C1Q Deficiency

Mendelian MONDO:0013343 Pathograph 33 Show in embeddings browser Complement Disorder

Hereditary C1q deficiency is a rare autosomal recessive inborn error of immunity caused by biallelic variants in any one of the three genes encoding the chains of C1q (C1QA, C1QB, C1QC). C1q is the recognition subunit of the first component of the classical complement pathway. Most variants abolish circulating C1q; some missense variants instead yield a non-functional low-molecular-weight C1q, and in both cases classical-pathway haemolytic activity (CH50) is absent while C3 and C4 are normal and the lectin and alternative pathways remain intact. Loss of C1q has three consequences that together account for the phenotype: the classical pathway cannot be initiated, so defence against encapsulated bacteria is impaired; apoptotic cells are cleared poorly and become a source of nuclear autoantigen; and C1q no longer restrains interferon-alpha production induced by immune complexes, so patients show a sustained type I interferon signature. C1q deficiency is the strongest single genetic risk factor for systemic lupus erythematosus: most patients develop SLE or an SLE-like illness in early childhood, dominated by discoid and other mucocutaneous lesions, with glomerulonephritis and central nervous system involvement (seizures, cerebral vasculitis, basal ganglia calcification) and comparatively few anti-dsDNA antibodies. About half also have severe or recurrent bacterial infections, including meningitis, and about a fifth of reported patients die, nearly all before the age of 20. Because C1q is made by monocyte-derived cells rather than the liver, allogeneic haematopoietic stem cell transplantation restores C1q production and can cure the disease; regular fresh frozen plasma infusion supplies C1q temporarily, and type I interferon blockade is an emerging option.

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Classifications

Harrison's Part
IMMUNE RHEUMATOLOGIC
IUIS Category
complement deficiency
🔗

Mappings

MONDO
MONDO:1060174 systemic lupus erythematosus related to C1QA Not Yet Curated
skos:relatedMatch manual curation
MONDO places this class under systemic lupus erythematosus, not under C1Q deficiency, and defines it as SLE caused by variation in C1QA. It covers the lupus manifestation of the C1QA subtype curated here, but C1Q deficiency 1 also includes patients with infections only or no symptoms, so neither class subsumes the other with certainty.
MONDO:1060228 systemic lupus erythematosus related to C1QB Not Yet Curated
skos:relatedMatch manual curation
As for the C1QA class: a gene-specific SLE class placed under systemic lupus erythematosus, overlapping the C1QB subtype curated here without being the same concept.
MONDO:1060227 systemic lupus erythematosus related to C1QC Not Yet Curated
skos:relatedMatch manual curation
As for the C1QA class: a gene-specific SLE class placed under systemic lupus erythematosus, overlapping the C1QC subtype curated here without being the same concept.
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Inheritance

1
Autosomal Recessive HP:0000007
Disease requires biallelic variants in one of the three C1q genes, usually homozygous and frequently in consanguineous families. Heterozygous parents and siblings are clinically unaffected.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:34993161 SUPPORT Human clinical
"It is a rare genetic condition inherited in an autosomal recessive manner, caused by mutations in C1q genes."
States the autosomal recessive inheritance.
PMID:20560256 SUPPORT Human clinical
"Molecular study disclosed a homozygous point mutation in the C1qA chain gene. Five members of the family, including the parents and three healthy siblings, were heterozygous for this mutation."
A homozygous proband with healthy heterozygous parents and siblings, consistent with recessive inheritance.
◆

Subtypes

3
C1Q deficiency 1 (C1QA) MONDO:0958182
C1QA hgnc:1241 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in C1QA (hgnc:1241). hgnc:1241 is a gene from the HUGO Gene Nomenclature Committee.
C1q deficiency caused by biallelic C1QA variants, including nonsense variants and a start-codon variant that prevents translation.
Show evidence (2 references)
PMID:22472776 SUPPORT Human clinical
"In an African-American patient with lupus and C1q deficiency, we identified and confirmed a novel homozygote start codon mutation in C1qA gene that changes amino acid methionine to arginine at position 1."
A homozygous C1QA variant in a patient with C1q deficiency and lupus.
PMID:29113537 SUPPORT Human clinical
"C1QA gene of two patients had homozygous nonsense mutation"
Homozygous C1QA nonsense variants in C1q-deficient patients with SLE.
C1Q deficiency 2 (C1QB) MONDO:0958187
C1QB hgnc:1242 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in C1QB (hgnc:1242). hgnc:1242 is a gene from the HUGO Gene Nomenclature Committee.
C1q deficiency caused by biallelic C1QB variants, including splice-site and missense variants. A homozygous missense variant in an Inuit family abolished detectable serum C1q antigen, and a non-coding splice variant abolished C1QB mRNA in a boy with infections and no lupus.
Show evidence (2 references)
PMID:24160257 SUPPORT Human clinical
"We identified a novel homozygous splicing mutation in the C1qB gene, c.187 + 1G > T, which is the first mutation to be confirmed in a Japanese individual."
A homozygous C1QB splice variant in a C1q-deficient child with SLE features.
PMID:17513176 SUPPORT Human clinical
"Sequencing of the C1q genes revealed a novel missense mutation (Gly-Arg) in codon 217 of the B chain. All sisters were homozygous for the mutation: both parents were heterozygous."
A homozygous C1QB missense variant segregating with C1q deficiency.
C1Q deficiency 3 (C1QC) MONDO:0958188
C1QC hgnc:1245 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in C1QC (hgnc:1245). hgnc:1245 is a gene from the HUGO Gene Nomenclature Committee.
C1q deficiency caused by biallelic C1QC variants, including nonsense variants and collagen-region missense variants that impair assembly and secretion of C1q.
Show evidence (2 references)
PMID:34993161 SUPPORT Human clinical
"The girl has pathogenic homozygous nonsense mutation in C1qC gene, Arg69Ter (c205>T)."
A homozygous C1QC nonsense variant in a child with early-onset SLE and C1q deficiency.
PMID:20635792 SUPPORT Human clinical
"revealed a novel homozygous missense mutation at codon 48 in the C1q C gene causing a glycine-to-arginine substitution affecting the collagen-like region of C1q"
A homozygous C1QC missense variant in a girl with recurrent meningitis and pneumonia.
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Pathophysiology

7
Absent or Dysfunctional C1q
Biallelic variants in C1QA, C1QB or C1QC either abolish C1q (nonsense, splice, start-codon and some missense variants that prevent assembly or secretion) or yield a low-molecular-weight C1q that circulates at low level but is not functional. Loss of a single chain is enough to prevent C1q production even when the other two chains are made.
C1QA hgnc:1241 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves C1QA (hgnc:1241). hgnc:1241 is a gene from the HUGO Gene Nomenclature Committee. C1QB hgnc:1242 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves C1QB (hgnc:1242). hgnc:1242 is a gene from the HUGO Gene Nomenclature Committee. C1QC hgnc:1245 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves C1QC (hgnc:1245). hgnc:1245 is a gene from the HUGO Gene Nomenclature Committee.
immunoglobulin binding by the C1q globular heads GO:0019865 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased immunoglobulin binding by the C1q globular heads, annotated with immunoglobulin binding (GO:0019865). GO:0019865 is a molecular function from the Gene Ontology.
Downstream
Classical Complement Pathway Initiation Failure Without functional C1q, the C1 complex cannot recognise immune complexes or other targets, so the classical pathway is not initiated.
Loss of C1q Restraint on Immune Complex-Induced Interferon-alpha Production C1q itself binds immune complexes and plasmacytoid dendritic cells and limits interferon-alpha induction; its absence removes this restraint.
Decreased Circulating C1q Absent or non-functional C1q is measured as undetectable or very low serum C1q antigen.
Show evidence (4 references)
PMID:29692784 SUPPORT REVIEW SYNTHESIS Other
"Complement component C1q plays an important recognition role in adaptive, and innate, immunity through its ability to interact, via its six globular head regions, with both immunoglobulin and non-immunoglobulin activators of the complement system"
States the normal molecular function of C1q that is lost in the deficiency: binding of immunoglobulin (and other activators) through its globular heads, which is the recognition step that starts the classical pathway.
PMID:28082982 SUPPORT REVIEW SYNTHESIS Human clinical
"A mutation in one of the C1q genes can either lead to complete deficiency or to low C1q levels with C1q polypeptide in the form of low-molecular weight (LMW) C1q."
Describes the two molecular outcomes of C1q gene variants.
PMID:20635792 SUPPORT Human clinical
"The mutation affected both the formation and the secretion of C1q variant molecules."
A collagen-region missense variant prevents assembly and secretion of C1q.
+ 1 more reference
Classical Complement Pathway Initiation Failure
C1q is the pattern-recognition subunit of C1, the first component of the classical pathway. Without it, classical-pathway haemolytic activity is absent while C3 and C4 levels and the lectin and alternative pathways are normal, which is the diagnostic pattern.
complement activation, classical pathway GO:0006958 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased complement activation, classical pathway (GO:0006958). GO:0006958 is a biological process from the Gene Ontology.
Downstream
Impaired Complement-Dependent Defence Against Encapsulated Bacteria Without classical pathway activation, antibody-bound encapsulated bacteria are poorly opsonised.
Defective Clearance of Apoptotic Cells C1q and the early classical pathway components tag apoptotic cells for phagocytic clearance; without them apoptotic cells persist.
Reduced CH50 Failure of classical pathway initiation is measured as absent classical-pathway haemolytic activity.
Show evidence (2 references)
PMID:17513176 SUPPORT Human clinical
"Initial examination for complement deficiency showed no function of the classical complement activation pathway in the patients; the lectin and alternative pathways were intact."
Absent classical pathway function with intact lectin and alternative pathways in homozygous patients.
PMID:34993161 SUPPORT Human clinical
"Total complement activity, classical pathway (hemolytic test) was deficient and C1q antigen was below the detection limit supporting the presence of C1q deficiency."
Absent classical pathway haemolytic activity in a genetically confirmed patient.
Impaired Complement-Dependent Defence Against Encapsulated Bacteria
Patients are susceptible to recurrent and severe infection with polysaccharide-encapsulated bacteria, including meningitis and pneumonia. The usual explanation is loss of classical-pathway C3b deposition on antibody-coated organisms, which phagocytes need for efficient uptake; no cited study measures opsonophagocytosis directly in C1q-deficient patients.
Downstream
Recurrent Bacterial Infections Impaired defence against encapsulated organisms manifests as recurrent or severe bacterial infection.
Recurrent Meningitis Bacterial meningitis is among the severe infections reported.
Show evidence (2 references)
PMID:20560256 SUPPORT BACKGROUND Human clinical
"Hereditary deficiency of complement component C1q is a rare genetic disorder with susceptibility to recurrent infections with polysaccharide-containing encapsulated microorganisms"
States the susceptibility to encapsulated organisms.
PMID:34993161 SUPPORT BACKGROUND Human clinical
"Hereditary C1q deficiency is associated with early-onset autoimmunity causing SLE or SLE-like disease as well as increased risk for infections with encapsulated bacteria."
States the encapsulated-bacteria infection risk alongside the autoimmunity.
Defective Clearance of Apoptotic Cells
C1q binds apoptotic cells and, with the early classical pathway components, promotes their removal by macrophages. In C1q-deficient mice apoptotic bodies accumulate in glomeruli and are cleared poorly from the peritoneum. This is the basis of the waste-disposal hypothesis, in which persisting apoptotic material supplies the nuclear autoantigens of SLE. The defect has been demonstrated in mice rather than measured directly in patients.
macrophage CL:0000235 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves macrophage (CL:0000235). CL:0000235 is a cell type from the Cell Ontology.
apoptotic cell clearance GO:0043277 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased apoptotic cell clearance (GO:0043277). GO:0043277 is a biological process from the Gene Ontology.
Animal models
C1qa knockout mouse Mouse recapitulates Apoptotic bodies accumulate in glomeruli of C1q-deficient mice.
Downstream
Loss of Tolerance to Nuclear Autoantigens Persisting apoptotic cells are a sustained source of nuclear autoantigen.
Show evidence (2 references)
PMID:9590289 SUPPORT Model organism
"Among mice without glomerulonephritis, there were significantly greater numbers of glomerular apoptotic bodies in C1q-deficient mice compared with controls."
Apoptotic bodies accumulate in C1q-deficient mouse glomeruli even without nephritis.
PMID:10934224 SUPPORT Model organism
"Here we demonstrate, using novel in vivo models of apoptotic cell clearance during sterile peritonitis, a similar hierarchical role for classical pathway complement proteins in vivo in the clearance of apoptotic cells by macrophages."
In vivo macrophage clearance of apoptotic cells depends on the classical pathway proteins, in the same hierarchy as human SLE risk, in which C1q deficiency carries the highest risk.
Loss of C1q Restraint on Immune Complex-Induced Interferon-alpha Production
Nucleic-acid-containing immune complexes induce interferon-alpha in plasmacytoid dendritic cells. Physiological concentrations of C1q inhibit this, in part by directing immune complexes to monocytes rather than plasmacytoid dendritic cells. Without C1q this brake is lost.
plasmacytoid dendritic cell CL:0000784 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves plasmacytoid dendritic cell (CL:0000784). CL:0000784 is a cell type from the Cell Ontology. monocyte CL:0000576 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves monocyte (CL:0000576). CL:0000576 is a cell type from the Cell Ontology.
negative regulation of type I interferon production GO:0032480 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased negative regulation of type I interferon production (GO:0032480). GO:0032480 is a biological process from the Gene Ontology.
Downstream
Type I Interferon Pathway Activation Unrestrained interferon-alpha production drives a systemic type I interferon signature.
Show evidence (2 references)
PMID:19790049 SUPPORT In vitro / ex vivo
"C1q significantly inhibited PBMC IFNalpha production induced by RNA-containing immune complexes (ICs), herpes simplex virus (HSV), and CpG DNA."
C1q inhibits immune complex-induced interferon-alpha in human blood cells, so its absence removes this inhibition.
PMID:20844193 SUPPORT In vitro / ex vivo
"Our experiments revealed that C1q preferentially promotes the binding of SLE ICs to monocytes rather than plasmacytoid dendritic cells"
Proposes the cellular route of the C1q effect.
Type I Interferon Pathway Activation
Patients have elevated interferon-stimulated gene expression in blood and raised interferon-alpha in serum and cerebrospinal fluid, which places C1q deficiency close to the monogenic type I interferonopathies. Chilblain-like acral lesions and basal ganglia calcification, seen in some patients, are features shared with those disorders.
type I interferon-mediated signaling pathway GO:0060337 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased type I interferon-mediated signaling pathway (GO:0060337). GO:0060337 is a biological process from the Gene Ontology.
Downstream
Systemic Lupus Erythematosus Type I interferon is a central driver of lupus autoimmunity.
Chilblains Chilblain-like acral lesions are an interferonopathy feature reported in C1q deficiency.
Basal Ganglia Calcification Basal ganglia calcification is reported alongside raised CSF interferon-alpha, as in the type I interferonopathies.
Increased CSF Interferon-alpha Intrathecal interferon-alpha is the measurable readout of the pathway in the central nervous system.
Cerebral Vasculitis Central nervous system inflammation, including vasculitis, is frequent in patients with an interferon signature; the causal route from interferon to vascular inflammation is not established.
Seizures Seizures are the commonest neuropsychiatric presentation of the central nervous system inflammation that accompanies the interferon signature; the causal route is not established.
Show evidence (2 references)
PMID:39196411 SUPPORT Human clinical
"Elevated ISG expression was observed in all patients tested (n = 10/10), and serum and CSF IFNα elevated in 2/2 patients."
An interferon signature in every genetically confirmed patient tested.
PMID:20844193 SUPPORT Human clinical
"In patients with C1q deficiency, serum and cerebrospinal fluid levels of IFN-α and IFN-γ-inducible protein-10 levels were elevated and strongly correlated with Ro autoantibodies"
Raised interferon-alpha in serum and cerebrospinal fluid of C1q-deficient patients.
Loss of Tolerance to Nuclear Autoantigens
Sustained exposure to nuclear autoantigens from uncleared apoptotic material leads to antinuclear autoantibody production and immune-complex disease. C1q-deficient mice develop autoantibodies and immune-complex glomerulonephritis, though expression depends strongly on genetic background. In patients antinuclear antibodies are usual but anti-dsDNA antibodies are less frequent than in sporadic SLE.
Animal models
C1qa knockout mouse Mouse partially recapitulates Autoantibodies and glomerulonephritis develop, but only on some genetic backgrounds.
Downstream
Systemic Lupus Erythematosus Loss of tolerance manifests as SLE or an SLE-like illness in most patients.
Antinuclear Antibody Positivity Antinuclear antibodies are the serological readout of lost tolerance.
Glomerulonephritis Immune complex deposition in the kidney causes glomerulonephritis.
Discoid Lupus Rash Cutaneous lupus lesions are the commonest manifestation of the autoimmune disease.
Oral Ulcers Mucosal ulceration is a lupus manifestation of the autoimmune disease.
Malar Rash Malar rash is a lupus manifestation of the autoimmune disease.
Cutaneous Photosensitivity Photosensitive rash is a lupus manifestation of the autoimmune disease.
Arthritis Inflammatory arthritis is a lupus manifestation, though less frequent than in sporadic SLE.
Show evidence (2 references)
PMID:9590289 SUPPORT Model organism
"C1qa-/- mice had increased mortality and higher titres of autoantibodies, compared with strain-matched controls. Of the C1qa-/- mice, 25% had glomerulonephritis with immune deposits and multiple apoptotic cell bodies."
C1q deficiency alone produces autoantibodies and immune-complex glomerulonephritis in mice.
PMID:11859149 SUPPORT Model organism
"These data demonstrate that the expression of autoimmunity in C1q-deficient mice is strongly influenced by other background genes."
The autoimmune outcome of C1q loss depends on genetic background in mice.
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Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for C1Q Deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

