Complement System Deficiencies

. DEFECTS OF INNATE IMMUNITY .

Complement System Deficiencies panel [38 genes]

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

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
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
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
Sullivan KE, Stiehm ER. Stiehm’s Immune Deficiencies. Elsevier; 2014. doi:10.1016/C2012-1-01317-3