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Inheritance

1

Autosomal recessive HP:0000007

Symptomatic individuals reported to date carry the FCGR3A L66H substitution in the homozygous state, and heterozygous relatives have not been described as affected, so inheritance is recorded as autosomal recessive. That recording should be read with the penetrance caveat: homozygosity is common in the general population and at least one homozygote is clinically well, so homozygosity is not by itself sufficient for disease. The common FCGR3A V158F polymorphism that modulates ADCC is a separate allele with a different functional consequence and should not be conflated with L66H.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:8608639 SUPPORT Human Clinical

"homozygous for a T to A substitution at position 230 of CD16-II cDNA, predicting a Leu(66) to His(66) change in the first immunoglobulin domain"

Establishes the homozygous state of the FCGR3A allele in the index patient.

PMID:34448085 SUPPORT Human Clinical

"The higher frequency in some populations suggests that the L66H variant alone is not sufficient to cause disease directly but instead may act as a risk factor with low disease penetrance."

Qualifies the recessive model, proposing low-penetrance risk rather than simple recessive causation.

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Discussions and Knowledge Gaps

3

Is homozygous FCGR3A L66H sufficient to cause immunodeficiency, or is it a low-penetrance risk factor that has been over-attributed?

CONTROVERSY OPEN l66h_pathogenicity_disputed

Attached to

genetic#FCGR3A pathophysiology#Deficient Spontaneous NK Cell Cytotoxicity

The four published homozygotes do not agree. Two had reduced spontaneous cytotoxicity with severe viral disease. A third had recurrent viral infection and a difficult course after BCG, Epstein-Barr and varicella zoster, yet formal testing showed normal spontaneous cytotoxicity and normal ADCC, and that report explicitly asked whether the genotype is causally related to NK deficiency. A fourth, found on newborn screening, is clinically well with normal NK lytic function and normal CD56-bright / CD56-dim distribution; her lymphopenia was traced to a 22q11.2 deletion. Population data are the strongest argument against simple causation: the allele sits near 5% frequency overall, with roughly a hundred homozygotes in gnomAD. A fully penetrant recessive immunodeficiency allele cannot be that common. The 2021 report concludes the variant is unlikely to be a direct genetic cause and proposes low-penetrance risk instead. Ascertainment is the obvious confounder in both directions: the affected patients were found because they were ill, and the well homozygote was found because of an unrelated screen. What would settle it is a systematic NK-function study of unselected homozygotes, which nobody has published. Until then this entry records the mechanism that was measured in affected patients without asserting that the genotype produces it in everyone.

Is reduced circulating NK cell number a feature of CD16 deficiency, a flow cytometry artifact, or neither?

CONTROVERSY OPEN nk_cytopenia_inconsistent

Attached to

phenotypes#Reduced total natural killer cell count

Three mechanisms are in play and they should not be collapsed. First, a genuine artifact. Because L66H abolishes the B73.1 epitope, a panel that gates NK cells as CD3-negative, CD56-positive AND CD16-positive scores an L66H homozygote as having almost no NK cells, while the same blood gated on CD3-negative, CD56-positive gives a normal count. That is exactly what happened in the newborn-screening case: under one gate NK cells were absent, under another they were 26%. The 1996 report predicted this, warning that combining CD16 and CD56 antibodies on the same fluorochrome would leave these homozygotes undiagnosed. Second, and importantly, this does not explain the index patient. Jawahar gated on CD56-positive, CD3-negative cells without CD16, so the reduced count reported there is not the artifact and remains unexplained. Treating the artifact as a blanket dismissal would be wrong. Third, the second and fourth patients had normal NK numbers outright. The practical consequence is that NK lymphopenia is not usable as a screening criterion for this entity, and that any reported NK count for an L66H homozygote has to be read together with the gating strategy that produced it.

Does the CD16-CD2 cytotoxicity defect account for the viral susceptibility, or is spontaneous cytotoxicity only one contributor?

KNOWLEDGE GAP OPEN cytotoxicity_to_viral_susceptibility_gap

Attached to

pathophysiology#Impaired Control of Herpesvirus and Papillomavirus Infection

The step from a measurable in vitro cytotoxicity deficit to severe, persistent EBV, VZV and HPV disease in vivo is asserted on plausibility and on the known role of NK cells in herpesvirus control, not demonstrated. No reported patient has had NK-specific reconstitution, there is no animal model of the L66H allele, and the quantitative contribution of this pathway to viral control in humans is unmeasured. The two homozygotes added in review widen this gap rather than narrowing it, and in opposite directions. One had a severe viral course - recurrent respiratory infection, a difficult course after BCG vaccination, and severe problems with Epstein-Barr and varicella zoster - while his spontaneous cytotoxicity and ADCC were both normal, so a comparable clinical picture arose without the mechanism this entry proposes. The other has the genotype, normal cytotoxicity, and no disease at all. Any account of how the cytotoxicity defect produces the infection phenotype now has to explain both.

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Pathophysiology

7

FCGR3A L66H Substitution

A homozygous T-to-A transversion at position 230 of the FCGR3A coding sequence replaces leucine 66 with histidine in the first (membrane-distal) immunoglobulin-like domain of CD16. The receptor is still made and still reaches the NK cell surface; the lesion is confined to the local conformation of one surface loop.

CD16-positive, CD56-dim natural killer cell CL:0000939

Genetic context FCGR3A hgnc:3619 variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: PARTIAL_LOSS_OF_FUNCTION

c.230T>A, p.Leu66His. Structural modelling of the mutant against the solved wild-type CD16 ectodomain predicts a shift in the B73.1 epitope loop with the overall fold otherwise preserved, consistent with selective loss of one function (spontaneous cytotoxicity) while Fc binding and ADCC are retained. It is therefore recorded as a partial, function-specific loss rather than a null allele.

Downstream

Loss of the CD16 B73.1 Conformational Epitope The substitution sits within the B73.1 recognition site, so the epitope is lost as a direct structural consequence of the amino-acid change.

Show evidence (1 reference)

PMID:8608639 SUPPORT Human Clinical

"homozygous for a T to A substitution at position 230 of CD16-II cDNA, predicting a Leu(66) to His(66) change in the first immunoglobulin domain"

Defines the causal variant at nucleotide and amino-acid level and localises it to the membrane-distal immunoglobulin domain.

Loss of the CD16 B73.1 Conformational Epitope

Patient NK cells are stained normally by the anti-CD16 antibody 3G8, which binds elsewhere on the receptor, but are not recognised by B73.1. CD16 is therefore present on the surface with a locally altered membrane-distal face. This is the structural pivot of the disease: it is what separates the arm of CD16 function that fails from the arm that does not.

CD16-positive, CD56-dim natural killer cell CL:0000939

Downstream

Failure of CD16-CD2 Association The altered face is the surface through which CD16 partners with CD2, so losing it abolishes the association.

Show evidence (1 reference)

PMID:8608639 SUPPORT Human Clinical

"which was not reactive with the anti-CD16-II MoAb B73.1"

Documents loss of the B73.1 epitope on patient NK cells while the receptor itself remains detectable.

Failure of CD16-CD2 Association

In healthy NK cells CD16 associates biochemically with CD2, a coactivation receptor, and the two co-cluster at the lytic immunological synapse, so that engaging CD2 elicits CD16 signalling. The L66H receptor does not enter this association, and CD2 ligation no longer triggers CD16 signalling. Note that the synapse still forms; what fails is the CD16-CD2 partnership within it.

CD16-positive, CD56-dim natural killer cell CL:0000939

cell adhesion molecule binding GO:0050839 ↓ DECREASED

Experimental models

NK-92 cells stably expressing CD16 L66H CELL LINE Expressing the patient allele in a CD16-null human NK line reproduced the loss of CD16-CD2 association and the loss of CD16 signalling after CD2 ligation.

Downstream

Reduced CD2 Surface Expression on CD56-dim NK Cells

Deficient Spontaneous NK Cell Cytotoxicity Loss of CD16-dependent costimulation through CD2 is the proximate cause of the natural-cytotoxicity defect.

Show evidence (2 references)

PMID:23006327 SUPPORT In Vitro

"An association between CD16 and CD2 was identified biochemically and at the immunological synapse, which elicited CD16 signaling after CD2 engagement."

Establishes the wild-type CD16-CD2 partnership. Graded partial because it documents the normal association rather than its failure; the item below carries the failure.

PMID:23006327 SUPPORT In Vitro

"Stable expression of CD16 L66H in NK-92 cells recapitulated the patient phenotype, abrogating association of CD16 with CD2 as well as CD16 signaling after CD2 ligation."

Shows that introducing the patient allele alone is sufficient to abolish the association, which is what makes this step causal rather than correlative.

