Severe Combined Immunodeficiency Due To CORO1A Deficiency

Mendelian MONDO:0014168 Pathograph 45 Show in embeddings browser Severe combined immunodeficiency Combined immunodeficiency

An autosomal recessive inborn error of immunity caused by biallelic loss-of-function variants in CORO1A, which encodes coronin-1A, an actin regulator expressed mainly in haematopoietic cells. The index patient had T-B+NK+ severe combined immunodeficiency with a thymus that was paradoxically detectable, and later families widened the picture to a combined immunodeficiency of childhood or young adulthood dominated by severe viral disease: EBV-driven B-cell lymphoproliferation and lymphoma, disseminated or post-vaccination varicella, epidermodysplasia verruciformis-like beta-HPV disease, molluscum contagiosum and herpetic ulcers. The mechanism is a failure of cytoskeletal regulation rather than of antigen receptor rearrangement or cytokine signalling. Coronin-1A restrains Arp2/3-dependent filamentous actin assembly; without it, lymphocytes accumulate F-actin, mature T cells migrate poorly and are not released from the thymus, and peripheral T cells die more readily. The result is a profound deficiency of naive T cells with a restricted repertoire and near-absent innate-like T cells (iNKT and MAIT). NK-cell killing also depends on coronin-1A-mediated F-actin deconstruction at the lytic synapse, and loss of T, NK and innate-like T-cell control of EBV-infected B cells is the route to the lymphoproliferative disease that marks this disorder. Two caveats shape the entry. First, the clinical series is very small, so the frequencies recorded here come from a nine-patient review table and should be read as such. Second, the mouse and human data disagree on one point: Coro1a-null mouse T cells have a severe calcium-mobilization defect that was proposed to explain their poor survival, whereas T cells from patients carrying a C-terminal frameshift allele have poor survival with near-normal calcium flux. That disagreement is recorded as a discussion rather than resolved in the pathograph. One patient's attention deficit hyperactivity disorder is attributed by its authors to the 600-kb 16p11.2 deletion that removed her second CORO1A allele, not to coronin-1A loss itself; the entry models it through a separate contiguous-gene node. No GeneReviews chapter exists for this disorder (checked against the Bookshelf index and PubMed). No pathophysiology node declares conforms_to; kb/modules/ has no module for cortical actin regulation in lymphocytes.

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Classifications

Harrison's Part

IUIS Category

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Inheritance

Autosomal recessive HP:0000007

Affected individuals carry two deleterious CORO1A alleles, homozygous in consanguineous families or compound heterozygous, including one case where the second allele was removed by a de novo 16p11.2 deletion.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:25073507 SUPPORT Human Clinical

"Coronin-1A deficiency is a recently recognized autosomal recessive primary immunodeficiency caused by mutations in CORO1A"

States the autosomal recessive mode of inheritance directly.

PMID:23522482 SUPPORT Human Clinical

"We identified a homozygous inherited missense mutation in the gene encoding Coronin-1A (CORO1A) in the 3 siblings."

Homozygosity in three affected siblings of a consanguineous family is the segregation pattern expected for recessive inheritance.

Discussions and Knowledge Gaps

Does defective TCR-induced calcium mobilization explain the T-cell survival defect in CORO1A-deficient patients, or is that mechanism specific to the mouse and to null alleles?

HUMAN MODEL MISMATCH OPEN coro1a_calcium_flux_mouse_human_mismatch

Attached to

pathophysiology#Reduced Peripheral T-Cell Survival

Coro1a-null mice have a profound defect in TCR-induced calcium mobilization that was proposed to cause their T-cell death. Patients with the C-terminal p.S401fs allele have the same poor T-cell survival but near-normal calcium flux, and their F-actin accumulation was proposed instead as the survival mechanism. The mouse mechanism therefore does not transfer to at least one human allele, leaving open whether calcium signalling matters in patients with null alleles, or whether F-actin accumulation is the common route.

Show evidence (2 references)

PMID:18345003 SUPPORT Model Organism

"resulted in a profound defect in Ca2+ mobilization, interleukin-2 production, T cell proliferation and T cell survival"

The murine calcium-dependent survival mechanism.

PMID:26476480 SUPPORT In Vitro

"calcium flux in our patients’ CD4+ and CD8+ T cells after anti-CD3 stimulation was minimally decreased, indicating that calcium flux is not the sole mechanism by which CORO1A regulates T cell survival"

The human data that contradict the murine calcium mechanism, which is the substance of this mismatch.

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Pathophysiology

Biallelic CORO1A Loss-of-Function Variants

Germline biallelic CORO1A variants: frameshift truncations, a homozygous beta-propeller missense change (p.V134M) that almost abolishes protein expression, a paternal 2-bp deletion paired with a de novo 16p11.2 deletion, and a homozygous C-terminal frameshift (p.S401fs) that is expressed but cannot oligomerize or associate with the cytoskeleton. Every reported allele removes coronin-1A protein or the domains it needs to act on actin.

CORO1A hgnc:2252

Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

actin filament binding GO:0051015 ↓ DECREASED

Downstream

Loss of Coronin-1A Inhibition of Arp2/3 Absent or truncated coronin-1A removes the protein's inhibitory action on the Arp2/3 actin-nucleation complex.

Show evidence (6 references)

PMID:26476480 SUPPORT BACKGROUND In Vitro

"CORO1A associates with the actin cytoskeleton, binds to F-actin, and localizes at sites of actin assembly."

Grounds the molecular-function binding: coronin-1A is an F-actin-binding protein. The same paper shows the S401fs allele loses cytoskeletal association, and the other alleles remove the protein, hence DECREASED.

PMID:18836449 SUPPORT Human Clinical

"a T cell-deficient, B cell-sufficient and natural killer cell-sufficient patient with severe combined immunodeficiency, whom we found had mutations in both CORO1A alleles"

The founding patient carried mutations on both CORO1A alleles.