17
Cardiovascular 1
Cerebral Vasculitis HP:0005318 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebral vasculitis (HP:0005318). HP:0005318 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28082982 SUPPORT REVIEW SYNTHESIS Human clinical
"An important number of cases present with seizures and the most frequent findings in neuroimaging are changes in basal ganglia and cerebral vasculitis."
Cerebral vasculitis as a frequent neuroimaging finding.
Genitourinary 1
Glomerulonephritis HP:0000099 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Glomerulonephritis (HP:0000099). HP:0000099 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28082982 SUPPORT REVIEW SYNTHESIS Human clinical
"Patients with C1q deficiency mainly present with cutaneous and renal involvement."
Renal involvement is one of the two main presentations.
PMID:39470951 SUPPORT Human clinical
"Patients with a severe autoimmune phenotype, defined as neurological and/or renal involvement, had the worst OS (40% vs 84%; p = 0.034)."
Renal involvement defines a severe phenotype with worse survival after transplantation.
Head and Neck 1
Oral Ulcers FREQUENT HP:0000155 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Oral ulcer (HP:0000155). HP:0000155 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:25846716 SUPPORT REVIEW SYNTHESIS Human clinical
"Discoid rash (56% versus 10%, p<0.001) and oral ulcers (49% versus 24%, p<0.001) occurred significantly more frequent in C1q deficiency-associated SLE/SLE-like disease than in sporadic SLE"
Oral ulcer frequency in C1q deficiency-associated SLE.
Immune 9
Systemic Lupus Erythematosus FREQUENT HP:0002725 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Systemic lupus erythematosus (HP:0002725). HP:0002725 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25846716 SUPPORT REVIEW SYNTHESIS Human clinical
"According to the American College of Rheumatology (ACR) diagnostic criteria for SLE 39/71 (55%) subjects could be classified as having SLE. Another 16/71 (22.5%) presented a SLE-like syndrome (defined as 3 positive ACR criteria) whereas in 16/71 (22.5%) no SLE could be diagnosed at time of publication."
Frequency of SLE and SLE-like disease across published patients.
PMID:26119135 SUPPORT Human clinical
"Of these patients 36 (80%) suffer from SLE, of which 16 suffer from SLE and infections, 5 (11%) suffer from infections only and 4 (9%) have no symptoms."
80% of 45 followed patients had SLE.
Discoid Lupus Rash FREQUENT HP:0007417 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Discoid lupus rash (HP:0007417). HP:0007417 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25846716 SUPPORT REVIEW SYNTHESIS Human clinical
"Discoid rash (56% versus 10%, p<0.001) and oral ulcers (49% versus 24%, p<0.001) occurred significantly more frequent in C1q deficiency-associated SLE/SLE-like disease than in sporadic SLE"
Discoid rash frequency in C1q deficiency-associated SLE.
PMID:29113537 SUPPORT Human clinical
"Initial and dominant complaints of three cases from two different families were cutaneous manifestations."
Skin disease as the presenting and dominant feature.
Malar Rash HP:0025300 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Malar rash (HP:0025300). HP:0025300 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39196411 SUPPORT Human clinical
"Overall, individuals with C1QDef demonstrate many characteristics of recognized monogenic interferonopathies: particularly, cutaneous involvement (malar rash, acral vasculitic/papular rash, chilblains), SLE-like disease, basal ganglia calcification, increased expression of ISGs in peripheral..."
Lists malar rash among the cutaneous features.
Chilblains HP:0009710 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chilblains (HP:0009710). HP:0009710 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39196411 SUPPORT Human clinical
"Overall, individuals with C1QDef demonstrate many characteristics of recognized monogenic interferonopathies: particularly, cutaneous involvement (malar rash, acral vasculitic/papular rash, chilblains), SLE-like disease, basal ganglia calcification, increased expression of ISGs in peripheral..."
Places chilblains among the interferonopathy-like features.
PMID:40316395 SUPPORT Human clinical
"Both of our patients had NP involvement, and the brother had chilblain lesions."
Chilblain lesions in a C1QA-homozygous patient.
Recurrent Bacterial Infections FREQUENT HP:0002718 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent bacterial infections (HP:0002718). HP:0002718 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26119135 SUPPORT Human clinical
"Of these patients 36 (80%) suffer from SLE, of which 16 suffer from SLE and infections, 5 (11%) suffer from infections only and 4 (9%) have no symptoms."
21 of 45 patients (16 with SLE and 5 without) had infections.
PMID:25846716 SUPPORT REVIEW SYNTHESIS Human clinical
"The severe course of disease in some patients seemed to be mostly due to severe infections at early ages and not in particular due to more aggressive SLE manifestations."
Early severe infection drives the severe course.
Recurrent Meningitis HP:0006946 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent meningitis (HP:0006946). HP:0006946 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20635792 SUPPORT Human clinical
"An 11-year-old girl was screened for immunodeficiency due to a history of recurrent meningitis and pneumonia."
Recurrent meningitis in a genetically confirmed C1QC-deficient patient.
Antinuclear Antibody Positivity HP:0003493 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Antinuclear antibody positivity (HP:0003493). HP:0003493 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:29113537 SUPPORT Human clinical
"Antinuclear antibody was positive in all cases, whereas anti-dsDNA was negative with normal levels of complement C3, C4 and decreased CH50 activity."
Positive ANA with negative anti-dsDNA in three patients.
PMID:25846716 SUPPORT REVIEW SYNTHESIS Human clinical
"whereas arthritis (38% versus 84%, p<001) and anti-ds-DNA (18% versus 78%, p<0.001) occurred less frequently"
Anti-dsDNA antibodies are much less frequent than in sporadic SLE.
Decreased Circulating C1q OBLIGATE Decreased circulating C1q concentration HP:0034601 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased circulating C1q concentration (HP:0034601). HP:0034601 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34993161 SUPPORT Human clinical
"Total complement activity, classical pathway (hemolytic test) was deficient and C1q antigen was below the detection limit supporting the presence of C1q deficiency."
Undetectable C1q antigen.
Reduced CH50 OBLIGATE Reduced circulating CH50 activity HP:0025434 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced circulating CH50 activity (HP:0025434). HP:0025434 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29113537 SUPPORT Human clinical
"Antinuclear antibody was positive in all cases, whereas anti-dsDNA was negative with normal levels of complement C3, C4 and decreased CH50 activity."
Decreased CH50 with normal C3 and C4.
Integument 1
Cutaneous Photosensitivity HP:0000992 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cutaneous photosensitivity (HP:0000992). HP:0000992 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42147803 SUPPORT Human clinical
"A 3-year-old girl presented with recurrent infections, a photosensitive rash, and persistent leukopenia"
Photosensitive rash at presentation in a C1QA-homozygous child.
Metabolism 1
Increased CSF Interferon-alpha HP:0009709 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased CSF interferon alpha (HP:0009709). HP:0009709 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39196411 SUPPORT Human clinical
"Elevated ISG expression was observed in all patients tested (n = 10/10), and serum and CSF IFNα elevated in 2/2 patients."
Raised CSF interferon-alpha in the patients measured.
Musculoskeletal 2
Arthritis FREQUENT HP:0001369 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Arthritis (HP:0001369). HP:0001369 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:25846716 SUPPORT REVIEW SYNTHESIS Human clinical
"whereas arthritis (38% versus 84%, p<001) and anti-ds-DNA (18% versus 78%, p<0.001) occurred less frequently"
Arthritis frequency in C1q deficiency-associated SLE against sporadic SLE.
PMID:40556690 SUPPORT Human clinical
"All patients exhibited mucocutaneous involvement, discoid lupus erythematosus, inflammatory polyarthritis, normal serum complements C3 and C4, coarse-speckled Antinuclear antibody positivity and antibodies to ribonucleoprotein."
Inflammatory polyarthritis in all four patients of a case series.
Basal Ganglia Calcification HP:0002135 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Basal ganglia calcification (HP:0002135). HP:0002135 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39196411 SUPPORT Human clinical
"Central nervous system (encompassing basal ganglia calcification, encephalitis, vasculitis, chronic pachymeningitis), mucocutaneous and renal involvement were present, respectively, in 10, 11 and 2 of 12 patients"
Central nervous system involvement including basal ganglia calcification in most of a 12-patient series.
PMID:23651859 SUPPORT Human clinical
"Cerebral imaging demonstrated acquired intracranial calcification and a cerebral vasculopathy reminiscent of moyamoya."
Acquired intracranial calcification in a C1QB-deficient patient.
Nervous System 1
Seizures HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28082982 SUPPORT REVIEW SYNTHESIS Human clinical
"An important number of cases present with seizures and the most frequent findings in neuroimaging are changes in basal ganglia and cerebral vasculitis."
Seizures as a common neuropsychiatric presentation.
PMID:28082982 SUPPORT REVIEW SYNTHESIS Human clinical
"Although less frequent, neuropsychiatric (NP) involvement has also been reported in 20% of the C1q-deficient patients."
Frequency of neuropsychiatric involvement overall.
🧬

Genetic Associations

3
C1QA
Gene: C1QA hgnc:1241 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is C1QA (hgnc:1241). hgnc:1241 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:22472776 SUPPORT Human clinical
"In an African-American patient with lupus and C1q deficiency, we identified and confirmed a novel homozygote start codon mutation in C1qA gene that changes amino acid methionine to arginine at position 1."
Homozygous C1QA variant causing C1q deficiency.
C1QB
Gene: C1QB hgnc:1242 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is C1QB (hgnc:1242). hgnc:1242 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:25454803 SUPPORT Human clinical
"Deep-sequencing revealed a homozygous mutation in the non-coding region of C1qB in the patient, whereas both parents were heterozygous."
Homozygous C1QB variant causing complete C1q deficiency.
C1QC
Gene: C1QC hgnc:1245 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is C1QC (hgnc:1245). hgnc:1245 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:34993161 SUPPORT Human clinical
"The girl has pathogenic homozygous nonsense mutation in C1qC gene, Arg69Ter (c205>T)."
Homozygous C1QC nonsense variant causing C1q deficiency.
💊

Medical Actions

6
Allogeneic Hematopoietic Stem Cell Transplantation
Action: allogeneic hematopoietic stem cell transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is allogeneic hematopoietic stem cell transplantation (NCIT:C46089). NCIT:C46089 is a clinical intervention from the NCI Thesaurus. Ontology label: Allogeneic Hematopoietic Stem Cell Transplantation NCIT:C46089
Platform: Cell therapy
Because C1q is made by monocyte-derived cells, allogeneic HSCT restores C1q production and classical pathway function and can cure the disease. In a multicentre series of 18 patients transplanted mainly for refractory autoimmunity, autoimmune features resolved in 11, but five died of transplant-related complications and survival was worst in patients with renal or neurological involvement, so patient selection is critical.
Mechanism Target:
RESTORES Absent or Dysfunctional C1q — Donor-derived monocytes and macrophages produce normal C1q.
Show evidence (4 references)
PMID:39470951 SUPPORT Human clinical
"In eleven patients HSCT led to resolution of autoimmune features and discontinuation of immunosuppressive treatments (follow-up time range 3-84 months). Five patients died due to transplant-related complications."
Outcome of HSCT in the largest series, including its mortality.
PMID:26516671 SUPPORT Human clinical
"A 9-year-old boy and a 12-year-old girl with refractory SLE restored C1q production after allo-HSCT. This resulted in normal functional properties of the classical complement pathway followed by reduced severity of SLE symptoms."
HSCT restored C1q production and classical pathway function.
PMID:33000368 SUPPORT Human clinical
"Complete donor chimerism has been maintained for 2 years after transplantation, leading to the restoration of C1q levels and the resolution of SLE symptoms. Normal C1q mRNA expression was observed in CD14 + cells."
C1q restored from donor CD14-positive monocytes after transplantation.
+ 1 more reference
Fresh Frozen Plasma
Action: fresh frozen plasma transfusionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is fresh frozen plasma transfusion (NCIT:C116475). NCIT:C116475 is a clinical intervention from the NCI Thesaurus. Ontology label: Fresh Frozen Plasma Transfusion NCIT:C116475
Platform: Protein replacement
Regular fresh frozen plasma infusion supplies C1q and has controlled refractory cutaneous and systemic disease in several reported patients, allowing corticosteroid reduction. The effect is temporary, so infusions must be repeated.
Mechanism Target:
RESTORES Absent or Dysfunctional C1q — Transiently supplies circulating C1q.
Show evidence (3 references)
PMID:29113537 SUPPORT Human clinical
"All symptoms of all three cases improved by daily fresh frozen plasma (FFP) infusions, and once cutaneous lesions subsided, the infusions were reduced to a frequency that would prevent the flare up of the symptoms."
Plasma infusion controlled disease in three patients.
PMID:34993161 SUPPORT Human clinical
"Regular fresh frozen plasma infusions keep her disease under control, and we were able to reduce the dose of corticosteroids."
Plasma infusion allowed steroid reduction.
PMID:24160257 SUPPORT Human clinical
"Because treatment with steroids and immunosuppressive drugs was not effective, we commenced use of fresh frozen plasma to provide C1q supplements."
Plasma used as C1q replacement after failure of immunosuppression.
Type I Interferon Receptor Blockade
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: anifrolumab NCIT:C166658 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses anifrolumab (NCIT:C166658). NCIT:C166658 is a therapeutic agent from the NCI Thesaurus.
Platform: Monoclonal antibody
Anifrolumab, a monoclonal antibody against the type I interferon receptor, resolved refractory mucocutaneous disease and allowed corticosteroid withdrawal in a single reported child.
Mechanism Target:
INHIBITS Type I Interferon Pathway Activation — Blocks signalling through the type I interferon receptor.
Show evidence (1 reference)
PMID:42597478 SUPPORT Human clinical
"She showed significant clinical improvement and full recovery of mucocutaneous lesions, restoration of laboratory parameters and successful discontinuation of corticosteroids after the seventh monthly infusion."
Response to anifrolumab in one C1QA-deficient child.
JAK Inhibitors
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: JAK inhibitor NCIT:C172200 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses JAK inhibitor (NCIT:C172200). NCIT:C172200 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
JAK inhibitors have been tried to block interferon signalling, with variable results: one of three reported patients responded.
Mechanism Target:
INHIBITS Type I Interferon Pathway Activation — Blocks JAK-dependent interferon receptor signalling.
Show evidence (1 reference)
PMID:39196411 SUPPORT Human clinical
"Three patients were treated with Janus-kinase inhibitors (JAKi), with variable outcome; one displaying an apparently favourable response in respect of cutaneous and neurological features, and two others experiencing persistent disease despite JAKi therapy."
Mixed outcome of JAK inhibition in three patients; supports its use as a treatment tried in this disease, not established efficacy.
Corticosteroids and Conventional Immunosuppression
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: corticosteroid CHEBI:50858 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses corticosteroid (CHEBI:50858). CHEBI:50858 is a therapeutic agent from Chemical Entities of Biological Interest. hydroxychloroquine CHEBI:5801 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses hydroxychloroquine (CHEBI:5801). CHEBI:5801 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Corticosteroids, hydroxychloroquine and steroid-sparing agents are used as in sporadic SLE, but cutaneous disease in particular often responds only to high-dose steroids and flares on tapering.
Show evidence (3 references)
PMID:29113537 SUPPORT Human clinical
"Previously, all of them had been treated with steroids, hydroxychloroquine and methotrexate or azathioprine."
The conventional regimen used.
PMID:29113537 REFUTE Human clinical
"It was learned that they had responded only to high dosage prednisolone and their symptoms flared up during dosage reduction even under methotrexate or azathioprine."
Disease was not controlled once conventional therapy was tapered.
PMID:42147803 REFUTE Human clinical
"Despite treatment with corticosteroids and hydroxychloroquine, the patient's disease activity remained suboptimal, leading to consideration of hematopoietic stem cell transplantation as a definitive therapeutic option."
Inadequate control on corticosteroids and hydroxychloroquine in a C1QA-deficient child.
Vaccination and Antibiotic Prophylaxis
Action: vaccinationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is vaccination (NCIT:C15346). NCIT:C15346 is a clinical intervention from the NCI Thesaurus. Ontology label: Vaccination NCIT:C15346
Platform: Vaccine
Vaccination against encapsulated bacteria and antibiotic prophylaxis are part of standard management to reduce the infection risk.
Mechanism Target:
BYPASSES Impaired Complement-Dependent Defence Against Encapsulated Bacteria — Reduces infection by encapsulated organisms despite the complement defect.
Show evidence (1 reference)
PMID:34993161 SUPPORT BACKGROUND Human clinical
"Treatment and management of this rare disease are very complex and include prophylactic vaccination, antibiotics, and immunosuppressive drugs."
Lists vaccination and antibiotics in management.
🔬