Reduced CD2 Surface Expression on CD56-dim NK Cells

Patient NK cells carry less surface CD2 than controls, and the reduction is restricted to the CD56-dim, CD16-positive subset - CD2 levels on the CD16-negative CD56-bright subset are unaffected. The compartment-restricted pattern is the argument that the CD2 loss is downstream of mutant CD16 rather than an independent trait, since it appears only where the mutant receptor is expressed.

CD16-positive, CD56-dim natural killer cell CL:0000939 CD16-negative, CD56-bright natural killer cell CL:0000938

Show evidence (3 references)

PMID:23006327 SUPPORT Human Clinical

"Patients with the L66H mutation had intact ADCC, but deficient spontaneous NK cell cytotoxicity and decreased surface expression of CD2, a coactivation receptor."

Documents the reduced CD2 surface expression in both reported patients alongside the dissociated cytotoxicity phenotype.

PMID:23006327 SUPPORT Human Clinical

"The decrease in CD2 surface expression on cells of patient 1 was limited to CD56 dim NK cells, which were primarily CD16"

The positive half of the subset restriction, which the abstract sentence does not carry. The CD2 decrease is confined to the subset that expresses the mutant receptor.

PMID:23006327 SUPPORT Human Clinical

"as CD2 expression on CD16–CD56bright NK cells was equivalent in patient 1 and the control"

The negative half of the same contrast. CD2 is unaffected on the CD16-negative CD56-bright subset, and it is the pairing of the two halves that makes this the argument that the CD2 loss follows the mutant receptor.

Preserved IgG Fc Binding and ADCC

Antibody-dependent cellular cytotoxicity is intact in patient cells, measured against antibody-coated targets. The Fc-binding surface is not part of the loop altered by L66H, which is why this arm of CD16 function survives while the CD2 partnership does not. A deliberate negative node. It records a function that is retained, which is unusual for a pathophysiology graph but necessary here: the selectivity of the defect is the mechanistic claim, and a graph showing only the failing arm would misrepresent the disease as a general NK deficiency. Nothing points downstream into it, because preservation is the absence of an effect rather than something the epitope loss causes, and the available causal link types would export such an edge as a causal arrow.

CD16-positive, CD56-dim natural killer cell CL:0000939

antibody-dependent cellular cytotoxicity GO:0001788

IgG binding GO:0019864

Show evidence (1 reference)

PMID:8608639 SUPPORT Human Clinical

"Spontaneous NK cell activity of the patient's peripheral blood mononuclear cells (PBMC) was markedly decreased, while antibody-dependent cellular cytotoxicity (ADCC) was unaffected."

Reports preserved ADCC in the index patient in the same assay series that showed loss of spontaneous killing.

Deficient Spontaneous NK Cell Cytotoxicity

Antibody-independent killing of susceptible target cells is markedly reduced in patient peripheral blood mononuclear cells. Because ADCC is preserved in the same cells, the defect is specific to the natural-cytotoxicity programme rather than to the lytic machinery as a whole - granule content and degranulation capacity are not the failing step.

CD16-positive, CD56-dim natural killer cell CL:0000939

natural killer cell mediated cytotoxicity GO:0042267 ↓ DECREASED

Experimental models

NK-92 cells stably expressing CD16 L66H CELL LINE Wild-type CD16 expression raised CD2 surface levels and conferred killing of a melanoma target that CD16-deficient NK-92 cells do not lyse, establishing a CD16 contribution to antibody-independent killing. The complementary loss with the L66H allele is shown for the association and signalling steps rather than as a matched cytotoxicity measurement against the same target, so the link to the cytotoxicity node is one step less direct than for the association node.

Downstream

Impaired Control of Herpesvirus and Papillomavirus Infection Natural cytotoxicity is a principal early defence against virus-infected cells, so its selective loss maps onto the observed infection spectrum. This step is inferred from the known role of NK cells rather than measured, and two homozygotes with normal cytotoxicity show it is not deterministic in either direction.

Decreased NK cell-induced killing of target cells The node's clinical measurement, tying the mechanism to the phenotype it is observed as.

Show evidence (4 references)

PMID:8608639 SUPPORT Human Clinical

"Spontaneous NK cell activity of the patient's peripheral blood mononuclear cells (PBMC) was markedly decreased, while antibody-dependent cellular cytotoxicity (ADCC) was unaffected."

Direct measurement of the reduced spontaneous cytotoxicity that defines the disease.

PMID:23006327 SUPPORT In Vitro

"Thus, CD16 serves a role in NK cell-mediated spontaneous cytotoxicity through a specific association with CD2 and represents a potential mechanism underlying a human congenital immunodeficiency."

States the mechanistic conclusion linking the CD16-CD2 association to spontaneous cytotoxicity and to this immunodeficiency.

PMID:8874200 REFUTE Human Clinical

"NK cell function, analyzed in vitro by direct cytotoxicity on K562 target cells and ADCC-activity on P815 target cells, was normal compared with an age-matched healthy control."

A homozygote in whom spontaneous cytotoxicity was normal. The defect is therefore not universal among carriers of the genotype, which is why this node is graded provisional.

+ 1 more reference

Impaired Control of Herpesvirus and Papillomavirus Infection

In affected individuals the clinical consequence is unusually severe, persistent or recurrent disease with herpesviruses - herpes simplex virus in the index patient, Epstein-Barr virus and varicella zoster virus in others - and with human papillomavirus, against an otherwise normal immunological assessment. One homozygote also had a difficult course after BCG vaccination. The narrowness of the infection spectrum - viral rather than pyogenic or opportunistic-fungal - is consistent with a lesion confined to NK natural cytotoxicity rather than a combined immunodeficiency.

Downstream

Recurrent viral infections The clinical manifestation by which this node is recognised.

Show evidence (2 references)

PMID:23006327 SUPPORT Human Clinical

"A homozygous missense mutation in CD16 (encoding a L66H substitution) is associated with severe herpesvirus infections in rare patients."

Links the genotype to the severe herpesvirus phenotype at the level of the clinical syndrome.

PMID:8608639 SUPPORT Human Clinical

"We have identified a child with recurrent infections, especially with herpes simplex virus, who had a decreased number of CD56(+)CD3(-) NK cells in circulation."

Reports the herpes simplex-predominant infection history of the index patient.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

4

Decreased NK cell-induced killing of target cells Immunological HP:0025808

Show evidence (1 reference)

PMID:8608639 SUPPORT Human Clinical

"Spontaneous NK cell activity of the patient's peripheral blood mononuclear cells (PBMC) was markedly decreased, while antibody-dependent cellular cytotoxicity (ADCC) was unaffected."

Reports the reduced spontaneous killing that this phenotype term captures.

Recurrent viral infections Immunological HP:0004429

Show evidence (1 reference)

PMID:23006327 SUPPORT Human Clinical

"A homozygous missense mutation in CD16 (encoding a L66H substitution) is associated with severe herpesvirus infections in rare patients."

Documents the severe viral infection phenotype associated with the genotype.

Recurrent herpes Immunological HP:0005353

Show evidence (1 reference)

PMID:8608639 SUPPORT Human Clinical

"We have identified a child with recurrent infections, especially with herpes simplex virus, who had a decreased number of CD56(+)CD3(-) NK cells in circulation."

Reports recurrent herpes simplex virus infection in the index patient.

Reduced total natural killer cell count OCCASIONAL Immunological HP:0040218

Show evidence (1 reference)

PMID:8608639 SUPPORT Human Clinical

"We have identified a child with recurrent infections, especially with herpes simplex virus, who had a decreased number of CD56(+)CD3(-) NK cells in circulation."

Reports the reduced circulating NK cell number in the index patient.

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Genetic Associations

1

FCGR3A (FCGR3A encodes CD16a (Fc-gamma receptor IIIA), the low-affinity IgG Fc receptor expressed on CD56-dim natural killer cells, where it is the triggering receptor for antibody-dependent cellular cytotoxicity. The candidate allele is a single germline missense substitution in the membrane-distal immunoglobulin domain, carried homozygously. Because the receptor is still expressed and still binds Fc, it is a function-specific partial loss rather than a null. The relationship is recorded as DISPUTED rather than CAUSATIVE. Two homozygotes have a measured spontaneous-cytotoxicity defect, but a third had normal cytotoxicity and normal ADCC, a fourth is asymptomatic with normal NK lytic function, and the allele reaches roughly 5% frequency with about a hundred homozygotes in gnomAD. The most recent report concludes the variant is unlikely to be a direct genetic cause and proposes it as a low-penetrance risk factor instead. Curators should not treat an L66H homozygous genotype as diagnostic on its own.)

Gene: FCGR3A hgnc:3619 relationship_type: DISPUTED variant_origin: GERMLINE

Show evidence (3 references)

PMID:23006327 SUPPORT Human Clinical

"A homozygous missense mutation in CD16 (encoding a L66H substitution) is associated with severe herpesvirus infections in rare patients."

Associates the homozygous FCGR3A L66H allele with the clinical immunodeficiency in the affected patients.