PMID:19097825 SUPPORT Human Clinical

"Molecular analysis revealed a 2 bp deletion in the paternal CORO1A coding sequence paired with a 600 kb de novo deletion encompassing CORO1A on the maternal allele."

The genotype of the same patient: a frameshift allele in trans with a deletion of the whole gene.

+ 3 more references

Loss of Coronin-1A Inhibition of Arp2/3

Coronin-1A binds F-actin and the Arp2/3 complex and restrains Arp2/3-mediated actin branching; its C-terminal coiled-coil domain is required for that inhibition. Loss of the protein or of that domain removes the brake on steady-state F-actin formation.

negative regulation of Arp2/3 complex-mediated actin nucleation GO:0034316 ↓ DECREASED

Downstream

Filamentous Actin Accumulation in Lymphocytes

Show evidence (1 reference)

PMID:16902139 SUPPORT Model Organism

"coronin 1 exerted an inhibitory effect on cellular steady-state F-actin formation via an Arp2/3-dependent mechanism"

Establishes the Arp2/3-dependent inhibitory activity that is lost.

Filamentous Actin Accumulation in Lymphocytes

T cells lacking functional coronin-1A carry excess F-actin, and at the NK lytic synapse the F-actin density that coronin-1A normally deconstructs is not cleared. Accumulated, poorly dynamic cortical actin is the shared cellular lesion behind the migration, survival and cytotoxicity defects that follow.

T cell CL:0000084 natural killer cell CL:0000623

actin filament depolymerization GO:0030042 ↓ DECREASED

Downstream

Impaired T-Cell Migration and Thymic Egress

Reduced Peripheral T-Cell Survival

Impaired NK-Cell Lytic Synapse Function

Show evidence (2 references)

PMID:26476480 SUPPORT In Vitro

"The F-actin content of the patients’ CD4+ and CD8+ T cells was significantly higher than that of control T cells"

Measured F-actin excess in patient CD4+ and CD8+ T cells.

PMID:24760828 SUPPORT In Vitro

"Coronin 1A (Coro1A) is the hematopoietic-specific member of the Coronin family of actin regulators that promote F-actin disassembly."

Coronin-1A's normal role is to promote F-actin disassembly.

Impaired T-Cell Migration and Thymic Egress

Mature T cells lacking coronin-1A migrate poorly and are not efficiently released from the thymus, so the thymus is present but peripheral output is low. In patients this shows as very few recent thymic emigrants and low T-cell receptor excision circles.

thymocyte CL:0000893 T cell CL:0000084

T cell migration GO:0072678 ↓ DECREASED thymocyte migration GO:0072679 ↓ DECREASED

Animal models

Coronin-1A knockout mouse Mouse recapitulates Coronin 1-deficient T cells fail chemokine-mediated migration, the same defect proposed to block thymic egress in patients.

Downstream

Profound Naive and Innate-Like T-Cell Deficiency

Abnormally low T cell receptor excision circle level Reduced thymic output means fewer recent thymic emigrants and hence few T-cell receptor excision circles.

Show evidence (3 references)

PMID:18836449 SUPPORT Model Organism

"Our findings establish a function for coronin 1A in T cell egress"

Coronin-1A mutant mice establish the thymic egress function, which the same paper connects to the human SCID patient.

PMID:19097825 SUPPORT Human Clinical

"Murine Coronin-1A is essential for the release of T cells from the thymus, consistent with the paradoxically detectable thymus in our patient."

A detectable thymus in a T-lymphopenic patient fits an egress block rather than failed thymopoiesis.

PMID:26476480 SUPPORT Human Clinical

"Quantification of CD4+CD31+CD45RA+ recent thymic emigrants in both patients demonstrated that CORO1ASer401fs severely impairs thymic output"

Direct measurement of low thymic output in patients.

Reduced Peripheral T-Cell Survival

Patient CD4+ T cells show increased apoptosis at rest and after stimulation, and re-expressing wild-type CORO1A in Coro1a-null mouse T cells reduces their apoptosis. In mice the survival defect was attributed to defective TCR-induced calcium mobilization; in patients with the S401fs allele calcium flux was near normal, so calcium is not the whole explanation (see the discussion below).

T cell CL:0000084

T cell apoptotic process GO:0070231 ↑ INCREASED

Animal models

Coronin-1A knockout mouse Mouse recapitulates Coro1a-null T cells survive poorly; the defect was attributed to impaired TCR-induced calcium mobilization, which is where the mouse and the human S401fs data diverge (see the discussion).

Downstream

Profound Naive and Innate-Like T-Cell Deficiency

Show evidence (3 references)

PMID:26476480 SUPPORT In Vitro

"resting and PHA-stimulated CD4+ T cells in both siblings had increased Annexin V staining compared to control cells"

Increased apoptosis measured in patient CD4+ T cells.

PMID:26476480 SUPPORT In Vitro

"lentiviral transduction with WT CORO1A, but not the CORO1ASer401fs mutant, reduced apoptosis in CORO1A−/− T cells"

Rescue of apoptosis by wild-type CORO1A in knockout T cells ties the survival defect to coronin-1A function.

PMID:18345003 SUPPORT Model Organism

"The absence of coronin-1, although it did not affect T cell development, resulted in a profound defect in Ca2+ mobilization, interleukin-2 production, T cell proliferation and T cell survival."

Knockout mice show the survival defect; the calcium-mobilization mechanism proposed here is not reproduced in patient cells with the S401fs allele.