Biochemical Markers

2
Serum C1q (DECREASED)
Show evidence (2 references)
PMID:34993161 SUPPORT Human clinical
"Total complement activity, classical pathway (hemolytic test) was deficient and C1q antigen was below the detection limit supporting the presence of C1q deficiency."
Undetectable C1q in a genetically confirmed patient.
PMID:28082982 SUPPORT REVIEW SYNTHESIS Human clinical
"A mutation in one of the C1q genes can either lead to complete deficiency or to low C1q levels with C1q polypeptide in the form of low-molecular weight (LMW) C1q."
The low-molecular-weight form is the exception to absent antigen.
Serum CH50 (classical pathway haemolytic activity) (DECREASED)
Show evidence (1 reference)
PMID:29113537 SUPPORT Human clinical
"Antinuclear antibody was positive in all cases, whereas anti-dsDNA was negative with normal levels of complement C3, C4 and decreased CH50 activity."
Decreased CH50 with normal C3 and C4.
🔬

Diagnosis

2
Complement screening (CH50, C3, C4, C1q antigen)
Classical pathway haemolytic activity (CH50) is absent while C3 and C4 are normal, which points to an early classical pathway component deficiency rather than the complement consumption of sporadic SLE. Undetectable C1q antigen then localises the defect. Secondary C1q deficiency (consumption, anti-C1q autoantibodies) must be excluded, and a missense variant producing low-molecular-weight C1q can leave antigen detectable despite absent function. The pattern should prompt testing in a young child with SLE-like skin disease, normal C3 and C4 and negative anti-dsDNA.
complement screening assay NCIT:C25294 NCI Thesaurus (NCIT)
Markers: CH50, serum C3, serum C4, serum C1q antigen
Show evidence (3 references)
PMID:29113537 SUPPORT Human clinical
"Antinuclear antibody was positive in all cases, whereas anti-dsDNA was negative with normal levels of complement C3, C4 and decreased CH50 activity."
The diagnostic complement pattern in three patients.
PMID:34993161 SUPPORT Human clinical
"Young patients with cutaneous lesions resembling SLE, early onset of autoimmunity, with normal C3, C4, elevated ANAs, and negative anti-dsDNA, C1q deficiency should be suspected and complement screening tests should be done."
States when to suspect the disease and screen complement.
PMID:34993161 SUPPORT Human clinical
"It is important to exclude secondary C1q deficiency."
Secondary C1q deficiency is the main differential of a low C1q.
C1QA, C1QB and C1QC sequencing
Sequencing of the three C1q genes confirms the diagnosis and identifies the biallelic variants, which allows carrier testing in the family. Whole-exome sequencing has been diagnostic in several reported patients; deep sequencing of non-coding regions was needed to find a splice-region C1QB variant.
C1q gene sequencing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (3 references)
PMID:42147803 SUPPORT Human clinical
"Western blot analysis and whole-exome sequencing identified a homozygous nonsense variant in C1qA"
Exome sequencing with western blot confirmed the diagnosis.
PMID:40556690 SUPPORT Human clinical
"We describe four cases of C1Q monogenic lupus identified by whole exome sequencing."
Exome sequencing identified all four patients in a case series.
PMID:25454803 SUPPORT Human clinical
"Deep-sequencing revealed a homozygous mutation in the non-coding region of C1qB in the patient, whereas both parents were heterozygous."
A non-coding variant found by deep sequencing, with parental segregation.
📊

Prevalence

1
Worldwide published cases
Cases/families reported in the literature Ultra-rare
A 2015 literature review counted 71 published patients from 45 families, and a 2024 transplantation study reviewed 69 genetically confirmed patients. These are literature counts, not population prevalence estimates.
Show evidence (2 references)
PMID:25846716 SUPPORT REVIEW SYNTHESIS Human clinical
"We identified 71 C1q-deficient patients descending from 45 families that had been published."
Count of published patients.
PMID:39470951 SUPPORT Human clinical
"Reviewing data of 69 genetically confirmed C1q deficient patients"
Count of genetically confirmed patients.
⚖️

Clinical Burden

Variable
Outcome ranges widely. About a fifth of reported patients have died, nearly all before the age of 20, mostly from severe infection in early childhood or from renal and central nervous system lupus, and most survivors need long-term immunosuppression or transplantation. A subset, including some patients with infections only or no symptoms, has an excellent prognosis, and at least half are expected to reach middle age.
Show evidence (2 references)
PMID:26119135 SUPPORT Human clinical
"In total 9 (20%) of the C1q deficient individuals had died. All except for one died before the age of 20 years."
Mortality in an international follow-up survey of 45 patients.
PMID:26119135 SUPPORT Human clinical
"Here we report the largest phenotypic data set on C1q deficiency to date, revealing high variance; with high mortality but also a subset of patients with an excellent prognosis."
The same survey characterises the outcome as highly variable, which is why the burden is recorded as variable rather than uniformly high.
🐁

Animal Models

1
C1qa knockout mouse
Gene-targeted C1qa-deficient mice develop autoantibodies and immune-complex glomerulonephritis with accumulation of apoptotic bodies, with penetrance strongly dependent on genetic background.
Species
Mouse
Genotype
C1qa(-/-)
Publication
PMID:9590289
Pathograph links
Defective Clearance of Apoptotic Cells recapitulates fidelity: moderate observes: tissue Apoptotic bodies accumulate in glomeruli of C1q-deficient mice.
Limitations: Apoptotic cell clearance is measured in mouse glomeruli and peritoneum; an equivalent defect has not been measured directly in patients.
Show evidence (1 reference)
PMID:9590289 SUPPORT Model organism
"Among mice without glomerulonephritis, there were significantly greater numbers of glomerular apoptotic bodies in C1q-deficient mice compared with controls."
Supports the model as informative for apoptotic cell clearance.
Loss of Tolerance to Nuclear Autoantigens partially recapitulates fidelity: low observes: organism Autoantibodies and glomerulonephritis develop, but only on some genetic backgrounds.
Limitations: On the C57BL/6 background C1q deficiency produces no autoimmune phenotype, whereas most human patients develop autoimmunity. The cited studies do not report the skin and central nervous system disease or the interferon signature that dominate the human phenotype.
Show evidence (1 reference)
PMID:11859149 SUPPORT Model organism
"In C1q-deficient C57BL/6 mice, no evidence of an autoimmune phenotype was found"
Shows the background dependence that limits fidelity.
{ }