PMID:34448085 REFUTE Human Clinical

"this case report highlights that the L66H variant is unlikely a direct genetic cause of NK cell dysfunction."

The most recent assessment of the allele, and the reason this gene-disease relationship is recorded as disputed.

PMID:8874200 SUPPORT Human Clinical

"Further analysis of the NK cell function in vitro and follow-up of the clinical course of Fc gamma RIIIA-48H/H homozygotes is required to ascertain whether this genotype is causally related to an NK cell immunodeficiency."

The original pathogenicity caveat, raised in 1996 and not since resolved.

Variants (1)

FCGR3A L66H (reported as c.230T>A, c.197T>A, or p.L48H) Uncertain Significance

The single allele reported in every described case. It disrupts the B73.1 monoclonal antibody epitope while leaving the 3G8 epitope and Fc binding intact. Recorded as of uncertain significance rather than pathogenic: about a hundred homozygotes appear in gnomAD, which is incompatible with a fully penetrant recessive immunodeficiency allele.

Show evidence (3 references)

PMID:8608639 SUPPORT Human Clinical

"homozygous for a T to A substitution at position 230 of CD16-II cDNA, predicting a Leu(66) to His(66) change in the first immunoglobulin domain"

Defines the variant at nucleotide and amino-acid level in the index patient.

PMID:34448085 REFUTE Human Clinical

"it is observed in 7.1% of alleles of European ancestry including 68 homozygotes, and a population frequency of about 5.0% including 100 homozygotes in overall populations"

Population frequency incompatible with a fully penetrant pathogenic recessive allele; the basis for grading this variant uncertain rather than pathogenic.

PMID:34448085 SUPPORT Human Clinical

"the study of a cohort of 346 children found that only 12 had loss of the B73.1 epitope, a lower frequency than reported by gnomAD"

A directly measured cohort frequency lower than the gnomAD estimate. Graded partial because it qualifies the population argument rather than simply supporting it - the allele remains far too common for full penetrance, but gnomAD may overstate how common.

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Diagnosis

3

Flow cytometry with paired anti-CD16 clones

The flow signature is a discordance between two anti-CD16 antibodies on the same cells: NK cells stain normally with clone 3G8 but are not recognised by clone B73.1. A panel using only one anti-CD16 clone will report CD16 as normally expressed and miss the finding entirely, which is the practical reason this entity is under-recognised. It is a screening signal, not a diagnostic one. Loss of the B73.1 epitope can occur independently of the L66H substitution, so the discordance has to be confirmed by sequencing rather than treated as sufficient.

Show evidence (2 references)

PMID:8608639 SUPPORT Human Clinical

"which was not reactive with the anti-CD16-II MoAb B73.1"

Establishes the selective loss of B73.1 reactivity that the paired-clone approach detects.

PMID:34448085 SUPPORT Human Clinical

"loss of B73.1 epitope detection should always be combined with Sanger sequencing to confirm the presence of the L66H allele if it is suspected."

Establishes that the flow discordance is not specific to L66H and must be confirmed genetically; graded partial because it qualifies the test rather than supporting it.

Paired spontaneous cytotoxicity and ADCC assays

Measuring natural cytotoxicity against a susceptible target and ADCC against an antibody-coated target in the same sample demonstrates the dissociation that defines the disease. Either assay alone is uninformative: a normal ADCC result does not exclude the diagnosis, and a low natural-cytotoxicity result alone does not distinguish it from other NK functional defects.

Show evidence (1 reference)

PMID:23006327 SUPPORT Human Clinical

"Patients with the L66H mutation had intact ADCC, but deficient spontaneous NK cell cytotoxicity and decreased surface expression of CD2, a coactivation receptor."

Reports the paired assay result in both patients that the diagnostic approach depends on.

FCGR3A sequencing

Sanger sequencing of FCGR3A demonstrates the homozygous L66H substitution. Finding it is necessary but not sufficient: the allele is common, roughly a hundred homozygotes appear in gnomAD, and at least one homozygote is clinically well, so the genotype does not establish the diagnosis on its own and must be read alongside the paired functional assays and the clinical picture. There is also a practical retrieval problem - a filtered exome or panel pipeline may discard the variant as too common to report. Interpretation must additionally keep this allele distinct from the common FCGR3A V158F functional polymorphism and from FCGR3B copy-number variation, neither of which causes this syndrome.

Show evidence (2 references)

PMID:34448085 SUPPORT Human Clinical

"NGS may not report the L66H variant because it is observed in 7.1% of alleles of European ancestry"

Documents the filtering pitfall by which a standard rare-variant pipeline misses the allele entirely.

PMID:8608639 SUPPORT Human Clinical

"homozygous for a T to A substitution at position 230 of CD16-II cDNA, predicting a Leu(66) to His(66) change in the first immunoglobulin domain"

Identifies the confirmatory sequencing finding.

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Prevalence

1

Worldwide

Cases In Literature Ultra Rare

Four homozygotes have been described in the literature: the 1996 index patient, a second 1996 patient with normal cytotoxicity, the 2012 patient, and a 2021 asymptomatic newborn-screening case. The band applies to the clinical syndrome, not to the genotype - homozygosity for L66H is common, with roughly a hundred homozygotes recorded in gnomAD, so the rarity here is the rarity of being reported as affected rather than the rarity of carrying the allele.

Show evidence (1 reference)

PMID:34448085 SUPPORT Human Clinical

"it is observed in 7.1% of alleles of European ancestry including 68 homozygotes, and a population frequency of about 5.0% including 100 homozygotes in overall populations"

Gives the population frequency that separates genotype frequency from the rarity of the reported syndrome.

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Experimental Models

1

NK-92 cells stably expressing CD16 L66H CELL_LINE

The immortalised human NK cell line NK-92, which lacks endogenous CD16, was reconstituted with either wild-type CD16 or the patient L66H allele. This is the experiment that converts the patient observation into a mechanism: it isolates the single substitution from the rest of the patients' genetic background.

Organism

human NCBITaxon:9606

Publication

PMID:23006327

Pathograph links

Failure of CD16-CD2 Association recapitulates fidelity: moderate Expressing the patient allele in a CD16-null human NK line reproduced the loss of CD16-CD2 association and the loss of CD16 signalling after CD2 ligation.

Limitations: NK-92 is a transformed, IL-2-dependent NK lymphoma line rather than a primary NK cell, and the reconstituted receptor is expressed from a transgene rather than at endogenous locus and copy number. It also cannot report on NK development, so it speaks to receptor function and not to the NK cytopenia seen in the index patient.

Readouts

CD16-CD2 biochemical association

Direction: ABOLISHED

Interpretation: The association present with wild-type CD16 is not formed by the L66H receptor, placing the substitution upstream of the partnership.

Show evidence (1 reference)

PMID:23006327 SUPPORT In Vitro

"Stable expression of CD16 L66H in NK-92 cells recapitulated the patient phenotype, abrogating association of CD16 with CD2 as well as CD16 signaling after CD2 ligation."

Reports the abolished association and abolished CD2-triggered CD16 signalling in the reconstituted line.

Show evidence (1 reference)

PMID:23006327 SUPPORT In Vitro

"Stable expression of CD16 L66H in NK-92 cells recapitulated the patient phenotype, abrogating association of CD16 with CD2 as well as CD16 signaling after CD2 ligation."

Supports treating this reconstituted line as informative for the CD16-CD2 association node.

Deficient Spontaneous NK Cell Cytotoxicity partially recapitulates fidelity: moderate Wild-type CD16 expression raised CD2 surface levels and conferred killing of a melanoma target that CD16-deficient NK-92 cells do not lyse, establishing a CD16 contribution to antibody-independent killing. The complementary loss with the L66H allele is shown for the association and signalling steps rather than as a matched cytotoxicity measurement against the same target, so the link to the cytotoxicity node is one step less direct than for the association node.

Limitations: The gain-of-function direction (adding CD16 to a CD16-null line) is the arm demonstrated against the melanoma target; NK-92 also differs from primary NK cells in receptor repertoire, so the size of the CD16 contribution to natural cytotoxicity in vivo is not established by this model.

Readouts

Killing of a CD16-dependent melanoma target

Direction: INCREASED

Interpretation: Restoring wild-type CD16 restores antibody-independent lysis of a target that CD16-negative NK-92 cells resist, which is the positive control for the mechanism failing in patients.

Show evidence (1 reference)

PMID:23006327 SUPPORT In Vitro

"Mechanistic studies in a human NK cell line, NK-92, demonstrated that CD16 expression correlated with CD2 surface levels and enabled killing of a melanoma cell line typically resistant to CD16-deficient NK-92 cells."

Reports the CD16-dependent killing of the melanoma target and the correlation with CD2 surface levels.

Show evidence (1 reference)

PMID:23006327 SUPPORT In Vitro

"Mechanistic studies in a human NK cell line, NK-92, demonstrated that CD16 expression correlated with CD2 surface levels and enabled killing of a melanoma cell line typically resistant to CD16-deficient NK-92 cells."