Impaired NK-Cell Lytic Synapse Function

NK cells need coronin-1A to clear synaptic F-actin so that lytic granules reach the target. NK cells from a coronin-1A-deficient patient and a patient with a hemizygous missense allele had reduced cytotoxicity. The S401fs siblings, whose truncated protein keeps its beta-propeller domain, had normal NK killing, so this defect appears to depend on the allele.

natural killer cell CL:0000623

natural killer cell mediated cytotoxicity GO:0042267 ↓ DECREASED

immunological synapse GO:0001772

Downstream

Failure of Immune Control of EBV-Infected B Cells

Show evidence (3 references)

PMID:24760828 SUPPORT In Vitro

"Here, we show that Coro1A is required for natural killer (NK) cell cytotoxic function in two human NK cell lines and ex vivo cells from a Coro1A-deficient patient."

Reduced cytotoxicity in ex vivo NK cells from a patient.

PMID:37915722 SUPPORT In Vitro

"The observed mutation resulted in impaired natural killer cell cytotoxicity and platelet calcium signaling."

A second patient allele with impaired NK cytotoxicity.

PMID:26476480 REFUTE In Vitro

"PBMCs from both patients demonstrated normal cytotoxic cell killing of K562 target cells at 4 hours"

Contradicts a universal NK killing defect: patients with the C-terminal S401fs allele had normal killing. The authors attribute this to the retained beta-propeller domain, so the defect is allele-dependent.

Profound Naive and Innate-Like T-Cell Deficiency

The defining immunological state: very low naive CD4+ and CD8+ T cells with a restricted T-cell repertoire, near-absent invariant NKT cells and severely reduced MAIT cells, while B-cell and NK-cell numbers are relatively preserved in the index SCID patient. Hypomorphic alleles produce the same naive T-cell defect with oligoclonal expansion of memory T cells.

naive CD4+ T cell CL:0000895 naive CD8+ T cell CL:0000900 invariant NKT cell CL:0000921 mucosal-associated invariant T cell CL:0000940

T cell homeostasis GO:0043029 ↓ DECREASED

Downstream

Impaired Cell-Mediated Immunity to Viruses and Intracellular Pathogens

Failure of Immune Control of EBV-Infected B Cells

Impaired T-Cell-Dependent Humoral Immunity

Severe combined immunodeficiency

Decreased total T cell count

Decreased naive CD4+ T cell proportion

Abnormal TCR repertoire

Decreased mucosal-associated invariant T cell proportion

Show evidence (2 references)

PMID:23522482 SUPPORT Human Clinical

"In addition to a significant diminution of naive T-cell numbers, we found impaired development of a diverse T-cell repertoire, near-to-absent invariant natural killer T cells, and severely diminished mucosal-associated invariant T cell numbers."

Documents every component of this node: naive T-cell loss, restricted repertoire, and loss of iNKT and MAIT cells.

PMID:29942301 SUPPORT REVIEW SYNTHESIS Human Clinical

"Patients with CORO1A deficiency are characterized by a profound T cell lymphopenia with strongly decreased or nearly absent naïve cells associated with defective thymic output."

Review synthesis across the reported patients.

Impaired Cell-Mediated Immunity to Viruses and Intracellular Pathogens

With few naive T cells, patients fail to contain viruses that are normally held in check by T cells: varicella zoster (including vaccine strain), beta-human papillomaviruses, molluscum contagiosum virus and herpes simplex virus. One patient also developed tuberculoid leprosy, an intracellular bacterial infection.

T cell mediated immunity GO:0002456 ↓ DECREASED

Downstream

Recurrent viral infections

Severe varicella zoster infection

Post-vaccination varicella zoster virus infection

Persistent beta-HPV infection with epidermodysplasia verruciformis-like lesions

Chronic warts

Unusual molluscum contagiosum

Unusual HSV skin infection

Unusual mycobacterial skin infection

Show evidence (1 reference)

PMID:26476480 SUPPORT Human Clinical

"CORO1A deficiency causes T(-)B(+) natural killer-positive severe combined immunodeficiency or T-cell lymphopenia with severe viral infections."

Severe viral infection is the clinical expression of the T-cell defect.

Impaired T-Cell-Dependent Humoral Immunity

Some patients have low memory B cells, hypogammaglobulinemia or poor vaccine responses, and several have high IgE. The mouse data place the defect in T-cell help rather than in B cells. It is not universal: the S401fs siblings had normal immunoglobulins and specific antibody responses.

B cell CL:0000236

Downstream

Decreased memory B cell proportion

Decreased circulating immunoglobulin concentration

Recurrent respiratory infections

Recurrent bacterial infections Hypogammaglobulinemia and impaired antibody responses predispose to recurrent bacterial infection.

Show evidence (2 references)

PMID:18199416 SUPPORT Model Organism

"T-dependent humoral responses were impaired, but no intrinsic B cell defects were detected."

Mouse evidence that the humoral defect is T-cell dependent.

PMID:25073507 SUPPORT Human Clinical

"manifested as absent CD4CD45RA(+) (naïve) T and memory B cells, low NK cells"

Patients lacking memory B cells alongside naive T cells.

Failure of Immune Control of EBV-Infected B Cells

EBV infection is normally held latent by cytotoxic T cells, NK cells and iNKT cells. With these compromised, EBV-infected B cells proliferate. Susceptibility to EBV-driven disease is the most consistent clinical feature across CORO1A kindreds.

B cell CL:0000236

Downstream

EBV-Driven B-Cell Lymphoproliferation

Unusual EBV infection

Show evidence (2 references)

PMID:23522482 SUPPORT Human Clinical

"Our findings define a new clinical entity of a primary immunodeficiency with increased susceptibility to EBV-induced lymphoproliferation in patients associated with hypomorphic Coronin-1A mutation."

Defines EBV susceptibility as a hallmark of the disorder.

PMID:29942301 SUPPORT REVIEW SYNTHESIS Human Clinical

"Among them are SH2D1A (SAP), XIAP, ITK, MAGT1, CD27, CD70, CTPS1, RASGRP1, and CORO1A deficiencies."

Lists CORO1A deficiency among the inherited disorders with a high risk of EBV-associated lymphoproliferative disease.