Source YAML

click to show 
name: C1Q Deficiency
creation_date: "2026-10-16T00:00:00Z"
category: Mendelian
description: >-
  Hereditary C1q deficiency is a rare autosomal recessive inborn error of
  immunity caused by biallelic variants in any one of the three genes encoding
  the chains of C1q (C1QA, C1QB, C1QC). C1q is the recognition subunit of the
  first component of the classical complement pathway. Most variants abolish
  circulating C1q; some missense variants instead yield a non-functional
  low-molecular-weight C1q, and in both cases classical-pathway haemolytic
  activity (CH50) is absent while C3 and C4 are normal and the lectin and
  alternative pathways remain intact. Loss of C1q has three consequences that
  together account for the phenotype: the classical pathway cannot be
  initiated, so defence against encapsulated bacteria is impaired; apoptotic
  cells are cleared poorly and become a source of nuclear autoantigen; and
  C1q no longer restrains interferon-alpha production induced by immune
  complexes, so patients show a sustained type I interferon signature. C1q
  deficiency is the strongest single genetic risk factor for systemic lupus
  erythematosus: most patients develop SLE or an SLE-like illness in early
  childhood, dominated by discoid and other mucocutaneous lesions, with
  glomerulonephritis and central nervous system involvement (seizures,
  cerebral vasculitis, basal ganglia calcification) and comparatively few
  anti-dsDNA antibodies. About half also have severe or recurrent bacterial
  infections, including meningitis, and about a fifth of reported patients
  die, nearly all before the age of 20. Because C1q is made by
  monocyte-derived cells rather than the liver, allogeneic haematopoietic stem
  cell transplantation restores C1q production and can cure the disease;
  regular fresh frozen plasma infusion supplies C1q temporarily, and type I
  interferon blockade is an emerging option.
disease_term:
  preferred_term: C1Q deficiency
  term:
    id: MONDO:0013343
    label: C1Q deficiency
synonyms:
- C1q deficiency
- C1QD
- hereditary C1q deficiency
- complement component C1q deficiency
parents:
- Complement Disorder
mappings:
  mondo_mappings:
  - term:
      id: MONDO:1060174
      label: systemic lupus erythematosus related to C1QA
    mapping_predicate: skos:relatedMatch
    mapping_source: manual curation
    mapping_justification: >-
      MONDO places this class under systemic lupus erythematosus, not under C1Q
      deficiency, and defines it as SLE caused by variation in C1QA. It covers
      the lupus manifestation of the C1QA subtype curated here, but C1Q
      deficiency 1 also includes patients with infections only or no symptoms,
      so neither class subsumes the other with certainty.
  - term:
      id: MONDO:1060228
      label: systemic lupus erythematosus related to C1QB
    mapping_predicate: skos:relatedMatch
    mapping_source: manual curation
    mapping_justification: >-
      As for the C1QA class: a gene-specific SLE class placed under systemic
      lupus erythematosus, overlapping the C1QB subtype curated here without
      being the same concept.
  - term:
      id: MONDO:1060227
      label: systemic lupus erythematosus related to C1QC
    mapping_predicate: skos:relatedMatch
    mapping_source: manual curation
    mapping_justification: >-
      As for the C1QA class: a gene-specific SLE class placed under systemic
      lupus erythematosus, overlapping the C1QC subtype curated here without
      being the same concept.
classifications:
  harrisons_chapter:
  - classification_value: IMMUNE_RHEUMATOLOGIC
    notes: >-
      A primary immunodeficiency presenting with lupus-like autoimmunity and
      bacterial infection, placing it in Harrison's immune/rheumatologic Part.
      Assigned to match the sibling Complement_Component_2_Deficiency and
      Complement_Component_3_Deficiency entries.
  iuis_category:
    classification_value: complement deficiency
    notes: >-
      A defect of C1q, the recognition subunit of the classical pathway C1
      complex, which is a row of the IUIS complement deficiencies table.
has_subtypes:
- name: C1QD1
  display_name: C1Q deficiency 1 (C1QA)
  description: >-
    C1q deficiency caused by biallelic C1QA variants, including nonsense
    variants and a start-codon variant that prevents translation.
  subtype_term:
    preferred_term: C1Q deficiency 1
    term:
      id: MONDO:0958182
      label: C1Q deficiency 1
  genes:
  - preferred_term: C1QA
    term:
      id: hgnc:1241
      label: C1QA
  evidence:
  - reference: PMID:22472776
    reference_title: "Identification of novel coding mutation in C1qA gene in an African-American pedigree with lupus and C1q deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In an African-American patient with lupus and C1q deficiency, we identified and confirmed a novel homozygote start codon mutation in C1qA gene that changes amino acid methionine to arginine at position 1."
    explanation: >-
      A homozygous C1QA variant in a patient with C1q deficiency and lupus.
  - reference: PMID:29113537
    reference_title: "Systemic lupus erythematosus with C1q deficiency: treatment with fresh frozen plasma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "C1QA gene of two patients had homozygous nonsense mutation"
    explanation: >-
      Homozygous C1QA nonsense variants in C1q-deficient patients with SLE.
- name: C1QD2
  display_name: C1Q deficiency 2 (C1QB)
  description: >-
    C1q deficiency caused by biallelic C1QB variants, including splice-site
    and missense variants. A homozygous missense variant in an Inuit family
    abolished detectable serum C1q antigen, and a non-coding splice variant
    abolished C1QB mRNA in a boy with infections and no lupus.
  subtype_term:
    preferred_term: C1Q deficiency 2
    term:
      id: MONDO:0958187
      label: C1Q deficiency 2
  genes:
  - preferred_term: C1QB
    term:
      id: hgnc:1242
      label: C1QB
  evidence:
  - reference: PMID:24160257
    reference_title: "The identification of a novel splicing mutation in C1qB in a Japanese family with C1q deficiency: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a novel homozygous splicing mutation in the C1qB gene, c.187 + 1G > T, which is the first mutation to be confirmed in a Japanese individual."
    explanation: >-
      A homozygous C1QB splice variant in a C1q-deficient child with SLE
      features.
  - reference: PMID:17513176
    reference_title: "C1q deficiency in an Inuit family: identification of a new class of C1q disease-causing mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sequencing of the C1q genes revealed a novel missense mutation (Gly-Arg) in codon 217 of the B chain. All sisters were homozygous for the mutation: both parents were heterozygous."
    explanation: >-
      A homozygous C1QB missense variant segregating with C1q deficiency.
- name: C1QD3
  display_name: C1Q deficiency 3 (C1QC)
  description: >-
    C1q deficiency caused by biallelic C1QC variants, including nonsense
    variants and collagen-region missense variants that impair assembly and
    secretion of C1q.
  subtype_term:
    preferred_term: C1Q deficiency 3
    term:
      id: MONDO:0958188
      label: C1Q deficiency 3
  genes:
  - preferred_term: C1QC
    term:
      id: hgnc:1245
      label: C1QC
  evidence:
  - reference: PMID:34993161
    reference_title: "Case Report: Early Onset Systemic Lupus Erythematosus Due to Hereditary C1q Deficiency Treated With Fresh Frozen Plasma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The girl has pathogenic homozygous nonsense mutation in C1qC gene, Arg69Ter (c205>T)."
    explanation: >-
      A homozygous C1QC nonsense variant in a child with early-onset SLE and
      C1q deficiency.
  - reference: PMID:20635792
    reference_title: "Homozygosity for a novel mutation in the C1q C chain gene in a Turkish family with hereditary C1q deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "revealed a novel homozygous missense mutation at codon 48 in the C1q C gene causing a glycine-to-arginine substitution affecting the collagen-like region of C1q"
    explanation: >-
      A homozygous C1QC missense variant in a girl with recurrent meningitis
      and pneumonia.
inheritance:
- name: Autosomal Recessive
  description: >-
    Disease requires biallelic variants in one of the three C1q genes, usually
    homozygous and frequently in consanguineous families. Heterozygous parents
    and siblings are clinically unaffected.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:34993161
    reference_title: "Case Report: Early Onset Systemic Lupus Erythematosus Due to Hereditary C1q Deficiency Treated With Fresh Frozen Plasma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is a rare genetic condition inherited in an autosomal recessive manner, caused by mutations in C1q genes."
    explanation: >-
      States the autosomal recessive inheritance.
  - reference: PMID:20560256
    reference_title: "Hereditary C1q deficiency: a new family with C1qA deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Molecular study disclosed a homozygous point mutation in the C1qA chain gene. Five members of the family, including the parents and three healthy siblings, were heterozygous for this mutation."
    explanation: >-
      A homozygous proband with healthy heterozygous parents and siblings,
      consistent with recessive inheritance.
pathophysiology:
- name: Absent or Dysfunctional C1q
  biological_scale: MOLECULAR
  description: >-
    Biallelic variants in C1QA, C1QB or C1QC either abolish C1q (nonsense,
    splice, start-codon and some missense variants that prevent assembly or
    secretion) or yield a low-molecular-weight C1q that circulates at low
    level but is not functional. Loss of a single chain is enough to prevent
    C1q production even when the other two chains are made.
  genes:
  - preferred_term: C1QA
    term:
      id: hgnc:1241
      label: C1QA
  - preferred_term: C1QB
    term:
      id: hgnc:1242
      label: C1QB
  - preferred_term: C1QC
    term:
      id: hgnc:1245
      label: C1QC
  molecular_functions:
  - preferred_term: immunoglobulin binding by the C1q globular heads
    term:
      id: GO:0019865
      label: immunoglobulin binding
    modifier: DECREASED
  evidence:
  - reference: PMID:29692784
    reference_title: "Complement Component C1q: Historical Perspective of a Functionally Versatile, and Structurally Unusual, Serum Protein."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Complement component C1q plays an important recognition role in adaptive, and innate, immunity through its ability to interact, via its six globular head regions, with both immunoglobulin and non-immunoglobulin activators of the complement system"
    explanation: >-
      States the normal molecular function of C1q that is lost in the
      deficiency: binding of immunoglobulin (and other activators) through its
      globular heads, which is the recognition step that starts the classical
      pathway.
  - reference: PMID:28082982
    reference_title: "C1q Deficiency and Neuropsychiatric Systemic Lupus Erythematosus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "A mutation in one of the C1q genes can either lead to complete deficiency or to low C1q levels with C1q polypeptide in the form of low-molecular weight (LMW) C1q."
    explanation: >-
      Describes the two molecular outcomes of C1q gene variants.
  - reference: PMID:20635792
    reference_title: "Homozygosity for a novel mutation in the C1q C chain gene in a Turkish family with hereditary C1q deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mutation affected both the formation and the secretion of C1q variant molecules."
    explanation: >-
      A collagen-region missense variant prevents assembly and secretion of
      C1q.
  - reference: PMID:25454803
    reference_title: "Identification of a novel non-coding mutation in C1qB in a Dutch child with C1q deficiency associated with recurrent infections."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Analyses of in vitro cultured cells from the patient revealed a lack of production of C1q and intracellular absence of C1qB in the presence of C1qA and C1qC peptides."
    explanation: >-
      Loss of a single chain (C1qB) abolishes C1q production even though the
      other two chains are made.
  downstream:
  - target: Classical Complement Pathway Initiation Failure
    description: >-
      Without functional C1q, the C1 complex cannot recognise immune complexes
      or other targets, so the classical pathway is not initiated.
  - target: Loss of C1q Restraint on Immune Complex-Induced Interferon-alpha Production
    description: >-
      C1q itself binds immune complexes and plasmacytoid dendritic cells and
      limits interferon-alpha induction; its absence removes this restraint.
  - target: Decreased Circulating C1q
    description: >-
      Absent or non-functional C1q is measured as undetectable or very low
      serum C1q antigen.
- name: Classical Complement Pathway Initiation Failure
  biological_scale: MOLECULAR
  description: >-
    C1q is the pattern-recognition subunit of C1, the first component of the
    classical pathway. Without it, classical-pathway haemolytic activity is
    absent while C3 and C4 levels and the lectin and alternative pathways are
    normal, which is the diagnostic pattern.
  biological_processes:
  - preferred_term: complement activation, classical pathway
    term:
      id: GO:0006958
      label: complement activation, classical pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:17513176
    reference_title: "C1q deficiency in an Inuit family: identification of a new class of C1q disease-causing mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Initial examination for complement deficiency showed no function of the classical complement activation pathway in the patients; the lectin and alternative pathways were intact."
    explanation: >-
      Absent classical pathway function with intact lectin and alternative
      pathways in homozygous patients.
  - reference: PMID:34993161
    reference_title: "Case Report: Early Onset Systemic Lupus Erythematosus Due to Hereditary C1q Deficiency Treated With Fresh Frozen Plasma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Total complement activity, classical pathway (hemolytic test) was deficient and C1q antigen was below the detection limit supporting the presence of C1q deficiency."
    explanation: >-
      Absent classical pathway haemolytic activity in a genetically confirmed
      patient.
  downstream:
  - target: Impaired Complement-Dependent Defence Against Encapsulated Bacteria
    description: >-
      Without classical pathway activation, antibody-bound encapsulated
      bacteria are poorly opsonised.
  - target: Defective Clearance of Apoptotic Cells
    description: >-
      C1q and the early classical pathway components tag apoptotic cells for
      phagocytic clearance; without them apoptotic cells persist.
  - target: Reduced CH50
    description: >-
      Failure of classical pathway initiation is measured as absent
      classical-pathway haemolytic activity.
- name: Impaired Complement-Dependent Defence Against Encapsulated Bacteria
  biological_scale: CELLULAR
  description: >-
    Patients are susceptible to recurrent and severe infection with
    polysaccharide-encapsulated bacteria, including meningitis and pneumonia.
    The usual explanation is loss of classical-pathway C3b deposition on
    antibody-coated organisms, which phagocytes need for efficient uptake; no
    cited study measures opsonophagocytosis directly in C1q-deficient
    patients.
  evidence:
  - reference: PMID:20560256
    reference_title: "Hereditary C1q deficiency: a new family with C1qA deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Hereditary deficiency of complement component C1q is a rare genetic disorder with susceptibility to recurrent infections with polysaccharide-containing encapsulated microorganisms"
    explanation: >-
      States the susceptibility to encapsulated organisms.
  - reference: PMID:34993161
    reference_title: "Case Report: Early Onset Systemic Lupus Erythematosus Due to Hereditary C1q Deficiency Treated With Fresh Frozen Plasma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Hereditary C1q deficiency is associated with early-onset autoimmunity causing SLE or SLE-like disease as well as increased risk for infections with encapsulated bacteria."
    explanation: >-
      States the encapsulated-bacteria infection risk alongside the
      autoimmunity.
  downstream:
  - target: Recurrent Bacterial Infections
    description: >-
      Impaired defence against encapsulated organisms manifests as recurrent
      or severe bacterial infection.
  - target: Recurrent Meningitis
    description: >-
      Bacterial meningitis is among the severe infections reported.
- name: Defective Clearance of Apoptotic Cells
  biological_scale: CELLULAR
  description: >-
    C1q binds apoptotic cells and, with the early classical pathway
    components, promotes their removal by macrophages. In C1q-deficient mice
    apoptotic bodies accumulate in glomeruli and are cleared poorly from the
    peritoneum. This is the basis of the waste-disposal hypothesis, in which
    persisting apoptotic material supplies the nuclear autoantigens of SLE.
    The defect has been demonstrated in mice rather than measured directly in
    patients.
  cell_types:
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: apoptotic cell clearance
    term:
      id: GO:0043277
      label: apoptotic cell clearance
    modifier: DECREASED
  evidence:
  - reference: PMID:9590289
    reference_title: "Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Among mice without glomerulonephritis, there were significantly greater numbers of glomerular apoptotic bodies in C1q-deficient mice compared with controls."
    explanation: >-
      Apoptotic bodies accumulate in C1q-deficient mouse glomeruli even
      without nephritis.
  - reference: PMID:10934224
    reference_title: "A hierarchical role for classical pathway complement proteins in the clearance of apoptotic cells in vivo."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here we demonstrate, using novel in vivo models of apoptotic cell clearance during sterile peritonitis, a similar hierarchical role for classical pathway complement proteins in vivo in the clearance of apoptotic cells by macrophages."
    explanation: >-
      In vivo macrophage clearance of apoptotic cells depends on the classical
      pathway proteins, in the same hierarchy as human SLE risk, in which C1q
      deficiency carries the highest risk.
  downstream:
  - target: Loss of Tolerance to Nuclear Autoantigens
    description: >-
      Persisting apoptotic cells are a sustained source of nuclear autoantigen.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Loss of C1q Restraint on Immune Complex-Induced Interferon-alpha Production
  biological_scale: CELLULAR
  description: >-
    Nucleic-acid-containing immune complexes induce interferon-alpha in
    plasmacytoid dendritic cells. Physiological concentrations of C1q inhibit
    this, in part by directing immune complexes to monocytes rather than
    plasmacytoid dendritic cells. Without C1q this brake is lost.
  cell_types:
  - preferred_term: plasmacytoid dendritic cell
    term:
      id: CL:0000784
      label: plasmacytoid dendritic cell
  - preferred_term: monocyte
    term:
      id: CL:0000576
      label: monocyte
  biological_processes:
  - preferred_term: negative regulation of type I interferon production
    term:
      id: GO:0032480
      label: negative regulation of type I interferon production
    modifier: DECREASED
  evidence:
  - reference: PMID:19790049
    reference_title: "C1q inhibits immune complex-induced interferon-alpha production in plasmacytoid dendritic cells: a novel link between C1q deficiency and systemic lupus erythematosus pathogenesis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "C1q significantly inhibited PBMC IFNalpha production induced by RNA-containing immune complexes (ICs), herpes simplex virus (HSV), and CpG DNA."
    explanation: >-
      C1q inhibits immune complex-induced interferon-alpha in human blood
      cells, so its absence removes this inhibition.
  - reference: PMID:20844193
    reference_title: "C1q deficiency leads to the defective suppression of IFN-alpha in response to nucleoprotein containing immune complexes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Our experiments revealed that C1q preferentially promotes the binding of SLE ICs to monocytes rather than plasmacytoid dendritic cells"
    explanation: >-
      Proposes the cellular route of the C1q effect.
  downstream:
  - target: Type I Interferon Pathway Activation
    description: >-
      Unrestrained interferon-alpha production drives a systemic type I
      interferon signature.
- name: Type I Interferon Pathway Activation
  biological_scale: ORGANISM
  description: >-
    Patients have elevated interferon-stimulated gene expression in blood and
    raised interferon-alpha in serum and cerebrospinal fluid, which places C1q
    deficiency close to the monogenic type I interferonopathies. Chilblain-like
    acral lesions and basal ganglia calcification, seen in some patients, are
    features shared with those disorders.
  biological_processes:
  - preferred_term: type I interferon-mediated signaling pathway
    term:
      id: GO:0060337
      label: type I interferon-mediated signaling pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:39196411
    reference_title: "Hereditary C1q Deficiency is Associated with Type 1 Interferon-Pathway Activation and a High Risk of Central Nervous System Inflammation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Elevated ISG expression was observed in all patients tested (n = 10/10), and serum and CSF IFNα elevated in 2/2 patients."
    explanation: >-
      An interferon signature in every genetically confirmed patient tested.
  - reference: PMID:20844193
    reference_title: "C1q deficiency leads to the defective suppression of IFN-alpha in response to nucleoprotein containing immune complexes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In patients with C1q deficiency, serum and cerebrospinal fluid levels of IFN-α and IFN-γ-inducible protein-10 levels were elevated and strongly correlated with Ro autoantibodies"