Supports a CD16 role in antibody-independent killing, but via the reconstitution arm rather than a matched L66H cytotoxicity comparison, which is why the relationship is recorded as partial recapitulation.

{ }

Source YAML

click to show

name: CD16 Deficiency
creation_date: "2026-08-28T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: CD16 deficiency
  term:
    id: MONDO:0014313
    label: autosomal recessive primary immunodeficiency with defective spontaneous
      natural killer cell cytotoxicity
synonyms:
- immunodeficiency 20
- IMD20
- CD16 deficiency
- FCGR3A deficiency
- autosomal recessive primary immunodeficiency with defective spontaneous NK cell
  cytotoxicity
description: >-
  CD16 deficiency (immunodeficiency 20, IMD20) is an autosomal recessive inborn
  error of immunity caused by a homozygous FCGR3A missense variant, c.230T>A,
  which substitutes histidine for leucine at residue 66 (L66H) in the first
  extracellular immunoglobulin domain of CD16 (Fc-gamma receptor IIIA). Affected
  individuals present with unusually severe and persistent herpesvirus and human
  papillomavirus disease against an otherwise unremarkable immunological
  workup.

  The reason this entity is worth curating separately from the broader natural
  killer cell deficiencies is that it is a dissociated functional defect rather
  than an absence of cells or of a receptor. CD16 is expressed on the NK cell
  surface and still binds IgG Fc, so antibody-dependent cellular cytotoxicity is
  intact. What the substitution destroys is a conformational epitope on the
  membrane-distal face of the receptor - the same surface recognised by the
  monoclonal antibody B73.1 - and with it CD16's ability to associate with CD2.
  Spontaneous (antibody-independent) killing, which depends on that CD16-CD2
  partnership at the lytic immunological synapse, fails while ADCC continues.

  This makes CD16 a costimulatory partner in natural cytotoxicity rather than
  only an Fc receptor, and it means the two NK effector functions must be
  modelled as separate nodes: collapsing them into a single "NK dysfunction"
  step would erase the finding the disease exists to demonstrate.

  Whether the L66H allele is by itself sufficient to cause disease is
  genuinely unsettled, and the entry is written around that rather than past
  it. Four homozygotes have been described. Two had deficient spontaneous
  cytotoxicity with severe herpesvirus and papillomavirus disease. A third had
  recurrent viral infection and a difficult course after BCG, Epstein-Barr and
  varicella zoster, but normal spontaneous cytotoxicity and normal ADCC on
  formal testing, and that report closed by asking whether the genotype is
  causally related to NK deficiency at all. A fourth was ascertained
  incidentally on newborn screening, is clinically well, and has normal NK
  lytic function; her lymphopenia was traced to a 22q11.2 deletion rather than
  to FCGR3A. Population data compound the problem: L66H sits at roughly 5%
  allele frequency overall with about a hundred homozygotes in gnomAD, which is
  far too common for a fully penetrant recessive immunodeficiency.

  The gene-disease relationship is therefore recorded as DISPUTED and the
  allele as of uncertain significance, not as causative and pathogenic. The
  mechanism nodes below describe what was measured in the patients who were
  affected, and are not claims that every homozygote has them.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Symptomatic individuals reported to date carry the FCGR3A L66H substitution
    in the homozygous state, and heterozygous relatives have not been described
    as affected, so inheritance is recorded as autosomal recessive. That
    recording should be read with the penetrance caveat: homozygosity is common
    in the general population and at least one homozygote is clinically well,
    so homozygosity is not by itself sufficient for disease. The common FCGR3A
    V158F polymorphism that modulates ADCC is a separate allele with a
    different functional consequence and should not be conflated with L66H.
  evidence:
  - reference: PMID:8608639
    reference_title: "Natural Killer (NK) cell deficiency associated with an epitope-deficient
      Fc receptor type IIIA (CD16-II)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "homozygous for a T to A substitution at position 230 of CD16-II cDNA,
      predicting a Leu(66) to His(66) change in the first immunoglobulin domain"
    explanation: Establishes the homozygous state of the FCGR3A allele in the index
      patient.
  - reference: PMID:34448085
    reference_title: "Undetectable NK Cells due to the FCGR3A Variant, L66H, Which
      May Not Be Directly Disease-Causing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The higher frequency in some populations suggests that the L66H variant
      alone is not sufficient to cause disease directly but instead may act as a risk
      factor with low disease penetrance."
    explanation: Qualifies the recessive model, proposing low-penetrance risk rather
      than simple recessive causation.
genetic:
- name: FCGR3A
  gene_term:
    preferred_term: FCGR3A
    term:
      id: hgnc:3619
      label: FCGR3A
  relationship_type: DISPUTED
  variant_origin: GERMLINE
  association: >-
    FCGR3A encodes CD16a (Fc-gamma receptor IIIA), the low-affinity IgG Fc
    receptor expressed on CD56-dim natural killer cells, where it is the
    triggering receptor for antibody-dependent cellular cytotoxicity. The
    candidate allele is a single germline missense substitution in the
    membrane-distal immunoglobulin domain, carried homozygously. Because the
    receptor is still expressed and still binds Fc, it is a function-specific
    partial loss rather than a null.

    The relationship is recorded as DISPUTED rather than CAUSATIVE. Two
    homozygotes have a measured spontaneous-cytotoxicity defect, but a third
    had normal cytotoxicity and normal ADCC, a fourth is asymptomatic with
    normal NK lytic function, and the allele reaches roughly 5% frequency with
    about a hundred homozygotes in gnomAD. The most recent report concludes the
    variant is unlikely to be a direct genetic cause and proposes it as a
    low-penetrance risk factor instead. Curators should not treat an L66H
    homozygous genotype as diagnostic on its own.
  variants:
  - name: "FCGR3A L66H (reported as c.230T>A, c.197T>A, or p.L48H)"
    description: >-
      The single allele reported in every described case. It disrupts the B73.1
      monoclonal antibody epitope while leaving the 3G8 epitope and Fc binding
      intact. Recorded as of uncertain significance rather than pathogenic:
      about a hundred homozygotes appear in gnomAD, which is incompatible with
      a fully penetrant recessive immunodeficiency allele.
    clinical_significance: UNCERTAIN_SIGNIFICANCE
    evidence:
    - reference: PMID:8608639
      reference_title: "Natural Killer (NK) cell deficiency associated with an epitope-deficient
        Fc receptor type IIIA (CD16-II)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "homozygous for a T to A substitution at position 230 of CD16-II cDNA,
        predicting a Leu(66) to His(66) change in the first immunoglobulin domain"
      explanation: Defines the variant at nucleotide and amino-acid level in the index
        patient.
    - reference: PMID:34448085
      reference_title: "Undetectable NK Cells due to the FCGR3A Variant, L66H, Which
        May Not Be Directly Disease-Causing."
      supports: REFUTE
      evidence_source: HUMAN_CLINICAL
      snippet: "it is observed in 7.1% of alleles of European ancestry including 68
        homozygotes, and a population frequency of about 5.0% including 100 homozygotes
        in overall populations"
      explanation: Population frequency incompatible with a fully penetrant pathogenic
        recessive allele; the basis for grading this variant uncertain rather than
        pathogenic.
    - reference: PMID:34448085
      reference_title: "Undetectable NK Cells due to the FCGR3A Variant, L66H, Which
        May Not Be Directly Disease-Causing."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the study of a cohort of 346 children found that only 12 had loss
        of the B73.1 epitope, a lower frequency than reported by gnomAD"
      explanation: A directly measured cohort frequency lower than the gnomAD estimate.
        Graded partial because it qualifies the population argument rather than simply
        supporting it - the allele remains far too common for full penetrance, but
        gnomAD may overstate how common.
  evidence:
  - reference: PMID:23006327
    reference_title: "Human immunodeficiency-causing mutation defines CD16 in spontaneous
      NK cell cytotoxicity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A homozygous missense mutation in CD16 (encoding a L66H substitution)
      is associated with severe herpesvirus infections in rare patients."
    explanation: Associates the homozygous FCGR3A L66H allele with the clinical immunodeficiency
      in the affected patients.
  - reference: PMID:34448085
    reference_title: "Undetectable NK Cells due to the FCGR3A Variant, L66H, Which
      May Not Be Directly Disease-Causing."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "this case report highlights that the L66H variant is unlikely a direct
      genetic cause of NK cell dysfunction."
    explanation: The most recent assessment of the allele, and the reason this gene-disease
      relationship is recorded as disputed.
  - reference: PMID:8874200
    reference_title: "Identification of an unusual Fc gamma receptor IIIa (CD16) on
      natural killer cells in a patient with recurrent infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Further analysis of the NK cell function in vitro and follow-up of the
      clinical course of Fc gamma RIIIA-48H/H homozygotes is required to ascertain
      whether this genotype is causally related to an NK cell immunodeficiency."
    explanation: The original pathogenicity caveat, raised in 1996 and not since resolved.
pathophysiology:
- name: FCGR3A L66H Substitution
  biological_scale: MOLECULAR
  description: >-
    A homozygous T-to-A transversion at position 230 of the FCGR3A coding
    sequence replaces leucine 66 with histidine in the first (membrane-distal)
    immunoglobulin-like domain of CD16. The receptor is still made and still
    reaches the NK cell surface; the lesion is confined to the local
    conformation of one surface loop.
  genetic_context:
    genes:
    - preferred_term: FCGR3A
      term:
        id: hgnc:3619
        label: FCGR3A
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
    description: >-
      c.230T>A, p.Leu66His. Structural modelling of the mutant against the
      solved wild-type CD16 ectodomain predicts a shift in the B73.1 epitope
      loop with the overall fold otherwise preserved, consistent with selective
      loss of one function (spontaneous cytotoxicity) while Fc binding and ADCC
      are retained. It is therefore recorded as a partial, function-specific
      loss rather than a null allele.
  cell_types:
  - preferred_term: CD16-positive, CD56-dim natural killer cell
    term:
      id: CL:0000939
      label: "CD16-positive, CD56-dim natural killer cell, human"
  evidence:
  - reference: PMID:8608639
    reference_title: "Natural Killer (NK) cell deficiency associated with an epitope-deficient
      Fc receptor type IIIA (CD16-II)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "homozygous for a T to A substitution at position 230 of CD16-II cDNA,
      predicting a Leu(66) to His(66) change in the first immunoglobulin domain"
    explanation: Defines the causal variant at nucleotide and amino-acid level and
      localises it to the membrane-distal immunoglobulin domain.
  downstream:
  - target: Loss of the CD16 B73.1 Conformational Epitope
    causal_link_type: DIRECT
    description: >-
      The substitution sits within the B73.1 recognition site, so the epitope is
      lost as a direct structural consequence of the amino-acid change.