EBV-Driven B-Cell Lymphoproliferation

EBV-positive B-cell lymphoproliferative disease and B-cell lymphoma, often in early childhood and in several cases fatal.

B cell CL:0000236

Downstream

Lymphoproliferative disorder

B-cell lymphoma

Show evidence (2 references)

PMID:23522482 SUPPORT Human Clinical

"We evaluated 3 siblings from a consanguineous family presenting with EBV-associated B-cell lymphoproliferation at an early age"

EBV-associated B-cell lymphoproliferation in three affected siblings.

PMID:25073507 SUPPORT Human Clinical

"the female died of EBV+ lymphomas at age 16 years"

A fatal EBV-positive lymphoma in a second kindred.

Co-occurring 16p11.2 Contiguous Gene Deletion

In at least two patients the second CORO1A allele was removed by a 16p11.2 microdeletion that also deletes neighbouring genes. The neurodevelopmental features of the deletion are a contiguous-gene effect and are not attributed to coronin-1A loss.

Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

Downstream

Biallelic CORO1A Loss-of-Function Variants The deletion removes CORO1A on one chromosome and so supplies one of the two deficient alleles.

Cognitive impairment Candidate explanation only. At least two patients carried the 16p11.2 deletion, but the review reporting cognitive impairment in 3 of 9 patients does not say which patients were affected, so the contribution of the deletion versus coronin-1A loss is not established.

Attention deficit hyperactivity disorder

Show evidence (2 references)

PMID:19097825 SUPPORT Human Clinical

"a 600 kb de novo deletion encompassing CORO1A on the maternal allele"

The deletion that forms one CORO1A allele in the first reported patient.

PMID:37915722 SUPPORT Human Clinical

"in combination with a de novo heterozygous microdeletion of chromosome 16p11.2"

A second patient in whom a 16p11.2 microdeletion accompanies the CORO1A variant.

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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

Blood 15

Decreased total T cell count HP:0005403

Show evidence (1 reference)

PMID:18836449 SUPPORT Human Clinical

"a T cell-deficient, B cell-sufficient and natural killer cell-sufficient patient with severe combined immunodeficiency"

T-cell deficiency with preserved B and NK cells in the index patient.

Decreased total CD4+ T cell count VERY_FREQUENT HP:5210418

Show evidence (2 references)

PMID:26476480 SUPPORT Human Clinical

"Both patients had CD4(+) T-cell lymphopenia and decreased lymphocyte proliferation to mitogens."

CD4+ lymphopenia in both affected siblings.

PMID:29942301 SUPPORT REVIEW SYNTHESIS Human Clinical

"↓ CD4+ 8/9 ↓ MAIT 1/1 ↓ iNKT 1/1"

From the CORO1A row of the review's Table 1 (n = 9): reduced CD4+ T cells in 8 of 9, supporting VERY_FREQUENT.

Decreased naive CD4+ T cell proportion HP:0410378

Show evidence (2 references)

PMID:25073507 SUPPORT Human Clinical

"manifested as absent CD4CD45RA(+) (naïve) T and memory B cells, low NK cells"

Absent naive (CD45RA+) CD4+ T cells in both siblings.

DOI:10.14785/lymphosign-2019-0001 SUPPORT Human Clinical

"The patient presented with T cell lymphopenia, reduction in CD4+CD45Ra+ cells and hypogammaglobulinemia."

Reduced naive CD4+ T cells in a newborn-screened patient.

Abnormally low T cell receptor excision circle level HP:0031545

Show evidence (2 references)

DOI:10.14785/lymphosign-2019-0004 SUPPORT Human Clinical

"Lymphocyte responses to mitogens and T cell receptor excision circle levels were markedly reduced, consistent with the diagnosis of severe combined immunodeficiency."

Markedly reduced TRECs in a patient.

DOI:10.14785/lymphosign-2019-0001 SUPPORT Human Clinical

"Coronin 1A deficiency can be detected after birth by T cell receptor excision circle-based newborn screening."

Low TRECs led to detection by newborn screening.

Abnormal TCR repertoire HP:0025845

Show evidence (1 reference)

PMID:23522482 SUPPORT Human Clinical

"we found impaired development of a diverse T-cell repertoire"

Impaired T-cell repertoire diversity in patients.

Decreased mucosal-associated invariant T cell proportion HP:4000039

Show evidence (1 reference)

PMID:23522482 SUPPORT Human Clinical

"near-to-absent invariant natural killer T cells, and severely diminished mucosal-associated invariant T cell numbers"

Loss of both innate-like T-cell populations.

Decreased mitogen-induced T-cell proliferation HP:0031381

Show evidence (1 reference)

PMID:26476480 SUPPORT Human Clinical

"Both patients had CD4(+) T-cell lymphopenia and decreased lymphocyte proliferation to mitogens."

Reduced mitogen proliferation in both siblings.

Increased double-negative T cell number HP:0002851

Show evidence (1 reference)

PMID:25073507 SUPPORT Human Clinical

"low NK cells and abnormally increased double-negative (DN)"

Increased double-negative T cells (gamma-delta, per the full sentence) in the compound heterozygous siblings.

Decreased memory B cell proportion HP:0030374

Show evidence (1 reference)

PMID:25073507 SUPPORT Human Clinical

"manifested as absent CD4CD45RA(+) (naïve) T and memory B cells"

Absent memory B cells in the compound heterozygous siblings.

Decreased circulating immunoglobulin concentration HP:0004313

Show evidence (2 references)

DOI:10.14785/lymphosign-2019-0001 SUPPORT Human Clinical

"The patient presented with T cell lymphopenia, reduction in CD4+CD45Ra+ cells and hypogammaglobulinemia."

Hypogammaglobulinemia in a newborn-screened patient.

PMID:40464874 SUPPORT BACKGROUND Human Clinical

"This condition presents with lymphopenia, hypogammaglobulinemia, recurrent Epstein-Barr virus (EBV) infections, EBV-associated B-cell lymphoma and epidermodysplasia verruciformis."