    explanation: >-
      Raised interferon-alpha in serum and cerebrospinal fluid of
      C1q-deficient patients.
  downstream:
  - target: Systemic Lupus Erythematosus
    description: >-
      Type I interferon is a central driver of lupus autoimmunity.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Chilblains
    description: >-
      Chilblain-like acral lesions are an interferonopathy feature reported in
      C1q deficiency.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Basal Ganglia Calcification
    description: >-
      Basal ganglia calcification is reported alongside raised CSF
      interferon-alpha, as in the type I interferonopathies.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Increased CSF Interferon-alpha
    description: >-
      Intrathecal interferon-alpha is the measurable readout of the pathway in
      the central nervous system.
  - target: Cerebral Vasculitis
    description: >-
      Central nervous system inflammation, including vasculitis, is frequent
      in patients with an interferon signature; the causal route from
      interferon to vascular inflammation is not established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Seizures
    description: >-
      Seizures are the commonest neuropsychiatric presentation of the central
      nervous system inflammation that accompanies the interferon signature;
      the causal route is not established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Loss of Tolerance to Nuclear Autoantigens
  biological_scale: ORGANISM
  description: >-
    Sustained exposure to nuclear autoantigens from uncleared apoptotic
    material leads to antinuclear autoantibody production and immune-complex
    disease. C1q-deficient mice develop autoantibodies and immune-complex
    glomerulonephritis, though expression depends strongly on genetic
    background. In patients antinuclear antibodies are usual but anti-dsDNA
    antibodies are less frequent than in sporadic SLE.
  evidence:
  - reference: PMID:9590289
    reference_title: "Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "C1qa-/- mice had increased mortality and higher titres of autoantibodies, compared with strain-matched controls. Of the C1qa-/- mice, 25% had glomerulonephritis with immune deposits and multiple apoptotic cell bodies."
    explanation: >-
      C1q deficiency alone produces autoantibodies and immune-complex
      glomerulonephritis in mice.
  - reference: PMID:11859149
    reference_title: "C1q deficiency and autoimmunity: the effects of genetic background on disease expression."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These data demonstrate that the expression of autoimmunity in C1q-deficient mice is strongly influenced by other background genes."
    explanation: >-
      The autoimmune outcome of C1q loss depends on genetic background in
      mice.
  downstream:
  - target: Systemic Lupus Erythematosus
    description: >-
      Loss of tolerance manifests as SLE or an SLE-like illness in most
      patients.
  - target: Antinuclear Antibody Positivity
    description: >-
      Antinuclear antibodies are the serological readout of lost tolerance.
  - target: Glomerulonephritis
    description: >-
      Immune complex deposition in the kidney causes glomerulonephritis.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Discoid Lupus Rash
    description: >-
      Cutaneous lupus lesions are the commonest manifestation of the
      autoimmune disease.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Oral Ulcers
    description: >-
      Mucosal ulceration is a lupus manifestation of the autoimmune disease.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Malar Rash
    description: >-
      Malar rash is a lupus manifestation of the autoimmune disease.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Cutaneous Photosensitivity
    description: >-
      Photosensitive rash is a lupus manifestation of the autoimmune disease.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Arthritis
    description: >-
      Inflammatory arthritis is a lupus manifestation, though less frequent
      than in sporadic SLE.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- category: Immunological
  name: Systemic Lupus Erythematosus
  frequency: FREQUENT
  description: >-
    SLE or an SLE-like illness develops in most patients, usually in early
    childhood. In a 2015 literature review 55% of 71 reported patients met ACR
    criteria for SLE and a further 22.5% had an SLE-like syndrome; an
    international follow-up survey of 45 patients found SLE in 80%. Compared
    with sporadic SLE, discoid rash and oral ulcers are more common and
    arthritis and anti-dsDNA antibodies less common.
  phenotype_term:
    preferred_term: Systemic lupus erythematosus
    term:
      id: HP:0002725
      label: Systemic lupus erythematosus
  evidence:
  - reference: PMID:25846716
    reference_title: "Clinical presentation of human C1q deficiency: How much of a lupus?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "According to the American College of Rheumatology (ACR) diagnostic criteria for SLE 39/71 (55%) subjects could be classified as having SLE. Another 16/71 (22.5%) presented a SLE-like syndrome (defined as 3 positive ACR criteria) whereas in 16/71 (22.5%) no SLE could be diagnosed at time of publication."
    explanation: >-
      Frequency of SLE and SLE-like disease across published patients.
  - reference: PMID:26119135
    reference_title: "Marked variability in clinical presentation and outcome of patients with C1q immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of these patients 36 (80%) suffer from SLE, of which 16 suffer from SLE and infections, 5 (11%) suffer from infections only and 4 (9%) have no symptoms."
    explanation: >-
      80% of 45 followed patients had SLE.
- category: Dermatological
  name: Discoid Lupus Rash
  frequency: FREQUENT
  description: >-
    Discoid lesions occur in about half of patients with C1q
    deficiency-associated SLE, far more often than in sporadic SLE, and skin
    disease is often the initial and dominant complaint.
  phenotype_term:
    preferred_term: Discoid lupus rash
    term:
      id: HP:0007417
      label: Discoid lupus rash
  evidence:
  - reference: PMID:25846716
    reference_title: "Clinical presentation of human C1q deficiency: How much of a lupus?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Discoid rash (56% versus 10%, p<0.001) and oral ulcers (49% versus 24%, p<0.001) occurred significantly more frequent in C1q deficiency-associated SLE/SLE-like disease than in sporadic SLE"
    explanation: >-
      Discoid rash frequency in C1q deficiency-associated SLE.
  - reference: PMID:29113537
    reference_title: "Systemic lupus erythematosus with C1q deficiency: treatment with fresh frozen plasma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Initial and dominant complaints of three cases from two different families were cutaneous manifestations."
    explanation: >-
      Skin disease as the presenting and dominant feature.
- category: Dermatological
  name: Oral Ulcers
  frequency: FREQUENT
  description: >-
    Oral ulcers occur in about half of patients with C1q deficiency-associated
    SLE.
  phenotype_term:
    preferred_term: Oral ulcer
    term:
      id: HP:0000155
      label: Oral ulcer
  evidence:
  - reference: PMID:25846716
    reference_title: "Clinical presentation of human C1q deficiency: How much of a lupus?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Discoid rash (56% versus 10%, p<0.001) and oral ulcers (49% versus 24%, p<0.001) occurred significantly more frequent in C1q deficiency-associated SLE/SLE-like disease than in sporadic SLE"
    explanation: >-
      Oral ulcer frequency in C1q deficiency-associated SLE.
- category: Dermatological
  name: Malar Rash
  description: >-
    Malar rash is part of the mucocutaneous presentation.
  phenotype_term:
    preferred_term: Malar rash
    term:
      id: HP:0025300
      label: Malar rash
  evidence:
  - reference: PMID:39196411
    reference_title: "Hereditary C1q Deficiency is Associated with Type 1 Interferon-Pathway Activation and a High Risk of Central Nervous System Inflammation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall, individuals with C1QDef demonstrate many characteristics of recognized monogenic interferonopathies: particularly, cutaneous involvement (malar rash, acral vasculitic/papular rash, chilblains), SLE-like disease, basal ganglia calcification, increased expression of ISGs in peripheral blood, and elevated levels of CSF IFNα."
    explanation: >-
      Lists malar rash among the cutaneous features.
- category: Dermatological
  name: Chilblains
  description: >-
    Chilblain-like and acral vasculitic lesions, a feature shared with the
    type I interferonopathies.
  phenotype_term:
    preferred_term: Chilblains
    term:
      id: HP:0009710
      label: Chilblains
  evidence:
  - reference: PMID:39196411
    reference_title: "Hereditary C1q Deficiency is Associated with Type 1 Interferon-Pathway Activation and a High Risk of Central Nervous System Inflammation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall, individuals with C1QDef demonstrate many characteristics of recognized monogenic interferonopathies: particularly, cutaneous involvement (malar rash, acral vasculitic/papular rash, chilblains), SLE-like disease, basal ganglia calcification, increased expression of ISGs in peripheral blood, and elevated levels of CSF IFNα."
    explanation: >-
      Places chilblains among the interferonopathy-like features.
  - reference: PMID:40316395
    reference_title: "Rare C1q deficiency presenting as pediatric SLE: A case study of two consanguineous siblings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both of our patients had NP involvement, and the brother had chilblain lesions."
    explanation: >-
      Chilblain lesions in a C1QA-homozygous patient.
- category: Dermatological
  name: Cutaneous Photosensitivity
  description: >-
    Photosensitive rash is part of the mucocutaneous lupus presentation and
    can be the presenting sign in early childhood.
  phenotype_term:
    preferred_term: Cutaneous photosensitivity
    term:
      id: HP:0000992
      label: Cutaneous photosensitivity
  evidence:
  - reference: PMID:42147803
    reference_title: "Homozygous C1qA Deficiency Presenting as Early-Onset Systemic Lupus Erythematosus: A Case Report With a Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 3-year-old girl presented with recurrent infections, a photosensitive rash, and persistent leukopenia"
    explanation: >-
      Photosensitive rash at presentation in a C1QA-homozygous child.
- category: Musculoskeletal
  name: Arthritis
  frequency: FREQUENT
  description: >-
    Inflammatory arthritis occurs in about a third of patients with C1q
    deficiency-associated SLE, less often than in sporadic SLE.
  phenotype_term:
    preferred_term: Arthritis
    term:
      id: HP:0001369
      label: Arthritis
  evidence:
  - reference: PMID:25846716
    reference_title: "Clinical presentation of human C1q deficiency: How much of a lupus?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "whereas arthritis (38% versus 84%, p<001) and anti-ds-DNA (18% versus 78%, p<0.001) occurred less frequently"
    explanation: >-
      Arthritis frequency in C1q deficiency-associated SLE against sporadic
      SLE.
  - reference: PMID:40556690
    reference_title: "C1q monogenic lupus: a case series and review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients exhibited mucocutaneous involvement, discoid lupus erythematosus, inflammatory polyarthritis, normal serum complements C3 and C4, coarse-speckled Antinuclear antibody positivity and antibodies to ribonucleoprotein."
    explanation: >-
      Inflammatory polyarthritis in all four patients of a case series.
- category: Renal
  name: Glomerulonephritis
  description: >-
    Renal involvement is, with skin disease, the main organ manifestation, and
    renal or neurological involvement marks the most severe phenotype.
  phenotype_term:
    preferred_term: Glomerulonephritis
    term:
      id: HP:0000099
      label: Glomerulonephritis
  evidence:
  - reference: PMID:28082982
    reference_title: "C1q Deficiency and Neuropsychiatric Systemic Lupus Erythematosus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Patients with C1q deficiency mainly present with cutaneous and renal involvement."
    explanation: >-
      Renal involvement is one of the two main presentations.
  - reference: PMID:39470951
    reference_title: "Hematopoietic Stem Cell Transplantation for C1q Deficiency: A Study on Behalf of the EBMT Inborn Errors Working Party."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with a severe autoimmune phenotype, defined as neurological and/or renal involvement, had the worst OS (40% vs 84%; p = 0.034)."
    explanation: >-
      Renal involvement defines a severe phenotype with worse survival after
      transplantation.
- category: Neurological
  name: Seizures
  description: >-
    Neuropsychiatric involvement is reported in about a fifth of patients and
    is more severe than in complement-competent SLE; seizures are a common
    presentation.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:28082982
    reference_title: "C1q Deficiency and Neuropsychiatric Systemic Lupus Erythematosus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "An important number of cases present with seizures and the most frequent findings in neuroimaging are changes in basal ganglia and cerebral vasculitis."
    explanation: >-
      Seizures as a common neuropsychiatric presentation.
  - reference: PMID:28082982
    reference_title: "C1q Deficiency and Neuropsychiatric Systemic Lupus Erythematosus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Although less frequent, neuropsychiatric (NP) involvement has also been reported in 20% of the C1q-deficient patients."
    explanation: >-
      Frequency of neuropsychiatric involvement overall.
- category: Neurological
  name: Cerebral Vasculitis
  description: >-
    Cerebral vasculitis is among the commonest neuroimaging findings.
  phenotype_term:
    preferred_term: Cerebral vasculitis
    term:
      id: HP:0005318
      label: Cerebral vasculitis
  evidence:
  - reference: PMID:28082982
    reference_title: "C1q Deficiency and Neuropsychiatric Systemic Lupus Erythematosus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "An important number of cases present with seizures and the most frequent findings in neuroimaging are changes in basal ganglia and cerebral vasculitis."
    explanation: >-
      Cerebral vasculitis as a frequent neuroimaging finding.
- category: Neurological
  name: Basal Ganglia Calcification
  description: >-
    Basal ganglia and other intracranial calcification is reported, as part of
    a central nervous system picture (basal ganglia calcification,
    encephalitis, vasculitis, pachymeningitis) present in 10 of 12 patients in
    one series.
  phenotype_term:
    preferred_term: Basal ganglia calcification
    term:
      id: HP:0002135
      label: Basal ganglia calcification
  evidence:
  - reference: PMID:39196411
    reference_title: "Hereditary C1q Deficiency is Associated with Type 1 Interferon-Pathway Activation and a High Risk of Central Nervous System Inflammation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Central nervous system (encompassing basal ganglia calcification, encephalitis, vasculitis, chronic pachymeningitis), mucocutaneous and renal involvement were present, respectively, in 10, 11 and 2 of 12 patients"
    explanation: >-
      Central nervous system involvement including basal ganglia
      calcification in most of a 12-patient series.
  - reference: PMID:23651859
    reference_title: "Systemic lupus erythematosus due to C1q deficiency with progressive encephalopathy, intracranial calcification and acquired moyamoya cerebral vasculopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cerebral imaging demonstrated acquired intracranial calcification and a cerebral vasculopathy reminiscent of moyamoya."
    explanation: >-
      Acquired intracranial calcification in a C1QB-deficient patient.
- category: Laboratory
  name: Increased CSF Interferon-alpha
  description: >-
    Interferon-alpha is raised in cerebrospinal fluid as well as serum.
  phenotype_term:
    preferred_term: Increased CSF interferon alpha
    term:
      id: HP:0009709
      label: Increased CSF interferon alpha
  evidence:
  - reference: PMID:39196411
    reference_title: "Hereditary C1q Deficiency is Associated with Type 1 Interferon-Pathway Activation and a High Risk of Central Nervous System Inflammation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Elevated ISG expression was observed in all patients tested (n = 10/10), and serum and CSF IFNα elevated in 2/2 patients."
    explanation: >-
      Raised CSF interferon-alpha in the patients measured.
- category: Infectious
  name: Recurrent Bacterial Infections
  frequency: FREQUENT
  description: >-
    Severe or recurrent bacterial infections, typically with encapsulated
    organisms, occur in about half of patients, alone or with SLE, and
    infection at an early age accounts for much of the severe course.
  phenotype_term:
    preferred_term: Recurrent bacterial infections
    term:
      id: HP:0002718
      label: Recurrent bacterial infections
  evidence:
  - reference: PMID:26119135
    reference_title: "Marked variability in clinical presentation and outcome of patients with C1q immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of these patients 36 (80%) suffer from SLE, of which 16 suffer from SLE and infections, 5 (11%) suffer from infections only and 4 (9%) have no symptoms."
    explanation: >-
      21 of 45 patients (16 with SLE and 5 without) had infections.
  - reference: PMID:25846716
    reference_title: "Clinical presentation of human C1q deficiency: How much of a lupus?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "The severe course of disease in some patients seemed to be mostly due to severe infections at early ages and not in particular due to more aggressive SLE manifestations."
    explanation: >-
      Early severe infection drives the severe course.
- category: Infectious
  name: Recurrent Meningitis
  description: >-
    Bacterial meningitis, including recurrent meningitis, is reported.
  phenotype_term:
    preferred_term: Recurrent meningitis
    term:
      id: HP:0006946
      label: Recurrent meningitis
  evidence:
  - reference: PMID:20635792
    reference_title: "Homozygosity for a novel mutation in the C1q C chain gene in a Turkish family with hereditary C1q deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An 11-year-old girl was screened for immunodeficiency due to a history of recurrent meningitis and pneumonia."
    explanation: >-
      Recurrent meningitis in a genetically confirmed C1QC-deficient patient.
- category: Laboratory
  name: Antinuclear Antibody Positivity
  description: >-
    Antinuclear antibodies are usually positive, but anti-dsDNA antibodies are
    found in under a fifth of patients, against about three quarters in
    sporadic SLE.
  phenotype_term:
    preferred_term: Antinuclear antibody positivity
    term:
      id: HP:0003493
      label: Antinuclear antibody positivity
  evidence:
  - reference: PMID:29113537
    reference_title: "Systemic lupus erythematosus with C1q deficiency: treatment with fresh frozen plasma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Antinuclear antibody was positive in all cases, whereas anti-dsDNA was negative with normal levels of complement C3, C4 and decreased CH50 activity."
    explanation: >-
      Positive ANA with negative anti-dsDNA in three patients.
  - reference: PMID:25846716
    reference_title: "Clinical presentation of human C1q deficiency: How much of a lupus?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "whereas arthritis (38% versus 84%, p<001) and anti-ds-DNA (18% versus 78%, p<0.001) occurred less frequently"
    explanation: >-
      Anti-dsDNA antibodies are much less frequent than in sporadic SLE.
- category: Laboratory
  name: Decreased Circulating C1q
  frequency: OBLIGATE
  description: >-
    C1q is undetectable in serum, or present only as a non-functional
    low-molecular-weight form.
  phenotype_term:
    preferred_term: Decreased circulating C1q concentration
    term:
      id: HP:0034601
      label: Decreased circulating C1q concentration
  evidence:
  - reference: PMID:34993161
    reference_title: "Case Report: Early Onset Systemic Lupus Erythematosus Due to Hereditary C1q Deficiency Treated With Fresh Frozen Plasma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Total complement activity, classical pathway (hemolytic test) was deficient and C1q antigen was below the detection limit supporting the presence of C1q deficiency."
    explanation: >-
      Undetectable C1q antigen.
- category: Laboratory
  name: Reduced CH50
  frequency: OBLIGATE
  description: >-
    Classical pathway haemolytic activity is absent, with normal C3 and C4.
  phenotype_term:
    preferred_term: Reduced circulating CH50 activity
    term:
      id: HP:0025434
      label: Reduced circulating CH50 activity
  evidence:
  - reference: PMID:29113537
    reference_title: "Systemic lupus erythematosus with C1q deficiency: treatment with fresh frozen plasma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Antinuclear antibody was positive in all cases, whereas anti-dsDNA was negative with normal levels of complement C3, C4 and decreased CH50 activity."
    explanation: >-
      Decreased CH50 with normal C3 and C4.
biochemical:
- name: Serum C1q
  presence: DECREASED
  notes: >-
    Undetectable in most patients; some missense variants give a detectable
    but non-functional low-molecular-weight C1q, so detectable antigen with
    absent CH50 does not exclude the diagnosis. Secondary C1q deficiency
    (consumption, anti-C1q autoantibodies) must be excluded.
  evidence:
  - reference: PMID:34993161