- name: Loss of the CD16 B73.1 Conformational Epitope
  biological_scale: MOLECULAR
  description: >-
    Patient NK cells are stained normally by the anti-CD16 antibody 3G8, which
    binds elsewhere on the receptor, but are not recognised by B73.1. CD16 is
    therefore present on the surface with a locally altered membrane-distal
    face. This is the structural pivot of the disease: it is what separates the
    arm of CD16 function that fails from the arm that does not.
  cell_types:
  - preferred_term: CD16-positive, CD56-dim natural killer cell
    term:
      id: CL:0000939
      label: "CD16-positive, CD56-dim natural killer cell, human"
  evidence:
  - reference: PMID:8608639
    reference_title: "Natural Killer (NK) cell deficiency associated with an epitope-deficient
      Fc receptor type IIIA (CD16-II)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "which was not reactive with the anti-CD16-II MoAb B73.1"
    explanation: Documents loss of the B73.1 epitope on patient NK cells while the
      receptor itself remains detectable.
  downstream:
  - target: Failure of CD16-CD2 Association
    causal_link_type: DIRECT
    description: >-
      The altered face is the surface through which CD16 partners with CD2, so
      losing it abolishes the association.

- name: Failure of CD16-CD2 Association
  biological_scale: MOLECULAR
  description: >-
    In healthy NK cells CD16 associates biochemically with CD2, a coactivation
    receptor, and the two co-cluster at the lytic immunological synapse, so that
    engaging CD2 elicits CD16 signalling. The L66H receptor does not enter this
    association, and CD2 ligation no longer triggers CD16 signalling. Note that
    the synapse still forms; what fails is the CD16-CD2 partnership within it.
  cell_types:
  - preferred_term: CD16-positive, CD56-dim natural killer cell
    term:
      id: CL:0000939
      label: "CD16-positive, CD56-dim natural killer cell, human"
  molecular_functions:
  - preferred_term: cell adhesion molecule binding
    term:
      id: GO:0050839
      label: cell adhesion molecule binding
    modifier: DECREASED
  evidence:
  - reference: PMID:23006327
    reference_title: "Human immunodeficiency-causing mutation defines CD16 in spontaneous
      NK cell cytotoxicity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "An association between CD16 and CD2 was identified biochemically and
      at the immunological synapse, which elicited CD16 signaling after CD2 engagement."
    explanation: Establishes the wild-type CD16-CD2 partnership. Graded partial because
      it documents the normal association rather than its failure; the item below
      carries the failure.
  - reference: PMID:23006327
    reference_title: "Human immunodeficiency-causing mutation defines CD16 in spontaneous
      NK cell cytotoxicity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Stable expression of CD16 L66H in NK-92 cells recapitulated the patient
      phenotype, abrogating association of CD16 with CD2 as well as CD16 signaling
      after CD2 ligation."
    explanation: Shows that introducing the patient allele alone is sufficient to
      abolish the association, which is what makes this step causal rather than correlative.
  downstream:
  - target: Reduced CD2 Surface Expression on CD56-dim NK Cells
    causal_link_type: DIRECT
  - target: Deficient Spontaneous NK Cell Cytotoxicity
    causal_link_type: DIRECT
    description: >-
      Loss of CD16-dependent costimulation through CD2 is the proximate cause of
      the natural-cytotoxicity defect.

- name: Reduced CD2 Surface Expression on CD56-dim NK Cells
  biological_scale: CELLULAR
  description: >-
    Patient NK cells carry less surface CD2 than controls, and the reduction is
    restricted to the CD56-dim, CD16-positive subset - CD2 levels on the
    CD16-negative CD56-bright subset are unaffected. The compartment-restricted
    pattern is the argument that the CD2 loss is downstream of mutant CD16
    rather than an independent trait, since it appears only where the mutant
    receptor is expressed.
  cell_types:
  - preferred_term: CD16-positive, CD56-dim natural killer cell
    term:
      id: CL:0000939
      label: "CD16-positive, CD56-dim natural killer cell, human"
  - preferred_term: CD16-negative, CD56-bright natural killer cell
    term:
      id: CL:0000938
      label: "CD16-negative, CD56-bright natural killer cell, human"
  evidence:
  - reference: PMID:23006327
    reference_title: "Human immunodeficiency-causing mutation defines CD16 in spontaneous
      NK cell cytotoxicity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with the L66H mutation had intact ADCC, but deficient spontaneous
      NK cell cytotoxicity and decreased surface expression of CD2, a coactivation
      receptor."
    explanation: Documents the reduced CD2 surface expression in both reported patients
      alongside the dissociated cytotoxicity phenotype.
  - reference: PMID:23006327
    reference_title: "Human immunodeficiency-causing mutation defines CD16 in spontaneous
      NK cell cytotoxicity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The decrease in CD2 surface expression on cells of patient 1 was limited
      to CD56 dim NK cells, which were primarily CD16"
    explanation: The positive half of the subset restriction, which the abstract sentence
      does not carry. The CD2 decrease is confined to the subset that expresses the
      mutant receptor.
  - reference: PMID:23006327
    reference_title: "Human immunodeficiency-causing mutation defines CD16 in spontaneous
      NK cell cytotoxicity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "as CD2 expression on CD16–CD56bright NK cells was equivalent in patient
      1 and the control"
    explanation: The negative half of the same contrast. CD2 is unaffected on the
      CD16-negative CD56-bright subset, and it is the pairing of the two halves that
      makes this the argument that the CD2 loss follows the mutant receptor.

- name: Preserved IgG Fc Binding and ADCC
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Antibody-dependent cellular cytotoxicity is intact in patient cells,
    measured against antibody-coated targets. The Fc-binding surface is not
    part of the loop altered by L66H, which is why this arm of CD16 function
    survives while the CD2 partnership does not.

    A deliberate negative node. It records a function that is retained, which
    is unusual for a pathophysiology graph but necessary here: the selectivity
    of the defect is the mechanistic claim, and a graph showing only the
    failing arm would misrepresent the disease as a general NK deficiency.
    Nothing points downstream into it, because preservation is the absence of
    an effect rather than something the epitope loss causes, and the available
    causal link types would export such an edge as a causal arrow.
  cell_types:
  - preferred_term: CD16-positive, CD56-dim natural killer cell
    term:
      id: CL:0000939
      label: "CD16-positive, CD56-dim natural killer cell, human"
  biological_processes:
  - preferred_term: antibody-dependent cellular cytotoxicity
    term:
      id: GO:0001788
      label: antibody-dependent cellular cytotoxicity
  molecular_functions:
  - preferred_term: IgG binding
    term:
      id: GO:0019864
      label: IgG binding
  evidence:
  - reference: PMID:8608639
    reference_title: "Natural Killer (NK) cell deficiency associated with an epitope-deficient
      Fc receptor type IIIA (CD16-II)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Spontaneous NK cell activity of the patient's peripheral blood mononuclear
      cells (PBMC) was markedly decreased, while antibody-dependent cellular cytotoxicity
      (ADCC) was unaffected."
    explanation: Reports preserved ADCC in the index patient in the same assay series
      that showed loss of spontaneous killing.