Background summary of the disorder in a case report, listing hypogammaglobulinemia among its features.

Increased circulating IgE concentration VERY_FREQUENT HP:0003212

Show evidence (1 reference)

PMID:29942301 SUPPORT REVIEW SYNTHESIS Human Clinical

"↓ iNKT 1/1 | High IgE level 4/5"

CORO1A row of the review's Table 1: high IgE in 4 of 5 patients tested.

Decreased natural killer cell-induced killing of target cells HP:0025808

Show evidence (1 reference)

PMID:24760828 SUPPORT In Vitro

"Here, we show that Coro1A is required for natural killer (NK) cell cytotoxic function in two human NK cell lines and ex vivo cells from a Coro1A-deficient patient."

Defective killing by ex vivo patient NK cells.

Lymphoproliferative disorder HP:0005523

Show evidence (1 reference)

PMID:23522482 SUPPORT Human Clinical

"EBV-associated B-cell lymphoproliferation at an early age"

EBV-associated lymphoproliferation in the affected siblings.

B-cell lymphoma FREQUENT HP:0012191

Show evidence (2 references)

PMID:25073507 SUPPORT Human Clinical

"the female died of EBV+ lymphomas at age 16 years"

A fatal EBV-positive B-cell lymphoma.

PMID:29942301 SUPPORT REVIEW SYNTHESIS Human Clinical

"Patients presented with severe infections, and five developed EBV-driven B cell lymphoma."

Review statement that 5 of the 9 reported CORO1A patients developed EBV-driven B-cell lymphoma, supporting the FREQUENT band.

Decreased total neutrophil count HP:0001875

Show evidence (1 reference)

DOI:10.14785/lymphosign-2019-0001 SUPPORT Human Clinical

"Uniquely, she also had persistent severe neutropenia."

Persistent severe neutropenia, described as a unique finding.

Immune 12

Severe combined immunodeficiency HP:0004430

Show evidence (2 references)

PMID:19097825 SUPPORT Human Clinical

"we identified absence of Coronin-1A in a girl with T-B+NK+ SCID who suffered recurrent infections including severe post-vaccination varicella at age 13 months"

The founding patient's T-B+NK+ SCID phenotype.

DOI:10.14785/lymphosign-2019-0004 SUPPORT Human Clinical

"Null mutations in coronin 1A result in severe combined immunodeficiency, whereas hypomorphic mutations have been associated with a somewhat milder immunological phenotype."

States the allele-dependent spectrum: SCID with null alleles, milder combined immunodeficiency with hypomorphic ones.

Recurrent viral infections HP:0004429

Show evidence (1 reference)

PMID:26476480 SUPPORT Human Clinical

"CORO1A deficiency causes T(-)B(+) natural killer-positive severe combined immunodeficiency or T-cell lymphopenia with severe viral infections."

Severe viral infection is a defining feature.

Severe varicella zoster infection FREQUENT HP:0032170

Show evidence (2 references)

PMID:26476480 SUPPORT Human Clinical

"2 young adult siblings with a history of disseminated varicella, cutaneous warts, and CD4(+) T-cell lymphopenia"

Disseminated varicella in the S401fs sibship.

PMID:29942301 SUPPORT REVIEW SYNTHESIS Human Clinical

"EBV 5/9 HPV 4/9, VZV 5/9 HSV 2/9 Parvovirus B19 1/9"

CORO1A row of the review's Table 1: VZV infection in 5 of 9 patients, supporting the FREQUENT band.

Post-vaccination varicella zoster virus infection HP:4000166

Show evidence (1 reference)

PMID:19097825 SUPPORT Human Clinical

"severe post-vaccination varicella at age 13 months"

The index patient's severe reaction to varicella vaccine.

Persistent beta-HPV infection with epidermodysplasia verruciformis-like lesions FREQUENT Persistent human papillomavirus infection HP:0020114

Show evidence (2 references)

PMID:25073507 SUPPORT Human Clinical

"Distinguishing characteristics were late clinical debut with an unusual mucocutaneous syndrome of epidermodysplasia verruciformis-human papilloma virus (EV-HPV)"

The EV-HPV mucocutaneous syndrome in the compound heterozygous siblings.

PMID:29942301 SUPPORT REVIEW SYNTHESIS Human Clinical

"Four patients had severe mucocutaneous-immunodeficiency manifestations including epidermodysplasia verruciformis-HPV (EV-HPV)"

EV-HPV in 4 patients in the review, supporting FREQUENT.

Chronic warts HP:5210306

Show evidence (1 reference)

PMID:26476480 SUPPORT Human Clinical

"2 young adult siblings with a history of disseminated varicella, cutaneous warts, and CD4(+) T-cell lymphopenia"

Chronic cutaneous warts in the S401fs siblings.

Unusual molluscum contagiosum HP:0032163

Show evidence (1 reference)

PMID:25073507 SUPPORT Human Clinical

"an unusual mucocutaneous syndrome of epidermodysplasia verruciformis-human papilloma virus (EV-HPV), molluscum contagiosum and oral-cutaneous herpetic ulcers"

Molluscum contagiosum in the compound heterozygous siblings.

Unusual HSV skin infection HP:5210233

Show evidence (1 reference)

PMID:25073507 SUPPORT Human Clinical

"molluscum contagiosum and oral-cutaneous herpetic ulcers"

Oral-cutaneous HSV-1 ulcers in the compound heterozygous siblings.

Unusual mycobacterial skin infection HP:5210242

Show evidence (1 reference)

PMID:25073507 SUPPORT Human Clinical

"the older female sibling also had a disfiguring granulomatous tuberculoid leprosy"

Tuberculoid leprosy in one sibling.