    reference_title: "Case Report: Early Onset Systemic Lupus Erythematosus Due to Hereditary C1q Deficiency Treated With Fresh Frozen Plasma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Total complement activity, classical pathway (hemolytic test) was deficient and C1q antigen was below the detection limit supporting the presence of C1q deficiency."
    explanation: >-
      Undetectable C1q in a genetically confirmed patient.
  - reference: PMID:28082982
    reference_title: "C1q Deficiency and Neuropsychiatric Systemic Lupus Erythematosus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "A mutation in one of the C1q genes can either lead to complete deficiency or to low C1q levels with C1q polypeptide in the form of low-molecular weight (LMW) C1q."
    explanation: >-
      The low-molecular-weight form is the exception to absent antigen.
- name: Serum CH50 (classical pathway haemolytic activity)
  presence: DECREASED
  notes: >-
    Absent, with normal C3 and C4, which distinguishes primary C1q deficiency
    from classical pathway consumption in sporadic SLE.
  evidence:
  - reference: PMID:29113537
    reference_title: "Systemic lupus erythematosus with C1q deficiency: treatment with fresh frozen plasma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Antinuclear antibody was positive in all cases, whereas anti-dsDNA was negative with normal levels of complement C3, C4 and decreased CH50 activity."
    explanation: >-
      Decreased CH50 with normal C3 and C4.
diagnosis:
- name: Complement screening (CH50, C3, C4, C1q antigen)
  description: >-
    Classical pathway haemolytic activity (CH50) is absent while C3 and C4
    are normal, which points to an early classical pathway component
    deficiency rather than the complement consumption of sporadic SLE.
    Undetectable C1q antigen then localises the defect. Secondary C1q
    deficiency (consumption, anti-C1q autoantibodies) must be excluded, and
    a missense variant producing low-molecular-weight C1q can leave antigen
    detectable despite absent function. The pattern should prompt testing in
    a young child with SLE-like skin disease, normal C3 and C4 and negative
    anti-dsDNA.
  diagnosis_term:
    preferred_term: complement screening assay
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  markers: CH50, serum C3, serum C4, serum C1q antigen
  evidence:
  - reference: PMID:29113537
    reference_title: "Systemic lupus erythematosus with C1q deficiency: treatment with fresh frozen plasma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Antinuclear antibody was positive in all cases, whereas anti-dsDNA was negative with normal levels of complement C3, C4 and decreased CH50 activity."
    explanation: >-
      The diagnostic complement pattern in three patients.
  - reference: PMID:34993161
    reference_title: "Case Report: Early Onset Systemic Lupus Erythematosus Due to Hereditary C1q Deficiency Treated With Fresh Frozen Plasma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Young patients with cutaneous lesions resembling SLE, early onset of autoimmunity, with normal C3, C4, elevated ANAs, and negative anti-dsDNA, C1q deficiency should be suspected and complement screening tests should be done."
    explanation: >-
      States when to suspect the disease and screen complement.
  - reference: PMID:34993161
    reference_title: "Case Report: Early Onset Systemic Lupus Erythematosus Due to Hereditary C1q Deficiency Treated With Fresh Frozen Plasma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is important to exclude secondary C1q deficiency."
    explanation: >-
      Secondary C1q deficiency is the main differential of a low C1q.
- name: C1QA, C1QB and C1QC sequencing
  description: >-
    Sequencing of the three C1q genes confirms the diagnosis and identifies
    the biallelic variants, which allows carrier testing in the family.
    Whole-exome sequencing has been diagnostic in several reported patients;
    deep sequencing of non-coding regions was needed to find a splice-region
    C1QB variant.
  diagnosis_term:
    preferred_term: C1q gene sequencing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:42147803
    reference_title: "Homozygous C1qA Deficiency Presenting as Early-Onset Systemic Lupus Erythematosus: A Case Report With a Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Western blot analysis and whole-exome sequencing identified a homozygous nonsense variant in C1qA"
    explanation: >-
      Exome sequencing with western blot confirmed the diagnosis.
  - reference: PMID:40556690
    reference_title: "C1q monogenic lupus: a case series and review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe four cases of C1Q monogenic lupus identified by whole exome sequencing."
    explanation: >-
      Exome sequencing identified all four patients in a case series.
  - reference: PMID:25454803
    reference_title: "Identification of a novel non-coding mutation in C1qB in a Dutch child with C1q deficiency associated with recurrent infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Deep-sequencing revealed a homozygous mutation in the non-coding region of C1qB in the patient, whereas both parents were heterozygous."
    explanation: >-
      A non-coding variant found by deep sequencing, with parental
      segregation.
genetic:
- name: C1QA
  gene_term:
    preferred_term: C1QA
    term:
      id: hgnc:1241
      label: C1QA
  relationship_type: CAUSATIVE
  subtype: C1QD1
  evidence:
  - reference: PMID:22472776
    reference_title: "Identification of novel coding mutation in C1qA gene in an African-American pedigree with lupus and C1q deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In an African-American patient with lupus and C1q deficiency, we identified and confirmed a novel homozygote start codon mutation in C1qA gene that changes amino acid methionine to arginine at position 1."
    explanation: >-
      Homozygous C1QA variant causing C1q deficiency.
- name: C1QB
  gene_term:
    preferred_term: C1QB
    term:
      id: hgnc:1242
      label: C1QB
  relationship_type: CAUSATIVE
  subtype: C1QD2
  evidence:
  - reference: PMID:25454803
    reference_title: "Identification of a novel non-coding mutation in C1qB in a Dutch child with C1q deficiency associated with recurrent infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Deep-sequencing revealed a homozygous mutation in the non-coding region of C1qB in the patient, whereas both parents were heterozygous."
    explanation: >-
      Homozygous C1QB variant causing complete C1q deficiency.
- name: C1QC
  gene_term:
    preferred_term: C1QC
    term:
      id: hgnc:1245
      label: C1QC
  relationship_type: CAUSATIVE
  subtype: C1QD3
  evidence:
  - reference: PMID:34993161
    reference_title: "Case Report: Early Onset Systemic Lupus Erythematosus Due to Hereditary C1q Deficiency Treated With Fresh Frozen Plasma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The girl has pathogenic homozygous nonsense mutation in C1qC gene, Arg69Ter (c205>T)."
    explanation: >-
      Homozygous C1QC nonsense variant causing C1q deficiency.
prevalence:
- population: Worldwide published cases
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    A 2015 literature review counted 71 published patients from 45 families,
    and a 2024 transplantation study reviewed 69 genetically confirmed
    patients. These are literature counts, not population prevalence
    estimates.
  evidence:
  - reference: PMID:25846716
    reference_title: "Clinical presentation of human C1q deficiency: How much of a lupus?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "We identified 71 C1q-deficient patients descending from 45 families that had been published."
    explanation: >-
      Count of published patients.
  - reference: PMID:39470951
    reference_title: "Hematopoietic Stem Cell Transplantation for C1q Deficiency: A Study on Behalf of the EBMT Inborn Errors Working Party."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Reviewing data of 69 genetically confirmed C1q deficient patients"
    explanation: >-
      Count of genetically confirmed patients.
clinical_burden:
  burden_level: VARIABLE
  rationale: >-
    Outcome ranges widely. About a fifth of reported patients have died,
    nearly all before the age of 20, mostly from severe infection in early
    childhood or from renal and central nervous system lupus, and most
    survivors need long-term immunosuppression or transplantation. A subset,
    including some patients with infections only or no symptoms, has an
    excellent prognosis, and at least half are expected to reach middle age.
  evidence:
  - reference: PMID:26119135
    reference_title: "Marked variability in clinical presentation and outcome of patients with C1q immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In total 9 (20%) of the C1q deficient individuals had died. All except for one died before the age of 20 years."
    explanation: >-
      Mortality in an international follow-up survey of 45 patients.
  - reference: PMID:26119135
    reference_title: "Marked variability in clinical presentation and outcome of patients with C1q immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report the largest phenotypic data set on C1q deficiency to date, revealing high variance; with high mortality but also a subset of patients with an excellent prognosis."
    explanation: >-
      The same survey characterises the outcome as highly variable, which is
      why the burden is recorded as variable rather than uniformly high.
animal_models:
- name: C1qa knockout mouse
  species: Mouse
  genotype: C1qa(-/-)
  publication: PMID:9590289
  description: >-
    Gene-targeted C1qa-deficient mice develop autoantibodies and
    immune-complex glomerulonephritis with accumulation of apoptotic bodies,
    with penetrance strongly dependent on genetic background.
  modeled_mechanisms:
  - target: Defective Clearance of Apoptotic Cells
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Apoptotic bodies accumulate in glomeruli of C1q-deficient mice.
    limitations: >-
      Apoptotic cell clearance is measured in mouse glomeruli and peritoneum;
      an equivalent defect has not been measured directly in patients.
    evidence:
    - reference: PMID:9590289
      reference_title: "Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Among mice without glomerulonephritis, there were significantly greater numbers of glomerular apoptotic bodies in C1q-deficient mice compared with controls."
      explanation: >-
        Supports the model as informative for apoptotic cell clearance.
  - target: Loss of Tolerance to Nuclear Autoantigens
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      Autoantibodies and glomerulonephritis develop, but only on some genetic
      backgrounds.
    limitations: >-
      On the C57BL/6 background C1q deficiency produces no autoimmune
      phenotype, whereas most human patients develop autoimmunity. The cited
      studies do not report the skin and central nervous system disease or the
      interferon signature that dominate the human phenotype.
    evidence:
    - reference: PMID:11859149
      reference_title: "C1q deficiency and autoimmunity: the effects of genetic background on disease expression."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In C1q-deficient C57BL/6 mice, no evidence of an autoimmune phenotype was found"
      explanation: >-
        Shows the background dependence that limits fidelity.
treatments:
- name: Allogeneic Hematopoietic Stem Cell Transplantation
  description: >-
    Because C1q is made by monocyte-derived cells, allogeneic HSCT restores C1q
    production and classical pathway function and can cure the disease. In a
    multicentre series of 18 patients transplanted mainly for refractory
    autoimmunity, autoimmune features resolved in 11, but five died of
    transplant-related complications and survival was worst in patients with
    renal or neurological involvement, so patient selection is critical.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: allogeneic hematopoietic stem cell transplantation
    term:
      id: NCIT:C46089
      label: Allogeneic Hematopoietic Stem Cell Transplantation
  target_mechanisms:
  - target: Absent or Dysfunctional C1q
    treatment_effect: RESTORES
    description: >-
      Donor-derived monocytes and macrophages produce normal C1q.
  evidence:
  - reference: PMID:39470951
    reference_title: "Hematopoietic Stem Cell Transplantation for C1q Deficiency: A Study on Behalf of the EBMT Inborn Errors Working Party."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In eleven patients HSCT led to resolution of autoimmune features and discontinuation of immunosuppressive treatments (follow-up time range 3-84 months). Five patients died due to transplant-related complications."
    explanation: >-
      Outcome of HSCT in the largest series, including its mortality.
  - reference: PMID:26516671
    reference_title: "Allogeneic Hematopoietic Stem Cell Transplantation in the Treatment of Human C1q Deficiency: The Karolinska Experience."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 9-year-old boy and a 12-year-old girl with refractory SLE restored C1q production after allo-HSCT. This resulted in normal functional properties of the classical complement pathway followed by reduced severity of SLE symptoms."
    explanation: >-
      HSCT restored C1q production and classical pathway function.
  - reference: PMID:33000368
    reference_title: "Bone marrow transplantation from a human leukocyte antigen-mismatched unrelated donor in a case with C1q deficiency associated with refractory systemic lupus erythematosus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Complete donor chimerism has been maintained for 2 years after transplantation, leading to the restoration of C1q levels and the resolution of SLE symptoms. Normal C1q mRNA expression was observed in CD14 + cells."
    explanation: >-
      C1q restored from donor CD14-positive monocytes after transplantation.
  - reference: PMID:15517607
    reference_title: "Restoration of C1q levels by bone marrow transplantation attenuates autoimmune disease associated with C1q deficiency in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In contrast, a significant delay in the development of autoantibodies and glomerulonephritis was observed in C1qa(-/-) mice reconstituted with wild-type BMC, and the impaired clearance of apoptotic cells, previously described in C1qa(-/-) mice, was rectified."
    explanation: >-
      Bone marrow transplantation corrects C1q deficiency and attenuates its
      autoimmunity in mice.
- name: Fresh Frozen Plasma
  description: >-
    Regular fresh frozen plasma infusion supplies C1q and has controlled
    refractory cutaneous and systemic disease in several reported patients,
    allowing corticosteroid reduction. The effect is temporary, so infusions
    must be repeated.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: fresh frozen plasma transfusion
    term:
      id: NCIT:C116475
      label: Fresh Frozen Plasma Transfusion
  target_mechanisms:
  - target: Absent or Dysfunctional C1q
    treatment_effect: RESTORES
    description: >-
      Transiently supplies circulating C1q.
  evidence:
  - reference: PMID:29113537
    reference_title: "Systemic lupus erythematosus with C1q deficiency: treatment with fresh frozen plasma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All symptoms of all three cases improved by daily fresh frozen plasma (FFP) infusions, and once cutaneous lesions subsided, the infusions were reduced to a frequency that would prevent the flare up of the symptoms."
    explanation: >-
      Plasma infusion controlled disease in three patients.
  - reference: PMID:34993161
    reference_title: "Case Report: Early Onset Systemic Lupus Erythematosus Due to Hereditary C1q Deficiency Treated With Fresh Frozen Plasma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Regular fresh frozen plasma infusions keep her disease under control, and we were able to reduce the dose of corticosteroids."
    explanation: >-
      Plasma infusion allowed steroid reduction.
  - reference: PMID:24160257
    reference_title: "The identification of a novel splicing mutation in C1qB in a Japanese family with C1q deficiency: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Because treatment with steroids and immunosuppressive drugs was not effective, we commenced use of fresh frozen plasma to provide C1q supplements."
    explanation: >-
      Plasma used as C1q replacement after failure of immunosuppression.
- name: Type I Interferon Receptor Blockade
  description: >-
    Anifrolumab, a monoclonal antibody against the type I interferon receptor,
    resolved refractory mucocutaneous disease and allowed corticosteroid
    withdrawal in a single reported child.
  therapeutic_modality: MONOCLONAL_ANTIBODY
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: anifrolumab
      term:
        id: NCIT:C166658
        label: Anifrolumab
  target_mechanisms:
  - target: Type I Interferon Pathway Activation
    treatment_effect: INHIBITS
    description: >-
      Blocks signalling through the type I interferon receptor.
  evidence:
  - reference: PMID:42597478
    reference_title: "Interferon-targeted therapy with anifrolumab in monogenic pediatric systemic lupus erythematosus due to C1q deficiency: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She showed significant clinical improvement and full recovery of mucocutaneous lesions, restoration of laboratory parameters and successful discontinuation of corticosteroids after the seventh monthly infusion."
    explanation: >-
      Response to anifrolumab in one C1QA-deficient child.
- name: JAK Inhibitors
  description: >-
    JAK inhibitors have been tried to block interferon signalling, with
    variable results: one of three reported patients responded.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: JAK inhibitor
      term:
        id: NCIT:C172200
        label: JAK Inhibitor
  target_mechanisms:
  - target: Type I Interferon Pathway Activation
    treatment_effect: INHIBITS
    description: >-
      Blocks JAK-dependent interferon receptor signalling.
  evidence:
  - reference: PMID:39196411
    reference_title: "Hereditary C1q Deficiency is Associated with Type 1 Interferon-Pathway Activation and a High Risk of Central Nervous System Inflammation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three patients were treated with Janus-kinase inhibitors (JAKi), with variable outcome; one displaying an apparently favourable response in respect of cutaneous and neurological features, and two others experiencing persistent disease despite JAKi therapy."
    explanation: >-
      Mixed outcome of JAK inhibition in three patients; supports its use as a
      treatment tried in this disease, not established efficacy.
- name: Corticosteroids and Conventional Immunosuppression
  description: >-
    Corticosteroids, hydroxychloroquine and steroid-sparing agents are used as
    in sporadic SLE, but cutaneous disease in particular often responds only to
    high-dose steroids and flares on tapering.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: corticosteroid
      term:
        id: CHEBI:50858
        label: corticosteroid
    - preferred_term: hydroxychloroquine
      term:
        id: CHEBI:5801
        label: hydroxychloroquine
  evidence:
  - reference: PMID:29113537
    reference_title: "Systemic lupus erythematosus with C1q deficiency: treatment with fresh frozen plasma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Previously, all of them had been treated with steroids, hydroxychloroquine and methotrexate or azathioprine."
    explanation: >-
      The conventional regimen used.
  - reference: PMID:29113537
    reference_title: "Systemic lupus erythematosus with C1q deficiency: treatment with fresh frozen plasma."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "It was learned that they had responded only to high dosage prednisolone and their symptoms flared up during dosage reduction even under methotrexate or azathioprine."
    explanation: >-
      Disease was not controlled once conventional therapy was tapered.
  - reference: PMID:42147803
    reference_title: "Homozygous C1qA Deficiency Presenting as Early-Onset Systemic Lupus Erythematosus: A Case Report With a Literature Review."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite treatment with corticosteroids and hydroxychloroquine, the patient's disease activity remained suboptimal, leading to consideration of hematopoietic stem cell transplantation as a definitive therapeutic option."
    explanation: >-
      Inadequate control on corticosteroids and hydroxychloroquine in a
      C1QA-deficient child.
- name: Vaccination and Antibiotic Prophylaxis
  description: >-
    Vaccination against encapsulated bacteria and antibiotic prophylaxis are
    part of standard management to reduce the infection risk.
  therapeutic_modality: VACCINE
  treatment_term:
    preferred_term: vaccination
    term:
      id: NCIT:C15346
      label: Vaccination
  target_mechanisms:
  - target: Impaired Complement-Dependent Defence Against Encapsulated Bacteria
    treatment_effect: BYPASSES
    description: >-
      Reduces infection by encapsulated organisms despite the complement
      defect.
  evidence:
  - reference: PMID:34993161
    reference_title: "Case Report: Early Onset Systemic Lupus Erythematosus Due to Hereditary C1q Deficiency Treated With Fresh Frozen Plasma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Treatment and management of this rare disease are very complex and include prophylactic vaccination, antibiotics, and immunosuppressive drugs."
    explanation: >-
      Lists vaccination and antibiotics in management.
notes: >-
  The three gene-defined MONDO subtypes (C1Q deficiency 1, 2 and 3) are
  curated as has_subtypes rows. MONDO also has gene-specific classes named
  "systemic lupus erythematosus related to C1QA/C1QB/C1QC", placed under
  systemic lupus erythematosus rather than under C1Q deficiency; they are
  recorded under mappings as relatedMatch because they cover the lupus
  manifestation of each subtype rather than the whole deficiency, which also
  includes patients with infection alone or no symptoms.
📚