- name: Deficient Spontaneous NK Cell Cytotoxicity
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Antibody-independent killing of susceptible target cells is markedly
    reduced in patient peripheral blood mononuclear cells. Because ADCC is
    preserved in the same cells, the defect is specific to the
    natural-cytotoxicity programme rather than to the lytic machinery as a
    whole - granule content and degranulation capacity are not the failing
    step.
  cell_types:
  - preferred_term: CD16-positive, CD56-dim natural killer cell
    term:
      id: CL:0000939
      label: "CD16-positive, CD56-dim natural killer cell, human"
  biological_processes:
  - preferred_term: natural killer cell mediated cytotoxicity
    term:
      id: GO:0042267
      label: natural killer cell mediated cytotoxicity
    modifier: DECREASED
  evidence:
  - reference: PMID:8608639
    reference_title: "Natural Killer (NK) cell deficiency associated with an epitope-deficient
      Fc receptor type IIIA (CD16-II)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Spontaneous NK cell activity of the patient's peripheral blood mononuclear
      cells (PBMC) was markedly decreased, while antibody-dependent cellular cytotoxicity
      (ADCC) was unaffected."
    explanation: Direct measurement of the reduced spontaneous cytotoxicity that defines
      the disease.
  - reference: PMID:23006327
    reference_title: "Human immunodeficiency-causing mutation defines CD16 in spontaneous
      NK cell cytotoxicity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Thus, CD16 serves a role in NK cell-mediated spontaneous cytotoxicity
      through a specific association with CD2 and represents a potential mechanism
      underlying a human congenital immunodeficiency."
    explanation: States the mechanistic conclusion linking the CD16-CD2 association
      to spontaneous cytotoxicity and to this immunodeficiency.
  - reference: PMID:8874200
    reference_title: "Identification of an unusual Fc gamma receptor IIIa (CD16) on
      natural killer cells in a patient with recurrent infections."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "NK cell function, analyzed in vitro by direct cytotoxicity on K562 target
      cells and ADCC-activity on P815 target cells, was normal compared with an age-matched
      healthy control."
    explanation: A homozygote in whom spontaneous cytotoxicity was normal. The defect
      is therefore not universal among carriers of the genotype, which is why this
      node is graded provisional.
  - reference: PMID:34448085
    reference_title: "Undetectable NK Cells due to the FCGR3A Variant, L66H, Which
      May Not Be Directly Disease-Causing."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "normal NK cell lytic function by killing assay compared to controls"
    explanation: A second homozygote with normal NK lytic function, ascertained incidentally
      rather than through infection.
  downstream:
  - target: Impaired Control of Herpesvirus and Papillomavirus Infection
    causal_link_type: DIRECT
    description: >-
      Natural cytotoxicity is a principal early defence against virus-infected
      cells, so its selective loss maps onto the observed infection spectrum.
      This step is inferred from the known role of NK cells rather than
      measured, and two homozygotes with normal cytotoxicity show it is not
      deterministic in either direction.
  - target: Decreased NK cell-induced killing of target cells
    causal_link_type: DIRECT
    description: >-
      The node's clinical measurement, tying the mechanism to the phenotype it
      is observed as.

- name: Impaired Control of Herpesvirus and Papillomavirus Infection
  biological_scale: ORGANISM
  mechanism_confidence: PROVISIONAL
  description: >-
    In affected individuals the clinical consequence is unusually severe,
    persistent or recurrent disease with herpesviruses - herpes simplex virus
    in the index patient, Epstein-Barr virus and varicella zoster virus in
    others - and with human papillomavirus, against an otherwise normal
    immunological assessment. One homozygote also had a difficult course after
    BCG vaccination. The narrowness of the infection
    spectrum - viral rather than pyogenic or opportunistic-fungal - is
    consistent with a lesion confined to NK natural cytotoxicity rather than a
    combined immunodeficiency.
  evidence:
  - reference: PMID:23006327
    reference_title: "Human immunodeficiency-causing mutation defines CD16 in spontaneous
      NK cell cytotoxicity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A homozygous missense mutation in CD16 (encoding a L66H substitution)
      is associated with severe herpesvirus infections in rare patients."
    explanation: Links the genotype to the severe herpesvirus phenotype at the level
      of the clinical syndrome.
  - reference: PMID:8608639
    reference_title: "Natural Killer (NK) cell deficiency associated with an epitope-deficient
      Fc receptor type IIIA (CD16-II)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We have identified a child with recurrent infections, especially with
      herpes simplex virus, who had a decreased number of CD56(+)CD3(-) NK cells in
      circulation."
    explanation: Reports the herpes simplex-predominant infection history of the index
      patient.
  downstream:
  - target: Recurrent viral infections
    causal_link_type: DIRECT
    description: >-
      The clinical manifestation by which this node is recognised.
phenotypes:
- category: Immunological
  name: Decreased NK cell-induced killing of target cells
  description: >-
    Reduced antibody-independent lysis of susceptible target cells by patient
    peripheral blood mononuclear cells, with antibody-dependent killing
    preserved in the same assay series.
  phenotype_term:
    preferred_term: Decreased natural killer cell-induced killing of target cells
    term:
      id: HP:0025808
      label: Decreased natural killer cell-induced killing of target cells
  evidence:
  - reference: PMID:8608639
    reference_title: "Natural Killer (NK) cell deficiency associated with an epitope-deficient
      Fc receptor type IIIA (CD16-II)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Spontaneous NK cell activity of the patient's peripheral blood mononuclear
      cells (PBMC) was markedly decreased, while antibody-dependent cellular cytotoxicity
      (ADCC) was unaffected."
    explanation: Reports the reduced spontaneous killing that this phenotype term captures.
- category: Immunological
  name: Recurrent viral infections
  description: >-
    Severe or persistent herpesvirus and human papillomavirus disease is the
    presenting clinical problem in reported patients.
  phenotype_term:
    preferred_term: Recurrent viral infections
    term:
      id: HP:0004429
      label: Recurrent viral infections
  evidence:
  - reference: PMID:23006327
    reference_title: "Human immunodeficiency-causing mutation defines CD16 in spontaneous
      NK cell cytotoxicity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A homozygous missense mutation in CD16 (encoding a L66H substitution)
      is associated with severe herpesvirus infections in rare patients."
    explanation: Documents the severe viral infection phenotype associated with the
      genotype.
- category: Immunological
  name: Recurrent herpes
  description: >-
    Recurrent herpes simplex virus infection dominated the presentation of the
    index patient.
  phenotype_term:
    preferred_term: Recurrent herpes
    term:
      id: HP:0005353
      label: Recurrent herpes
  evidence:
  - reference: PMID:8608639
    reference_title: "Natural Killer (NK) cell deficiency associated with an epitope-deficient
      Fc receptor type IIIA (CD16-II)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We have identified a child with recurrent infections, especially with
      herpes simplex virus, who had a decreased number of CD56(+)CD3(-) NK cells in
      circulation."
    explanation: Reports recurrent herpes simplex virus infection in the index patient.
- category: Immunological
  name: Reduced total natural killer cell count
  description: >-
    Reported in the index patient only. Of the four published homozygotes, one
    had a genuinely reduced count, two had normal counts, and one read as
    NK-absent under a CD16-inclusive flow gate while being normal under a
    CD56-only gate. Recorded as an inconsistent finding rather than a defining
    feature; the nk_cytopenia_inconsistent discussion separates the three
    mechanisms.
  phenotype_term:
    preferred_term: Reduced total natural killer cell count
    term:
      id: HP:0040218
      label: Reduced total natural killer cell count
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:8608639
    reference_title: "Natural Killer (NK) cell deficiency associated with an epitope-deficient
      Fc receptor type IIIA (CD16-II)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We have identified a child with recurrent infections, especially with
      herpes simplex virus, who had a decreased number of CD56(+)CD3(-) NK cells in
      circulation."
    explanation: Reports the reduced circulating NK cell number in the index patient.
experimental_models:
- name: NK-92 cells stably expressing CD16 L66H
  experimental_model_type: CELL_LINE
  description: >-
    The immortalised human NK cell line NK-92, which lacks endogenous CD16, was
    reconstituted with either wild-type CD16 or the patient L66H allele. This is
    the experiment that converts the patient observation into a mechanism: it
    isolates the single substitution from the rest of the patients' genetic
    background.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: natural killer cell
    term:
      id: CL:0000623
      label: natural killer cell
  publication: PMID:23006327
  modeled_mechanisms:
  - target: Failure of CD16-CD2 Association
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Expressing the patient allele in a CD16-null human NK line reproduced the
      loss of CD16-CD2 association and the loss of CD16 signalling after CD2
      ligation.
    limitations: >-
      NK-92 is a transformed, IL-2-dependent NK lymphoma line rather than a
      primary NK cell, and the reconstituted receptor is expressed from a
      transgene rather than at endogenous locus and copy number. It also cannot
      report on NK development, so it speaks to receptor function and not to the
      NK cytopenia seen in the index patient.
    readouts:
    - name: CD16-CD2 biochemical association
      target: Failure of CD16-CD2 Association
      direction: ABOLISHED
      interpretation: >-
        The association present with wild-type CD16 is not formed by the L66H
        receptor, placing the substitution upstream of the partnership.
      evidence:
      - reference: PMID:23006327
        reference_title: "Human immunodeficiency-causing mutation defines CD16 in spontaneous
          NK cell cytotoxicity."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Stable expression of CD16 L66H in NK-92 cells recapitulated the
          patient phenotype, abrogating association of CD16 with CD2 as well as CD16
          signaling after CD2 ligation."
        explanation: Reports the abolished association and abolished CD2-triggered
          CD16 signalling in the reconstituted line.
    evidence:
    - reference: PMID:23006327
      reference_title: "Human immunodeficiency-causing mutation defines CD16 in spontaneous
        NK cell cytotoxicity."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Stable expression of CD16 L66H in NK-92 cells recapitulated the patient
        phenotype, abrogating association of CD16 with CD2 as well as CD16 signaling
        after CD2 ligation."
      explanation: Supports treating this reconstituted line as informative for the
        CD16-CD2 association node.
  - target: Deficient Spontaneous NK Cell Cytotoxicity
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Wild-type CD16 expression raised CD2 surface levels and conferred killing
      of a melanoma target that CD16-deficient NK-92 cells do not lyse,
      establishing a CD16 contribution to antibody-independent killing. The
      complementary loss with the L66H allele is shown for the association and
      signalling steps rather than as a matched cytotoxicity measurement against
      the same target, so the link to the cytotoxicity node is one step less
      direct than for the association node.
    limitations: >-
      The gain-of-function direction (adding CD16 to a CD16-null line) is the
      arm demonstrated against the melanoma target; NK-92 also differs from
      primary NK cells in receptor repertoire, so the size of the CD16
      contribution to natural cytotoxicity in vivo is not established by this
      model.
    readouts:
    - name: Killing of a CD16-dependent melanoma target
      target: Deficient Spontaneous NK Cell Cytotoxicity
      direction: INCREASED
      interpretation: >-
        Restoring wild-type CD16 restores antibody-independent lysis of a target
        that CD16-negative NK-92 cells resist, which is the positive control for
        the mechanism failing in patients.
      evidence:
      - reference: PMID:23006327
        reference_title: "Human immunodeficiency-causing mutation defines CD16 in spontaneous
          NK cell cytotoxicity."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Mechanistic studies in a human NK cell line, NK-92, demonstrated
          that CD16 expression correlated with CD2 surface levels and enabled killing
          of a melanoma cell line typically resistant to CD16-deficient NK-92 cells."
        explanation: Reports the CD16-dependent killing of the melanoma target and
          the correlation with CD2 surface levels.
    evidence:
    - reference: PMID:23006327
      reference_title: "Human immunodeficiency-causing mutation defines CD16 in spontaneous
        NK cell cytotoxicity."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Mechanistic studies in a human NK cell line, NK-92, demonstrated that
        CD16 expression correlated with CD2 surface levels and enabled killing of a
        melanoma cell line typically resistant to CD16-deficient NK-92 cells."
      explanation: Supports a CD16 role in antibody-independent killing, but via the
        reconstitution arm rather than a matched L66H cytotoxicity comparison, which
        is why the relationship is recorded as partial recapitulation.
diagnosis:
- name: Flow cytometry with paired anti-CD16 clones
  description: >-
    The flow signature is a discordance between two anti-CD16 antibodies on the
    same cells: NK cells stain normally with clone 3G8 but are not recognised by
    clone B73.1. A panel using only one anti-CD16 clone will report CD16 as
    normally expressed and miss the finding entirely, which is the practical
    reason this entity is under-recognised.