Unusual EBV infection HP:5210286

Show evidence (1 reference)

PMID:29942301 SUPPORT REVIEW SYNTHESIS Human Clinical

"EBV 5/9 HPV 4/9, VZV 5/9 HSV 2/9 Parvovirus B19 1/9"

EBV infection in 5 of 9 patients in the review's CORO1A row.

Recurrent respiratory infections FREQUENT HP:0002205

Sequelae: Bronchiectasis

Show evidence (1 reference)

PMID:29942301 SUPPORT REVIEW SYNTHESIS Human Clinical

"Lung infections 7/9 Cutaneous leprosy 1/9 Visceral leishmaniasis 1/9"

Lung infections in 7 of 9 patients in the review's CORO1A row.

Recurrent bacterial infections HP:0002718

Show evidence (1 reference)

PMID:42318436 SUPPORT Human Clinical

"Her past medical history was remarkable for multiple hospital admissions secondary to community-acquired pneumonia and urinary tract infections"

Recurrent bacterial infections in a patient with a novel CORO1A variant.

Nervous System 2

Attention deficit hyperactivity disorder HP:0007018

Show evidence (1 reference)

PMID:19097825 SUPPORT Human Clinical

"This genomic region at 16p11.2 is subject to recurrent copy number variations associated with autism spectrum disorders, including attention deficit and hyperactivity, present in our patient."

ADHD attributed to the 16p11.2 copy number variation.

Cognitive impairment FREQUENT HP:0100543

Show evidence (2 references)

PMID:29942301 SUPPORT REVIEW SYNTHESIS Human Clinical

"Neurological involvement (cognitive impairment) 3/9"

The review's CORO1A table row: cognitive impairment in 3 of 9 patients (33%), supporting the FREQUENT band.

PMID:29942301 SUPPORT REVIEW SYNTHESIS Human Clinical

"Three patients also exhibited neurological abnormalities including autism-like symptoms."

The review's text on the same three patients, including autism-like features.

Respiratory 1

Bronchiectasis HP:0002110

Show evidence (1 reference)

PMID:25073507 SUPPORT Human Clinical

"Both had bilateral bronchiectasis and the female died of EBV+ lymphomas at age 16 years."

Bilateral bronchiectasis in both compound heterozygous siblings.

Cellular 1

Short telomere length HP:0031413

Show evidence (1 reference)

PMID:25073507 SUPPORT Human Clinical

"The younger surviving male, without malignancy, had reproducibly very short telomere lengths, not before appreciated in CORO1A mutations."

Very short telomeres in one patient, noted as a novel finding.

🧬

Genetic Associations

CORO1A

Gene: CORO1A hgnc:2252 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal recessive

Show evidence (2 references)

PMID:18836449 SUPPORT Human Clinical

"a T cell-deficient, B cell-sufficient and natural killer cell-sufficient patient with severe combined immunodeficiency, whom we found had mutations in both CORO1A alleles"

Establishes CORO1A as the causative gene in the index patient.

PMID:23522482 SUPPORT Human Clinical

"We identified a homozygous inherited missense mutation in the gene encoding Coronin-1A (CORO1A) in the 3 siblings."

Independent identification of a causative CORO1A allele.

💊

Medical Actions

Allogeneic hematopoietic stem cell transplantation

Action: hematopoietic stem cell transplantation Ontology label: Hematopoietic Cell Transplantation NCIT:C15431

Platform: Cell therapy

The only curative therapy. Because the defect is intrinsic to haematopoietic cells, donor stem cells reconstitute T-cell numbers and function; two long-term successful transplants are documented, and it is proposed as an immunologic cure.

Mechanism Target:

Biallelic CORO1A Loss-of-Function Variants — Replaces CORO1A-deficient haematopoietic cells with donor cells carrying functional CORO1A.

Show evidence (2 references)

DOI:10.14785/lymphosign-2019-0004 SUPPORT Human Clinical

"HSCT using a HLA-matched unrelated donor resulted in long term engraftment and solid immune reconstitution."

A documented successful transplant with long-term immune reconstitution.

PMID:25269405 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"complete absence of coronin 1A is associated with severe combined immunodeficiency in humans"

Review confirming the SCID phenotype that transplantation is intended to correct; the transplant outcome itself is cited from the case report above.

Immunoglobulin replacement and anti-infective prophylaxis

Action: Supportive Care NCIT:C15747

Agent: immunoglobulin replacement (IgG) NCIT:C80829

Platform: Other

Supportive care while awaiting or in place of transplant: immunoglobulin replacement for hypogammaglobulinemia and poor vaccine responses, plus antibacterial and antiviral prophylaxis. Live vaccines are contraindicated, given severe post-vaccination varicella.

Mechanism Target:

Impaired Cell-Mediated Immunity to Viruses and Intracellular Pathogens — Prophylaxis and passive antibody reduce the infection burden that follows from the immune defect; they do not correct it.

Show evidence (2 references)

PMID:19097825 SUPPORT INDIRECT Human Clinical

"severe post-vaccination varicella at age 13 months"

The severe reaction to live varicella vaccine is why live vaccines are avoided; cited as the basis for the safety caveat rather than for a prophylaxis trial.

PMID:42318436 SUPPORT Human Clinical

"Given the immunological findings, subcutaneous immunoglobulin therapy was initiated at a dosing schedule of every 2 weeks in the daycare unit."

Immunoglobulin replacement given to a CORO1A-deficient child, the basis for the immunoglobulin part of this treatment.

📊

Prevalence

Worldwide, reported cases

Cases In Literature Ultra Rare

No population-based estimate exists. A 2024 report counts fewer than 20 patients with germline biallelic CORO1A variants; a 2018 review table summarizes nine.

Show evidence (2 references)

PMID:37915722 SUPPORT Human Clinical

"To date, fewer than 20 patients have been identified as having germline biallelic mutations in the coronin-1A gene (CORO1A)"

Gives the size of the reported patient population.