References & Deep Research

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Create: C1Q_Deficiency · 2026-10-16T20:45:02Z · View source

Created the C1Q deficiency entry (MONDO:0013343) with the three gene-defined MONDO subtypes (C1Q deficiency 1/2/3; C1QA, C1QB, C1QC) as has_subtypes rows, replacing the three queue stubs. Pathograph: absent or dysfunctional C1q leads to classical pathway initiation failure (impaired defence against encapsulated bacteria; defective apoptotic cell clearance leading to loss of tolerance) and, independently, to loss of C1q restraint on immune complex-induced interferon-alpha and a type I interferon signature; phenotypes are wired to these nodes. Treatments: allogeneic HSCT, fresh frozen plasma, anifrolumab, JAK inhibitors, conventional immunosuppression, vaccination. MONDO's gene-specific SLE classes (MONDO:1060174, MONDO:1060228, MONDO:1060227) are recorded as relatedMatch mappings only. One OpenScientist deep-research report was generated and used as leads; every snippet was checked against PubMed abstracts fetched into references_cache. Validated with just validate, validate-terms, count-verified-snippets and validate-disorders.

OpenScientist ▸
C1q Deficiency (MONDO:0013343): A Comprehensive Disease Characteristics Report
openscientist-autonomous 25 citations 2026-10-16T20:29:10.321827

C1q Deficiency (MONDO:0013343): A Comprehensive Disease Characteristics Report

Autonomous discovery investigation — 5 iterations, 9 confirmed findings, 32 papers reviewed

Disease: C1q Deficiency (Complement component 1q deficiency) MONDO: MONDO:0013343 · OMIM: #613652 (C1q deficiency) · Orphanet: ORPHA:169147 · ICD-10: D84.1 · ICD-11: 4A00.1 (complement deficiency) · MeSH: "Complement C1q" (D015950); "Hereditary Complement Deficiency Diseases" (D055468)

Summary

C1q deficiency is an ultra-rare autosomal-recessive inborn error of immunity and the strongest known single-gene cause of systemic lupus erythematosus (SLE). It is caused by biallelic loss-of-function mutations in any one of the three genes encoding the C1q chains — C1QA, C1QB, or C1QC — clustered on chromosome 1p36.12. Because the mature C1q molecule is a hexameric assembly of six A-B-C heterotrimeric subunits, a damaging variant in a single chain prevents assembly of the entire molecule, producing complete functional C1q deficiency and abolishing initiation of the classical complement pathway. More than 90% of genetically confirmed C1q-deficient individuals develop SLE or an SLE-like disease — the highest penetrance of any known SLE susceptibility factor — typically with severe, early-childhood onset. Patients are also susceptible to invasive infection by encapsulated bacteria (Neisseria meningitidis, Streptococcus pneumoniae, Haemophilus influenzae).

The core mechanism is impaired complement-mediated clearance of apoptotic cells and immune complexes. C1q normally opsonizes dying cells and immune complexes for phagocytosis; in its absence, apoptotic material — a major reservoir of nuclear autoantigens — accumulates, driving autoantibody formation (ANA, anti-dsDNA), immune-complex deposition, and tissue injury (notably lupus nephritis and CNS disease). This "waste-disposal" / "clearance-deficiency" hypothesis is supported directly by gene-targeted C1q-knockout mice, which develop glomerulonephritis with abundant apoptotic bodies and immune deposits. Downstream, type I interferon dysregulation amplifies the autoimmune phenotype and represents a druggable node.

Diagnosis rests on a distinctive laboratory signature — absent total hemolytic complement activity (CH50) with normal C3 and C4 — plus demonstration of absent C1q protein and confirmatory sequencing (WES/single-gene). Management spans conventional SLE immunosuppression, type I interferon receptor blockade (anifrolumab), and — uniquely among the complement deficiencies — potentially curative allogeneic hematopoietic stem-cell transplantation (HSCT), which works because C1q is synthesized predominantly by monocytes/macrophages, so replacing the hematopoietic compartment restores circulating C1q. Outcomes are variable: roughly 20% of patients die before age 20 (severe renal/CNS disease carries the worst prognosis), yet at least half reach middle age.

Section-by-Section Report

1. Disease Information

Overview. C1q deficiency is a rare autosomal-recessive complement deficiency in which functional C1q — the recognition subunit of the C1 complex that initiates the classical complement pathway — is absent. The dominant clinical consequence is a severe, early-onset SLE-like autoimmune disease, accompanied by heightened susceptibility to pyogenic (encapsulated-bacterial) infection.

Key identifiers. - MONDO: MONDO:0013343; OMIM: #613652; Orphanet: ORPHA:169147; ICD-10: D84.1; ICD-11: 4A00.1 - Causal genes / loci: C1QA (OMIM 120550), C1QB (OMIM 120570), C1QC (OMIM 120575) — chromosome 1p36.12

Synonyms / alternative names. C1q deficiency; complement component 1q deficiency; hereditary C1q deficiency; C1q monogenic lupus; C1q-deficiency SLE.

Nature of evidence. The knowledge base is derived from aggregated disease-level resources and the published clinical/genetic literature — principally case reports, small case series, an international survey of 45 patients across 31 families (PMID: 26119135), and a multinational HSCT cohort (PMID: 39470951) — rather than individual EHR extraction.

2. Etiology

Primary cause — genetic. C1q deficiency is a monogenic, autosomal-recessive disorder. Biallelic loss-of-function mutations in any one of C1QA, C1QB, or C1QC abolish functional C1q.

"C1q deficiency is a rare autosomal recessive genetic condition characterized by mutations in genes C1qA, C1qB, or C1qC which can cause a SLE-like disease." — PMID: 40316395

Genetic risk factors. The causal variants themselves ARE the risk factor; this is a highly penetrant Mendelian condition rather than a complex-trait susceptibility locus. C1q deficiency confers the strongest and most severe genetic risk for SLE of any complement deficiency:

"The strongest susceptibility genes for the development of systemic lupus erythematosus (SLE) in humans are null mutants of classical pathway complement proteins. There is a hierarchy of disease susceptibility and severity according to the position of the missing protein in the activation pathway, with the severest disease associated with C1q deficiency." — PMID: 10934224

Environmental risk factors / triggers. As with SLE generally, environmental triggers (UV light driving photosensitive rash; infections) likely modulate expression. Consanguinity is a major demographic risk factor because the disease is recessive — multiple reported pedigrees are consanguineous (PMID: 40316395 describes consanguineous siblings). Epstein–Barr virus is implicated in anti-C1q autoantibody generation in polygenic lupus via molecular mimicry (PMID: 41929519), though this is distinct from the genetic deficiency.

Protective factors. No established genetic or environmental protective factors specific to C1q deficiency were identified. Restoration of C1q (via HSCT) is "protective" in the therapeutic sense but not a naturally occurring modifier.

Gene–environment interactions. UV exposure precipitating photosensitive mucocutaneous flares and infectious triggers of autoimmune activity are the principal gene–environment interactions; they operate on a fixed genetic background of absent clearance capacity.

3. Phenotypes

C1q deficiency produces a dual immunodeficiency–autoimmunity phenotype. Frequencies below derive chiefly from the international survey of 45 patients (PMID: 26119135):

Phenotype Type Frequency HPO suggestion
SLE / SLE-like disease Clinical syndrome 80% (36/45) HP:0002725 (Systemic lupus erythematosus)
Infections only (no SLE) Clinical 11% (5/45) HP:0002719 (Recurrent infections)
Asymptomatic — 9% (4/45) —
Photosensitive mucocutaneous rash Physical/sign Very common HP:0000992 (Photosensitivity); HP:0001025 (Urticaria)
Discoid lupus Physical Common HP:0005503 (Discoid lupus rash)
Oral ulcers Sign Common HP:0000155 (Oral ulcer)
Inflammatory polyarthritis Sign Common HP:0001369 (Arthritis)
Recurrent encapsulated-bacterial infection Clinical Common HP:0002721 (Immunodeficiency)
Lupus nephritis Clinical Subset (severe) HP:0000099 (Glomerulonephritis)
CNS involvement (incl. brain parenchymal calcification) Clinical/imaging Subset (severe) HP:0002518 (Periventricular calcification)
Absent CH50 with normal C3/C4 Lab abnormality Universal HP:0005339 (Abnormal complement system)

"Of these patients 36 (80%) suffer from SLE, of which 16 suffer from SLE and infections, 5 (11%) suffer from infections only and 4 (9%) have no symptoms." — PMID: 26119135

"All patients exhibited mucocutaneous involvement, discoid lupus erythematosus, inflammatory polyarthritis, normal serum complements C3 and C4, coarse-speckled Antinuclear antibody positivity." — PMID: 40556690

Characteristics. Onset is typically neonatal–childhood (case reports describe presentation as young as age 3; PMID: 42147803). Severity is variable but skews severe, with the most severe phenotype defined by renal and/or neurological involvement. Course is chronic with episodic lupus flares. Quality-of-life impact is substantial in severe cases (chronic immunosuppression, infection risk, renal/CNS morbidity), though formal EQ-5D/SF-36 data specific to C1q deficiency were not identified.

4. Genetic / Molecular Information

Causal genes. C1QA, C1QB, C1QC on chromosome 1p36.12 (HGNC: C1QA, C1QB, C1QC). Each encodes one chain of the C1q molecule; all three must co-assemble into A-B-C heterotrimers, six of which form the hexameric "bouquet of flowers" structure.

Variant spectrum. C1q deficiency arises from a diverse range of coding and non-coding loss-of-function variants:

Variant Gene Type Classification PMID
c.622C>T C1QA Nonsense Pathogenic 42147803
NM_001378156.1:c.263G>A C1QB Missense (novel) Likely pathogenic 40506420
Intronic, 2 nt before exon-2 splice site C1QB Non-coding / splice Pathogenic 25454803
Known A/B/C chain mutations (C1qA-Gln186, C1qB-Gly15, C1qB-Arg150, C1qC-Gly6, C1qC-Arg41) C1QA/B/C Nonsense/missense Pathogenic 18505047

A key mechanistic insight: the Dutch C1QB splice variant abolished C1qB mRNA, reduced C1qA mRNA, left C1qC mRNA normal, and caused intracellular absence of the C1qB peptide despite present C1qA/C1qC — demonstrating that loss of a single chain prevents hexamer assembly:

"Deep-sequencing revealed a homozygous mutation in the non-coding region of C1qB in the patient, whereas both parents were heterozygous. The mutation is located two nucleotides before the splice site of the second exon." — PMID: 25454803

"A novel homozygous likely pathogenic missense variant in the C1QB gene, NM_001378156.1:c.263G>A, was identified." — PMID: 40506420

Functional consequence: complete loss of function (null); recessive. Allele frequencies are extremely low (private/population-specific), consistent with an ultra-rare recessive disorder; heterozygous carriers are typically asymptomatic.

Somatic vs germline: germline. Modifier genes / epigenetics: no robustly established disease modifiers specific to C1q deficiency were identified, though autoantibody specificity stratifies organ involvement (see Diagnostics). Chromosomal abnormalities: not applicable — this is a single-gene point/small-variant disorder, not a structural/aneuploidy condition.

5. Environmental Information

  • Environmental factors. UV radiation precipitates the characteristic photosensitive cutaneous lupus; otherwise no specific toxin/occupational exposures are causally implicated.
  • Lifestyle factors. None specifically established beyond general SLE triggers.
  • Infectious agents. C1q deficiency does not have an infectious cause, but the deficiency increases susceptibility to encapsulated bacteria — Neisseria meningitidis, Streptococcus pneumoniae, Haemophilus influenzae — because the classical pathway contributes to opsonophagocytic defense (PMID: 19418946 discusses this susceptibility in hypocomplementemia generally). EBV is relevant to anti-C1q autoantibody biology in polygenic lupus but not to the genetic deficiency itself.

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation):

  1. Biallelic loss-of-function mutation in C1QA, C1QB, or C1QC (germline) leads to absence or non-functionality of one C1q chain.
  2. Missing chain prevents assembly of the A-B-C heterotrimer and therefore of the hexameric C1q molecule (demonstrated — intracellular chain studies, PMID: 25454803) → complete functional C1q deficiency.
  3. Absent C1q results in failure to initiate the classical complement pathway (no C1 complex formation) → absent CH50 with preserved C3/C4 (alternative/lectin pathways intact).
  4. Loss of C1q impairs opsonization and clearance of apoptotic cells and immune complexes (demonstrated in vivo; hierarchical role of classical-pathway proteins, PMID: 10934224).
  5. Uncleared apoptotic cells — a major source of nuclear autoantigens — accumulate (demonstrated: apoptotic bodies in glomeruli of C1q-KO mice, PMID: 10072632).
  6. Autoantigen exposure drives loss of tolerance → autoantibody formation (ANA, anti-dsDNA, and others) → immune-complex formation and tissue deposition.
  7. Branch A (autoimmunity): immune complexes deposit in kidney (lupus nephritis), skin, and brain → tissue injury → clinical SLE. Type I interferon dysregulation amplifies this arm (druggable; PMID: 42597478).
  8. Branch B (immunodeficiency): absent classical-pathway opsonization results in susceptibility to encapsulated-bacterial infection.
  9. Net clinical outcome: early-onset, often severe SLE (>90% penetrance) ± recurrent infection; severe renal/CNS involvement leads to ~20% childhood mortality.

Molecular pathways / cellular processes. Classical complement activation pathway (initiation step); apoptotic-cell clearance / efferocytosis; opsonophagocytosis; immune-complex processing; type I interferon signaling (downstream amplifier).

  • Suggested GO biological-process terms: GO:0006958 (complement activation, classical pathway); GO:0045087 (innate immune response); GO:0043277 (apoptotic cell clearance); GO:0006911 (phagocytosis, engulfment); GO:0034340 (response to type I interferon).
  • Suggested cell types (CL): CL:0000576 (monocyte) and CL:0000235 (macrophage) — the predominant C1q-producing and phagocytic cells; CL:0000236 (B cell, autoantibody production).

Protein dysfunction. C1q is a complex glycoprotein assembled from 18 polypeptide chains (6× A-B-C), each with an N-terminal collagen-like region and a C-terminal globular gC1q head mediating ligand recognition (PMID: 28601358; PMID: 29692784). In deficiency, the molecule is simply absent (loss of function), not misfolded-and-aggregated.

Immune system involvement. The disease sits at the intersection of immunodeficiency (failed opsonophagocytosis) and autoimmunity (failed clearance → autoantibodies). C1q additionally regulates cytokine production by antigen-presenting cells and T-cell maturation, and participates in CNS synaptic pruning — functions whose loss may contribute to the breadth of phenotype (PMID: 28601358).

"Apoptotic cells are thought to be a major source of the autoantigens of SLE, and impairment of their removal by complement may explain the link between hereditary complement deficiency and the development of SLE." — PMID: 10934224

7. Anatomical Structures Affected

  • Organ level (primary): skin (UBERON:0002097), kidney/glomerulus (UBERON:0002113 / UBERON:0000074), joints (UBERON:0001485), central nervous system / brain (UBERON:0000955).
  • Secondary / systems: immune/hematopoietic system (UBERON:0002405), mucous membranes (oral ulcers), and systemic involvement typical of SLE (cardiovascular, serosal).
  • Tissue/cell level: glomerular tissue (immune-complex deposition, apoptotic bodies); connective tissue/skin at the dermoepidermal junction; the key effector cells are monocytes/macrophages (CL:0000576 / CL:0000235), the main C1q source, and B lymphocytes producing autoantibodies.
  • Subcellular (GO Cellular Component): extracellular space/blood plasma (GO:0005615) where C1q normally circulates; GO:0005581 (collagen trimer) describes the collagen-like stalk of the assembled molecule.
  • Localization / laterality: manifestations (rash, nephritis, arthritis, cerebral calcification) are typically bilateral/systemic, consistent with a circulating-protein deficiency.

8. Temporal Development

  • Onset: congenital genetic lesion; clinical onset in infancy/early childhood is typical (cases as young as 3 years), making it a pediatric-onset monogenic lupus. Onset is usually insidious/chronic.
  • Progression: chronic, lifelong, with episodic (relapsing-remitting) lupus flares. Severity ranges from mild/manageable to treatment-resistant. A severe subset with renal/CNS disease progresses to organ failure.
  • Duration / outcome spread: highly variable. ~20% die before age 20, yet ≥50% reach middle age (PMID: 26119135).
  • Critical periods / intervention windows: early recognition is pivotal; HSCT is most beneficial before severe renal/neurological damage accrues, since those features predict worst transplant survival (PMID: 39470951).

9. Inheritance and Population

  • Inheritance pattern: Autosomal recessive. Parents of affected children are obligate heterozygous carriers (PMID: 25454803).
  • Penetrance: very high for SLE/SLE-like disease — >90% among genetically confirmed individuals (highest of any SLE susceptibility factor); a small minority (≈9%) remain asymptomatic, indicating penetrance is high but not absolute.
  • Expressivity: variable (mild-to-severe; organ involvement differs between patients).
  • Consanguinity: a major contributor; many pedigrees are consanguineous.
  • Founder effects / population distribution: private and population-specific variants reported across Middle Eastern (Iranian, Arab), European (Dutch, Swedish), Brazilian, and other cohorts; no single global founder allele. Carrier frequency is very low but elevated in consanguineous communities.
  • Epidemiology: ultra-rare; fewer than ~100 genetically confirmed patients described worldwide (international survey = 45 patients/31 families, PMID: 26119135; a review analyzed 69 genetically confirmed patients, PMID: 39470951). Precise population prevalence/incidence are not established.
  • Sex ratio / age distribution: predominantly pediatric onset; sex distribution not strongly skewed in the reported series (in contrast to polygenic SLE's female predominance).