    It is a screening signal, not a diagnostic one. Loss of the B73.1 epitope
    can occur independently of the L66H substitution, so the discordance has to
    be confirmed by sequencing rather than treated as sufficient.
  evidence:
  - reference: PMID:8608639
    reference_title: "Natural Killer (NK) cell deficiency associated with an epitope-deficient
      Fc receptor type IIIA (CD16-II)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "which was not reactive with the anti-CD16-II MoAb B73.1"
    explanation: Establishes the selective loss of B73.1 reactivity that the paired-clone
      approach detects.
  - reference: PMID:34448085
    reference_title: "Undetectable NK Cells due to the FCGR3A Variant, L66H, Which
      May Not Be Directly Disease-Causing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "loss of B73.1 epitope detection should always be combined with Sanger
      sequencing to confirm the presence of the L66H allele if it is suspected."
    explanation: Establishes that the flow discordance is not specific to L66H and
      must be confirmed genetically; graded partial because it qualifies the test
      rather than supporting it.
- name: Paired spontaneous cytotoxicity and ADCC assays
  description: >-
    Measuring natural cytotoxicity against a susceptible target and ADCC against
    an antibody-coated target in the same sample demonstrates the dissociation
    that defines the disease. Either assay alone is uninformative: a normal ADCC
    result does not exclude the diagnosis, and a low natural-cytotoxicity result
    alone does not distinguish it from other NK functional defects.
  evidence:
  - reference: PMID:23006327
    reference_title: "Human immunodeficiency-causing mutation defines CD16 in spontaneous
      NK cell cytotoxicity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with the L66H mutation had intact ADCC, but deficient spontaneous
      NK cell cytotoxicity and decreased surface expression of CD2, a coactivation
      receptor."
    explanation: Reports the paired assay result in both patients that the diagnostic
      approach depends on.
- name: FCGR3A sequencing
  description: >-
    Sanger sequencing of FCGR3A demonstrates the homozygous L66H substitution.
    Finding it is necessary but not sufficient: the allele is common, roughly a
    hundred homozygotes appear in gnomAD, and at least one homozygote is
    clinically well, so the genotype does not establish the diagnosis on its own
    and must be read alongside the paired functional assays and the clinical
    picture. There is also a practical retrieval problem - a
    filtered exome or panel pipeline may discard the variant as too common to
    report. Interpretation must additionally keep this allele distinct from the
    common FCGR3A V158F functional polymorphism and from FCGR3B copy-number
    variation, neither of which causes this syndrome.
  evidence:
  - reference: PMID:34448085
    reference_title: "Undetectable NK Cells due to the FCGR3A Variant, L66H, Which
      May Not Be Directly Disease-Causing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "NGS may not report the L66H variant because it is observed in 7.1% of
      alleles of European ancestry"
    explanation: Documents the filtering pitfall by which a standard rare-variant
      pipeline misses the allele entirely.
  - reference: PMID:8608639
    reference_title: "Natural Killer (NK) cell deficiency associated with an epitope-deficient
      Fc receptor type IIIA (CD16-II)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "homozygous for a T to A substitution at position 230 of CD16-II cDNA,
      predicting a Leu(66) to His(66) change in the first immunoglobulin domain"
    explanation: Identifies the confirmatory sequencing finding.
discussions:
- discussion_id: l66h_pathogenicity_disputed
  kind: CONTROVERSY
  status: OPEN
  prompt: >-
    Is homozygous FCGR3A L66H sufficient to cause immunodeficiency, or is it a
    low-penetrance risk factor that has been over-attributed?
  attaches_to:
  - genetic#FCGR3A
  - pathophysiology#Deficient Spontaneous NK Cell Cytotoxicity
  rationale: >-
    The four published homozygotes do not agree. Two had reduced spontaneous
    cytotoxicity with severe viral disease. A third had recurrent viral
    infection and a difficult course after BCG, Epstein-Barr and varicella
    zoster, yet formal testing showed normal spontaneous cytotoxicity and
    normal ADCC, and that report explicitly asked whether the genotype is
    causally related to NK deficiency. A fourth, found on newborn screening, is
    clinically well with normal NK lytic function and normal CD56-bright /
    CD56-dim distribution; her lymphopenia was traced to a 22q11.2 deletion.

    Population data are the strongest argument against simple causation: the
    allele sits near 5% frequency overall, with roughly a hundred homozygotes
    in gnomAD. A fully penetrant recessive immunodeficiency allele cannot be
    that common. The 2021 report concludes the variant is unlikely to be a
    direct genetic cause and proposes low-penetrance risk instead.