PMID:29942301 SUPPORT REVIEW SYNTHESIS Human Clinical

"Deficiency in the actin regulator CORO1A (Coronin-1A) has been identified in nine patients"

A review's count of the cases it tabulates; the source of the nine-patient denominators used for phenotype frequencies below.

🐁

Animal Models

Coronin-1A knockout mouse

Germline Coro1a-null mice have profound peripheral T-cell lymphopenia with impaired chemokine-directed migration and disturbed lymphocyte homeostasis, while T-cell receptor functions are relatively spared. The model reproduces the human peripheral T-cell deficiency and the migration lesion.

Species

Mouse

Genotype

Coro1a-/-

Publication

PMID:16902139

Pathograph links

Impaired T-Cell Migration and Thymic Egress recapitulates fidelity: moderate observes: cellular Coronin 1-deficient T cells fail chemokine-mediated migration, the same defect proposed to block thymic egress in patients.

Limitations: The mouse reproduces the T-cell migration and homeostasis defect but not the human-specific viral complications (EBV lymphoproliferation, beta-HPV disease), whose viruses do not infect mice.

Readouts

Chemokine-mediated T-cell migration

Direction: DECREASED

Interpretation: Migration defect corresponding to the human egress block.

Show evidence (1 reference)

PMID:16902139 SUPPORT Model Organism

"coronin 1 was required for chemokine-mediated migration"

The measured migration defect in knockout T cells.

Show evidence (1 reference)

PMID:16902139 SUPPORT Model Organism

"coronin 1 was required for chemokine-mediated migration, it was dispensable for T cell antigen receptor functions in T cells"

Establishes the model as informative for the migration node, with the TCR-sparing pattern seen in patients.

Reduced Peripheral T-Cell Survival recapitulates fidelity: moderate observes: cellular Coro1a-null T cells survive poorly; the defect was attributed to impaired TCR-induced calcium mobilization, which is where the mouse and the human S401fs data diverge (see the discussion).

Limitations: The calcium-mobilization mechanism proposed in mice is not reproduced in patients with the C-terminal S401fs allele, whose calcium flux is near normal. The mouse mechanism may therefore be allele- or species-specific.

Divergences from the human mechanism

species mismatch qualifying

Coro1a-null mouse T cells show a profound calcium-mobilization defect driving apoptosis, whereas patient T cells carrying the S401fs allele have near-normal calcium flux with the same survival defect, so the murine calcium mechanism does not transfer to that human allele.

Show evidence (1 reference)

PMID:18345003 SUPPORT Model Organism

"The absence of coronin-1, although it did not affect T cell development, resulted in a profound defect in Ca2+ mobilization, interleukin-2 production, T cell proliferation and T cell survival."

The murine survival defect and its proposed calcium mechanism.

Show evidence (1 reference)

PMID:16902139 SUPPORT Model Organism

"We generated coronin 1-/- mice and found that coronin 1 exerted an inhibitory effect on cellular steady-state F-actin formation via an Arp2/3-dependent mechanism."

Attests the model recapitulates the core actin-regulatory lesion.

{ }

Source YAML

click to show

name: Severe Combined Immunodeficiency Due To CORO1A Deficiency
creation_date: "2026-09-28T20:00:00Z"
category: Mendelian
synonyms:
- coronin-1A deficiency
- SCID due to CORO1A deficiency
- SCID due to coronin-1A deficiency
- severe combined immunodeficiency due to coronin-1A deficiency
- immunodeficiency 8
- immunodeficiency type 8
- immunodeficiency 8 with lymphoproliferation
- IMD8
disease_term:
  preferred_term: severe combined immunodeficiency due to CORO1A deficiency
  term:
    id: MONDO:0014168
    label: severe combined immunodeficiency due to CORO1A deficiency
parents:
- Severe combined immunodeficiency
- Combined immunodeficiency
description: >-
  An autosomal recessive inborn error of immunity caused by biallelic
  loss-of-function variants in CORO1A, which encodes coronin-1A, an actin
  regulator expressed mainly in haematopoietic cells. The index patient had
  T-B+NK+ severe combined immunodeficiency with a thymus that was paradoxically
  detectable, and later families widened the picture to a combined
  immunodeficiency of childhood or young adulthood dominated by severe viral
  disease: EBV-driven B-cell lymphoproliferation and lymphoma, disseminated or
  post-vaccination varicella, epidermodysplasia verruciformis-like beta-HPV
  disease, molluscum contagiosum and herpetic ulcers.

  The mechanism is a failure of cytoskeletal regulation rather than of antigen
  receptor rearrangement or cytokine signalling. Coronin-1A restrains
  Arp2/3-dependent filamentous actin assembly; without it, lymphocytes
  accumulate F-actin, mature T cells migrate poorly and are not released from
  the thymus, and peripheral T cells die more readily. The result is a profound
  deficiency of naive T cells with a restricted repertoire and near-absent
  innate-like T cells (iNKT and MAIT). NK-cell killing also depends on
  coronin-1A-mediated F-actin deconstruction at the lytic synapse, and loss of
  T, NK and innate-like T-cell control of EBV-infected B cells is the route to
  the lymphoproliferative disease that marks this disorder.

  Two caveats shape the entry. First, the clinical series is very small, so
  the frequencies recorded here come from a nine-patient review table and
  should be read as such. Second, the mouse and human data disagree on one
  point: Coro1a-null mouse T cells have a severe calcium-mobilization defect
  that was proposed to explain their poor survival, whereas T cells from
  patients carrying a C-terminal frameshift allele have poor survival with
  near-normal calcium flux. That disagreement is recorded as a discussion
  rather than resolved in the pathograph.