10. Diagnostics

Screening / first-line laboratory signature (pathognomonic pattern): - CH50 (total hemolytic complement): absent / markedly reduced - C3 and C4: normal

This combination strongly points to an early-classical-pathway component deficiency and distinguishes monogenic C1q lupus from classic polygenic SLE (where C3/C4 are typically consumed/low).

"Laboratory evaluation showed strongly positive antinuclear antibody (ANA) and anti-SSA antibodies, with normal C3 and C4 levels but markedly reduced CH50." — PMID: 42147803

Confirmatory tests: - C1q protein quantitation (absent) and functional classical-pathway assays. - Western blot to document absent C1q chains; mononuclear-cell C1q mRNA expression studies can characterize the molecular defect (PMID: 26017655). - Genetic testing: whole-exome sequencing is high-yield and was diagnostic in multiple cases (PMID: 42147803); single-gene / targeted C1QA/B/C sequencing confirms the biallelic variant; deep/whole-genome sequencing is needed to catch non-coding splice variants (PMID: 25454803). Parental carrier testing confirms recessive segregation. - Autoantibodies: ANA (coarse-speckled), anti-dsDNA, anti-Ro/SSA, anti-RNP help characterize disease and stratify organ risk (below).

Differential diagnosis. Polygenic SLE (C3/C4 usually low; C1q present); other early-classical-pathway deficiencies (C1r/s, C4, C2 — milder hierarchy); acquired C1q lowering with anti-C1q antibodies (e.g., hypocomplementemic urticarial vasculitis [HUV], PMID: 40852710; acquired angioedema / C1-INH deficiency, PMID: 28687105). The critical distinction: in genetic C1q deficiency the antigen itself is absent, whereas anti-C1q autoantibody syndromes require present C1q.

Prognostic autoantibody stratification (within genetic C1q deficiency). In 69 genetically confirmed patients, autoantibody specificity mapped to organ involvement:

"we found that anti-Ro antibodies are associated with neurologic involvement, and anti-RNP and anti-DNA antibodies with renal [involvement]." — PMID: 39470951

Note on anti-C1q antibodies (adjacent biology). In polygenic SLE, circulating anti-C1q autoantibodies are the best single serological marker of lupus-nephritis activity (ROC AUC 0.929; NPV 92%; PMID: 41546370) and independently predict thrombosis in membranous LN (highest tertile HR 2.71; PMID: 41895528). These markers characterize polygenic SLE/HUV, not Mendelian C1q deficiency, and are included here only for differential-diagnostic completeness.

11. Outcome / Prognosis

  • Mortality: ~20% case fatality before age 20 in the largest phenotypic survey, with almost all deaths occurring before age 20 — yet outcomes are highly variable and at least half of patients survive into middle age.

"In total 9 (20%) of the C1q deficient individuals had died. All except for one died before the age of 20 years." — PMID: 26119135

  • Prognostic factors: presence of renal and/or neurological involvement defines the severe phenotype and predicts the worst survival after HSCT (OS 40% vs 84%; p=0.034; PMID: 39470951). Autoantibody profile (anti-Ro → neurologic; anti-RNP/anti-DNA → renal) provides a serological route to risk stratification.
  • Morbidity: chronic immunosuppression burden, infection susceptibility, cutaneous disfigurement (discoid lupus), arthritis, renal insufficiency, and CNS sequelae.
  • Recovery potential: autoimmune features can resolve completely after successful HSCT with restoration of C1q, allowing discontinuation of immunosuppression.

12. Treatment

Conventional SLE-directed therapy. Corticosteroids, hydroxychloroquine, and immunosuppressants (mycophenolate, cyclophosphamide, azathioprine, rituximab) are used for autoimmune manifestations and nephritis, as in polygenic SLE. These control but do not cure the underlying deficiency.

Type I interferon-targeted therapy. Anifrolumab (anti-IFNAR1 monoclonal antibody) produced marked benefit in a genetically confirmed C1QA-deficient child with refractory mucocutaneous lupus:

"She showed significant clinical improvement and full recovery of mucocutaneous lesions, restoration of laboratory parameters and successful discontinuation of corticosteroids after the seventh monthly infusion." — PMID: 42597478

This implicates the type I IFN pathway as a downstream, druggable amplifier distinct from C1q replacement.

Curative allogeneic HSCT. Because C1q is produced predominantly by monocytes/macrophages, allogeneic HSCT replaces the deficient cellular source and can cure the disorder:

"Complete donor chimerism has been maintained for 2 years after transplantation, leading to the restoration of C1q levels and the resolution of SLE symptoms. Normal C1q mRNA expression was observed in CD14 + cells." — PMID: 33000368

The largest cohort (EBMT Inborn Errors Working Party; 18 patients, 20 HSCTs, median age 10 y) quantified outcomes:

"Overall survival (OS) was 71% and event-free survival was 59% at two years... In eleven patients HSCT led to resolution of autoimmune features and discontinuation of immunosuppressive treatments... Patients with a severe autoimmune phenotype, defined as neurological and/or renal involvement, had the worst OS (40% vs 84%; p = 0.034)." — PMID: 39470951

The Karolinska experience similarly demonstrated cure in refractory cases but also transplant-related mortality (PTLD, GVHD), underscoring that HSCT should be considered early, before severe organ damage (PMID: 26516671; PMID: 24035158).

Supportive / preventive. Prophylactic/therapeutic antibiotics and vaccination against encapsulated bacteria (pneumococcus, meningococcus, H. influenzae type b) address the infection-susceptibility arm.

Investigational / theoretical. Recombinant human C1q has been produced and is functional in vitro (PMID: 33621564), raising the prospect of C1q protein-replacement therapy, though no clinical replacement product is established. Gene therapy is conceptually attractive but not clinically available.

Suggested NCIT intervention terms: anifrolumab; allogeneic hematopoietic stem cell transplantation; corticosteroid therapy; rituximab; hydroxychloroquine; mycophenolate mofetil; cyclophosphamide.

13. Prevention

  • Primary prevention: none for the genetic lesion itself. Genetic counseling for consanguineous and carrier families; carrier screening and prenatal/preimplantation genetic testing are options once a familial variant is known.
  • Secondary prevention: early recognition via the CH50-absent/normal-C3-C4 signature in any child with early-onset lupus and/or recurrent infection, enabling timely genetic confirmation and consideration of HSCT before severe organ damage.
  • Tertiary prevention: vaccination against encapsulated bacteria; infection prophylaxis; vigilant monitoring/treatment of nephritis and CNS disease to prevent irreversible organ damage.
  • Counseling: recessive recurrence risk (25% per pregnancy for carrier couples); cascade testing of relatives.

14. Other Species / Natural Disease

  • Model-relevant taxonomy: Mus musculus (NCBI Taxon:10090) is the principal experimental species. C1q genes are conserved across vertebrates, and the gC1q domain has an ancient evolutionary history conserved from bacteria to mammals (PMID: 24400480).
  • Orthologous genes: murine C1qa, C1qb, C1qc.
  • Natural disease in other species: no well-characterized spontaneous companion-animal/wildlife C1q-deficiency disease was identified in this investigation; the evidence base is dominated by engineered mouse models rather than naturally occurring animal disease. (OMIA/veterinary entries were not confirmed here.)
  • Zoonotic potential: not applicable (non-infectious genetic disorder).

15. Model Organisms

  • Principal model: the gene-targeted C1q-knockout mouse (C1qa-deficient), which recapitulates the central human mechanism:

"C1q-deficient mice, generated by gene targeting, showed an increased mortality and 25% of the mice had histological evidence of glomerulonephritis characterised by multiple apoptotic cell bodies and immune deposits... These observations are compatible with the hypothesis that C1q deficiency causes autoimmunity by an impaired clearance of apoptotic cells." — PMID: 10072632

  • Phenotype recapitulation: strong — high-titer antinuclear antibodies in ~50% of animals, immune-complex glomerulonephritis in ~25%, and accumulation of apoptotic bodies in diseased glomeruli, directly modeling the human "clearance-deficiency → autoimmunity" axis (PMID: 9777411).
  • Limitations: murine lupus is background-dependent and does not fully reproduce the human severity spectrum, CNS calcification, or infection phenotype; penetrance is lower than in humans.
  • In vitro systems: recombinant human C1q production in HEK293-F cells enables structure–function and potential replacement-therapy studies (PMID: 33621564); patient CD14+ monocyte cultures document the cellular C1q-production defect and its correction post-HSCT (PMID: 33000368; PMID: 26017655).

Mechanistic Model / Interpretation

  Biallelic LOF mutation (C1QA / C1QB / C1QC, 1p36.12, autosomal recessive)
                 |
                 v
Missing chain -> hexameric C1q fails to assemble (DEMONSTRATED)
                 |
                 v
     Complete functional C1q deficiency -> no classical-pathway initiation
                 |
  +----------------------+----------------------+
  |                                             |
  v (AUTOIMMUNITY ARM)                          v (IMMUNODEFICIENCY ARM)
  Impaired clearance of apoptotic                Impaired opsonophagocytosis
  cells + immune complexes                       of encapsulated bacteria
  |                                             |
  v                                             v
  Nuclear-autoantigen accumulation              Recurrent invasive infection
  (apoptotic bodies, DEMONSTRATED in mice)      (N. meningitidis, S. pneumoniae,
  |                                       H. influenzae)
  v
  Loss of tolerance -> autoantibodies
  (ANA, anti-dsDNA, anti-Ro, anti-RNP)
  |
  v
  Immune-complex deposition (kidney, skin, brain)
  + TYPE I IFN amplification (druggable: anifrolumab)
  |
  v
  >90% develop early-onset SLE; severe renal/CNS disease -> ~20% childhood mortality
  |
  v
  CURE: allogeneic HSCT restores monocyte-derived C1q (OS 71%; worse if renal/CNS)

Laboratory signature table (diagnostic discriminator):

Marker Genetic C1q deficiency Classic polygenic SLE
CH50 Absent / markedly low Variable (often low in flare)
C3 Normal Often low (consumed)
C4 Normal Often low (consumed)
C1q antigen Absent Present (may be lowered by anti-C1q Ab)
Anti-C1q antibodies N/A (no antigen) Present; marks LN activity

The unifying concept is that C1q sits at the apex of a clearance hierarchy: the earlier in the classical pathway the deficiency, the more severe the lupus. C1q deficiency, being the most upstream, produces the most penetrant and severe disease (PMID: 10934224). Crucially, because the deficient protein is hematopoietically produced (monocyte/macrophage), the disorder is uniquely curable by HSCT — a rare instance of a monogenic autoimmune disease with a definitive cellular cure.

Evidence Base

PMID Role Key contribution
10934224 Supports F001, F002, F009 Establishes C1q as apex of the classical-pathway severity hierarchy; links apoptotic clearance to SLE
10072632 Supports F002, F009 C1q-KO mouse: glomerulonephritis + apoptotic bodies → mechanistic proof
9777411 Supports mechanism Reviews immune-complex/apoptosis hypothesis; murine ANA data
26119135 Supports F004, F009 Largest phenotype survey (45 pts): 80% SLE, 20% mortality
40556690 Supports F004 Case series: mucocutaneous/arthritis phenotype, normal C3/C4
42147803 Supports F006, diagnostics C1QA nonsense variant; CH50-low/normal-C3-C4 diagnostic pattern; WES utility
40316395 Supports F001 Confirms AR inheritance & three causal genes; consanguineous siblings
25454803 Supports F006 Non-coding splice variant; chain-assembly dependence; AR segregation
40506420 Supports F006 Novel C1QB missense (c.263G>A), expands spectrum
26017655 Supports genetics/diagnostics C1q mRNA expression studies in juvenile SLE
39470951 Supports F003, F008 EBMT HSCT cohort: OS 71%; severe-phenotype OS 40% vs 84%; autoantibody-organ mapping
33000368 Supports F003 HSCT restores CD14+ C1q production, resolves SLE
26516671 Supports F003 Karolinska HSCT cures; documents transplant risks
24035158 Supports F003 Early report of HSCT cure
42597478 Supports F005 Anifrolumab efficacy → type I IFN as downstream target
33621564 Supports treatment outlook Functional recombinant human C1q → replacement-therapy prospect
28601358 / 29692784 / 24400480 Background C1q structure (18 chains, gC1q head), multifunctionality, evolutionary conservation
19418946 Supports infection arm Hypocomplementemia → encapsulated-bacterial infection risk
41546370 / 41895528 Supports F007 (adjacent) Anti-C1q antibodies mark LN activity / predict thrombosis (polygenic SLE)
41929519 Differential/adjacent EBV mimicry induces pathogenic anti-C1q in lupus-prone mice
40852710 / 28687105 Differential dx HUV and acquired C1-INH deficiency (distinguish from genetic C1q loss)

Limitations and Knowledge Gaps

  1. Small-N evidence base. The disorder is ultra-rare; the largest datasets are a 45-patient survey and an 18-patient HSCT cohort. Prevalence/incidence are not formally established, and frequency estimates carry wide uncertainty.
  2. Anti-C1q antibody confound. Much of the richest "C1q" literature concerns acquired anti-C1q autoantibodies in polygenic SLE/HUV — biologically distinct from genetic deficiency (antigen absent vs present). Care is needed to avoid conflating the two; this report flags the distinction explicitly (Finding F007).
  3. Modifier genetics and epigenetics underlying the variable expressivity/penetrance (~9% asymptomatic) are essentially unknown.
  4. Quality-of-life and natural-history data specific to C1q deficiency are sparse; no validated EQ-5D/SF-36 datasets were identified.
  5. No naturally occurring animal disease was confirmed; comparative pathology rests on engineered mouse models with incomplete phenotype recapitulation.
  6. Replacement therapy remains preclinical; recombinant C1q is functional in vitro but untested clinically.
  7. Causal statements for the apoptotic-clearance mechanism are strongest in mice; the human causal chain from clearance failure to specific organ involvement is inferred from concordant (not interventional) human data.

Proposed Follow-up Experiments / Actions

  1. International registry & natural-history study to firm up prevalence, penetrance, organ-involvement frequencies, and long-term survival with standardized phenotyping (and QoL instruments).
  2. Prospective HSCT-timing trial/registry testing the hypothesis that transplanting before renal/CNS involvement improves OS beyond the current 71% — directly actionable given the 40% vs 84% split.
  3. Biomarker-guided risk stratification: validate the autoantibody→organ map (anti-Ro→CNS; anti-RNP/anti-dsDNA→renal) prospectively to guide early intervention/transplant decisions.
  4. Recombinant C1q replacement therapy: advance functional recombinant C1q (PMID: 33621564) toward pharmacokinetic/efficacy studies in C1q-KO mice, then first-in-human trials — a non-transplant option for patients ineligible for HSCT.
  5. Type I IFN pathway characterization: systematically measure IFN signatures across the C1q-deficient cohort to define which patients benefit from anifrolumab, building on the index case (PMID: 42597478).
  6. Gene-therapy feasibility: evaluate monocyte/HSC-directed gene addition or editing of C1QA/B/C as a less toxic alternative to allogeneic HSCT.
  7. Deep/whole-genome sequencing adoption in diagnostic workflows to capture non-coding splice variants that panels/WES may miss (PMID: 25454803).

Evidence source legend: human clinical (case reports/series, cohorts, surveys), model organism (C1q-KO mouse), in vitro (recombinant C1q, patient monocyte cultures). This report synthesizes 9 confirmed findings across 32 reviewed papers.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 26
Resolved 26
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 26
On topic 18
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 30
Resolved 26
Unresolved (possible confabulation) 1
Obsolete 1
Unverifiable 2
Terms whose name was checked 18
Terms named correctly 14
Terms named as a different term 0
Terms whose name is worth a second look 4

Unresolved terms

These identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:

  • HP:0005503 (1 mention), reported as "Discoid lupus rash" - HP does not contain this term

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • GO:0005615 (obsolete extracellular space) (1 mention) - replaced by GO:0005576

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • HP:0002518 (1 mention) - the report calls it "Periventricular calcification"; HP calls it Abnormal periventricular white matter morphology, and lists "Periventricular white matter abnormalities" among its other names
  • HP:0005339 (1 mention) - the report calls it "Abnormal complement system"; HP calls it Abnormality of complement system
  • CL:0000236 (1 mention) - the report calls it "B cell, autoantibody production"; CL calls it B cell
  • UBERON:0002405 (1 mention) - the report calls it "Secondary / systems: immune/hematopoietic system"; UBERON calls it immune system**

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, Taxon.