    Ascertainment is the obvious confounder in both directions: the affected
    patients were found because they were ill, and the well homozygote was
    found because of an unrelated screen. What would settle it is a systematic
    NK-function study of unselected homozygotes, which nobody has published.
    Until then this entry records the mechanism that was measured in affected
    patients without asserting that the genotype produces it in everyone.
- discussion_id: nk_cytopenia_inconsistent
  kind: CONTROVERSY
  status: OPEN
  prompt: >-
    Is reduced circulating NK cell number a feature of CD16 deficiency, a flow
    cytometry artifact, or neither?
  attaches_to:
  - phenotypes#Reduced total natural killer cell count
  rationale: >-
    Three mechanisms are in play and they should not be collapsed.

    First, a genuine artifact. Because L66H abolishes the B73.1 epitope, a
    panel that gates NK cells as CD3-negative, CD56-positive AND CD16-positive
    scores an L66H homozygote as having almost no NK cells, while the same
    blood gated on CD3-negative, CD56-positive gives a normal count. That is
    exactly what happened in the newborn-screening case: under one gate NK
    cells were absent, under another they were 26%. The 1996 report predicted
    this, warning that combining CD16 and CD56 antibodies on the same
    fluorochrome would leave these homozygotes undiagnosed.

    Second, and importantly, this does not explain the index patient. Jawahar
    gated on CD56-positive, CD3-negative cells without CD16, so the reduced
    count reported there is not the artifact and remains unexplained. Treating
    the artifact as a blanket dismissal would be wrong.

    Third, the second and fourth patients had normal NK numbers outright.

    The practical consequence is that NK lymphopenia is not usable as a
    screening criterion for this entity, and that any reported NK count for an
    L66H homozygote has to be read together with the gating strategy that
    produced it.
- discussion_id: cytotoxicity_to_viral_susceptibility_gap
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Does the CD16-CD2 cytotoxicity defect account for the viral susceptibility,
    or is spontaneous cytotoxicity only one contributor?
  attaches_to:
  - pathophysiology#Impaired Control of Herpesvirus and Papillomavirus Infection
  rationale: >-
    The step from a measurable in vitro cytotoxicity deficit to severe,
    persistent EBV, VZV and HPV disease in vivo is asserted on plausibility and
    on the known role of NK cells in herpesvirus control, not demonstrated. No
    reported patient has had NK-specific reconstitution, there is no animal
    model of the L66H allele, and the quantitative contribution of this pathway
    to viral control in humans is unmeasured.

    The two homozygotes added in review widen this gap rather than narrowing it,
    and in opposite directions. One had a severe viral course - recurrent
    respiratory infection, a difficult course after BCG vaccination, and severe
    problems with Epstein-Barr and varicella zoster - while his spontaneous
    cytotoxicity and ADCC were both normal, so a comparable clinical picture
    arose without the mechanism this entry proposes. The other has the
    genotype, normal cytotoxicity, and no disease at all. Any account of how
    the cytotoxicity defect produces the infection phenotype now has to explain
    both.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Four homozygotes have been described in the literature: the 1996 index
    patient, a second 1996 patient with normal cytotoxicity, the 2012 patient,
    and a 2021 asymptomatic newborn-screening case. The band applies to the
    clinical syndrome, not to the genotype - homozygosity for L66H is common,
    with roughly a hundred homozygotes recorded in gnomAD, so the rarity here
    is the rarity of being reported as affected rather than the rarity of
    carrying the allele.
  evidence:
  - reference: PMID:34448085
    reference_title: "Undetectable NK Cells due to the FCGR3A Variant, L66H, Which
      May Not Be Directly Disease-Causing."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "it is observed in 7.1% of alleles of European ancestry including 68
      homozygotes, and a population frequency of about 5.0% including 100 homozygotes
      in overall populations"
    explanation: Gives the population frequency that separates genotype frequency from
      the rarity of the reported syndrome.
notes: >-
  Scope. This entry covers the syndrome reported in association with homozygous
  FCGR3A L66H. It deliberately does not cover the common FCGR3A V158F
  (rs396991) polymorphism, which modulates IgG affinity and ADCC efficacy and is
  studied as a pharmacogenomic modifier of therapeutic antibody response; that
  is a different allele making a different claim, and FCGR3A appears elsewhere
  in this knowledge base only in that polymorphic sense.

  One substitution, three numbering conventions. The same change is written
  c.230T>A / p.Leu66His in the 1996 index report and the 2012 study, c.197T>A
  (p.L66H) in the 2021 report, and p.L48H in the 1996 Blood report, which
  numbered from the mature protein rather than including the signal peptide.
  These are not three alleles. Note also that the c. positions above are the
  sources' own cDNA-position phrasing rather than transcript-validated HGVS
  designations, and should not be treated as canonical HGVS.

  Causality. The gene-disease relationship is recorded as DISPUTED and the
  allele as UNCERTAIN_SIGNIFICANCE. See the l66h_pathogenicity_disputed
  discussion for the argument; briefly, two of four published homozygotes have
  the cytotoxicity defect, the allele is far too common for a fully penetrant
  recessive immunodeficiency, and the most recent report concludes it is
  unlikely to be a direct genetic cause.

  Treatments. No treatment section is curated because no disease-directed
  therapy has been reported for this entity. Management in the published cases
  was directed at the individual infections. Rather than record a generic
  supportive-care entry with no citable evidence behind it, the section is left
  absent.

  Evidence base. Four papers describing four homozygotes between them, with the
  cellular mechanism established in a reconstituted cell line rather than in
  primary patient cells. The entry is written to make that thinness and the
  disagreement visible rather than to smooth them over - hence the explicit
  preserved-function node, the partial-recapitulation grading on the
  cytotoxicity model link, the REFUTE-graded evidence on the cytotoxicity node,
  and the two controversy entries.

📚

References & Deep Research

Deep Research

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CD16 Deficiency Deep Research Fallback ▸

CD16 Deficiency Deep Research Fallback

Provider Attempts

No deep-research provider run was performed for this entry before the initial curation. That was a mistake, and it was causal rather than procedural: the two most important papers about this allele were missed, and both were reachable from the reference list of a paper already cached in the same PR. This record documents the literature sweep performed afterwards, in response to review.

Literature Scope

The entity is FCGR3A L66H homozygosity (MONDO:0014313, immunodeficiency 20). Four homozygotes are published. All four are now curated:

PMID:8608639 — Jawahar 1996, Clin Exp Immunol. Index patient. Reduced spontaneous cytotoxicity, intact ADCC, reduced circulating NK cells gated as CD56(+)CD3(-) without CD16.
PMID:8874200 — de Vries 1996, Blood. A second, independent homozygote, numbered p.L48H from the mature protein. Recurrent viral respiratory infection, severe course after BCG, EBV and VZV — but normal spontaneous cytotoxicity and normal ADCC on formal testing, and an explicit closing caveat asking whether the genotype is causally related to NK deficiency at all. Reachable from references_cache/PMID_23006327.md as reference 17.
PMID:23006327 — Grier 2012, J Clin Invest. Second affected patient plus the NK-92 reconstitution establishing the CD16-CD2 mechanism.
PMID:34448085 — Izadi 2021, J Clin Immunol. Asymptomatic homozygote found on newborn TREC screening, with normal NK lytic function and normal CD56-bright/CD56-dim distribution. Reports the gnomAD frequency (~5% overall, ~100 homozygotes) and concludes the variant is unlikely to be a direct genetic cause. Also documents the flow-cytometry gating artifact by which an L66H homozygote reads as NK-cytopenic under a CD16-inclusive gate.

What the sweep changed

The initial entry was built on two of the four homozygotes, and the two omitted were the two that argue hardest against a simple causal model. Incorporating them changed the entry substantively rather than cosmetically:

genetic.relationship_type moved from CAUSATIVE to DISPUTED.
The variant's clinical_significance moved from PATHOGENIC to UNCERTAIN_SIGNIFICANCE.
The Deficient Spontaneous NK Cell Cytotoxicity node gained two REFUTE-graded evidence items and a PROVISIONAL mechanism confidence.
A new l66h_pathogenicity_disputed CONTROVERSY was added, and the existing NK-count controversy was rewritten around three distinct mechanisms — gating artifact, genuinely low count in the index patient (whose gate did not include CD16, so the artifact does not explain it), and normal counts in two others.
prevalence now separates the rarity of the reported syndrome from the commonness of the genotype.

Searches run

PubMed, via the MCP PubMed server:

FCGR3A CD16 deficiency natural killer cell spontaneous cytotoxicity immunodeficiency
CD16 FCGR3A natural killer immunodeficiency herpesvirus
natural killer cell deficiency epitope-deficient Fc receptor type IIIA CD16
Grier CD16 spontaneous NK cell cytotoxicity human immunodeficiency-causing mutation
Reference-list traversal of references_cache/PMID_23006327.md (refs 16, 17)

GeneReviews: GeneReviews[TI] AND (FCGR3A OR "natural killer cell deficiency" OR "immunodeficiency 20") returns no chapter, so none is cited.

CD16 Deficiency

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