlin Heidelberg; 2017. doi:10.1007/978-3-662-52909-6
  3. Prohászka Z, Nilsson B, Frazer-Abel A, Kirschfink M. Complement analysis 2016: Clinical indications, laboratory diagnostics and quality control. 2016;221(11):1247-1258. doi:10.1016/J.IMBIO.2016.06.008
  4. Sullivan KE, Stiehm ER. Stiehm’s Immune Deficiencies. Elsevier; 2014. doi:10.1016/C2012-1-01317-3