  One patient's attention deficit hyperactivity disorder is attributed by its
  authors to the 600-kb 16p11.2 deletion that removed her second CORO1A allele,
  not to coronin-1A loss itself; the entry models it through a separate
  contiguous-gene node. No GeneReviews chapter exists for this disorder
  (checked against the Bookshelf index and PubMed). No pathophysiology node
  declares conforms_to; kb/modules/ has no module for cortical actin
  regulation in lymphocytes.
classifications:
  harrisons_chapter:
  - classification_value: IMMUNE_RHEUMATOLOGIC
    evidence:
    - reference: PMID:18836449
      reference_title: "The actin regulator coronin 1A is mutant in a thymic egress-deficient mouse strain and in a patient with severe combined immunodeficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "a T cell-deficient, B cell-sufficient and natural killer cell-sufficient patient with severe combined immunodeficiency, whom we found had mutations in both CORO1A alleles"
      explanation: >-
        The disorder is a severe combined immunodeficiency, an immune-system
        disease belonging to Harrison's immunology part.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:25073507
      reference_title: "Compound heterozygous CORO1A mutations in siblings with a mucocutaneous-immunodeficiency syndrome of epidermodysplasia verruciformis-HPV, molluscum contagiosum and granulomatous tuberculoid leprosy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Coronin-1A deficiency is a recently recognized autosomal recessive primary immunodeficiency caused by mutations in CORO1A"
      explanation: >-
        A monogenic, autosomal recessive disorder, supporting placement in
        Harrison's genetics-and-disease part as well.
  iuis_category:
    classification_value: combined immunodeficiency
    notes: >-
      The founding patient had the T-B+NK+ SCID immunophenotype, which the IUIS
      scheme files in Table 1 (immunodeficiencies affecting cellular and humoral
      immunity) rather than among the syndromic combined immunodeficiencies.
    evidence:
    - reference: PMID:18836449
      reference_title: "The actin regulator coronin 1A is mutant in a thymic egress-deficient mouse strain and in a patient with severe combined immunodeficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "a T cell-deficient, B cell-sufficient and natural killer cell-sufficient patient with severe combined immunodeficiency, whom we found had mutations in both CORO1A alleles"
      explanation: >-
        Establishes the T-B+NK+ severe combined immunodeficiency phenotype that
        places the disorder in the IUIS combined-immunodeficiency table.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Affected individuals carry two deleterious CORO1A alleles, homozygous in
    consanguineous families or compound heterozygous, including one case where
    the second allele was removed by a de novo 16p11.2 deletion.
  evidence:
  - reference: PMID:25073507
    reference_title: "Compound heterozygous CORO1A mutations in siblings with a mucocutaneous-immunodeficiency syndrome of epidermodysplasia verruciformis-HPV, molluscum contagiosum and granulomatous tuberculoid leprosy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Coronin-1A deficiency is a recently recognized autosomal recessive primary immunodeficiency caused by mutations in CORO1A"
    explanation: States the autosomal recessive mode of inheritance directly.
  - reference: PMID:23522482
    reference_title: "Whole-exome sequencing identifies Coronin-1A deficiency in 3 siblings with immunodeficiency and EBV-associated B-cell lymphoproliferation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a homozygous inherited missense mutation in the gene encoding Coronin-1A (CORO1A) in the 3 siblings."
    explanation: >-
      Homozygosity in three affected siblings of a consanguineous family is the
      segregation pattern expected for recessive inheritance.
prevalence:
- population: Worldwide, reported cases
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population-based estimate exists. A 2024 report counts fewer than 20
    patients with germline biallelic CORO1A variants; a 2018 review table
    summarizes nine.
  evidence:
  - reference: PMID:37915722
    reference_title: "Novel hemizygous CORO1A variant leads to combined immunodeficiency with defective platelet calcium signaling and cell mobility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To date, fewer than 20 patients have been identified as having germline biallelic mutations in the coronin-1A gene (CORO1A)"
    explanation: Gives the size of the reported patient population.
  - reference: PMID:29942301
    reference_title: "Inherited Immunodeficiencies With High Predisposition to Epstein-Barr Virus-Driven Lymphoproliferative Diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Deficiency in the actin regulator CORO1A (Coronin-1A) has been identified in nine patients"
    explanation: >-
      A review's count of the cases it tabulates; the source of the
      nine-patient denominators used for phenotype frequencies below.
pathophysiology:
- name: Biallelic CORO1A Loss-of-Function Variants
  biological_scale: MOLECULAR
  description: >-
    Germline biallelic CORO1A variants: frameshift truncations, a homozygous
    beta-propeller missense change (p.V134M) that almost abolishes protein
    expression, a paternal 2-bp deletion paired with a de novo 16p11.2
    deletion, and a homozygous C-terminal frameshift (p.S401fs) that is
    expressed but cannot oligomerize or associate with the cytoskeleton. Every
    reported allele removes coronin-1A protein or the domains it needs to act
    on actin.
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  genes:
  - preferred_term: CORO1A
    term:
      id: hgnc:2252
      label: CORO1A
  molecular_functions:
  - preferred_term: actin filament binding
    modifier: DECREASED
    term:
      id: GO:0051015
      label: actin filament binding
  downstream:
  - target: Loss of Coronin-1A Inhibition of Arp2/3
    causal_link_type: DIRECT
    description: >-
      Absent or truncated coronin-1A removes the protein's inhibitory action on
      the Arp2/3 actin-nucleation complex.
    evidence:
    - reference: PMID:26476480
      reference_title: "Recurrent viral infections associated with a homozygous CORO1A mutation that disrupts oligomerization and cytoskeletal association."
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: BACKGROUND
      snippet: "the CC domain is necessary for the inhibitory role of CORO1A on Arp2/3-dependent F-actin branching and accumulation"
      explanation: >-
        Background statement of an in-vitro biochemical finding: the C-terminal domain lost in
        the S401fs allele is the one required for Arp2/3 inhibition, linking the
        lesion to the loss of that activity.
  evidence:
  - reference: PMID:26476480
    reference_title: Recurrent viral infections associated with a homozygous CORO1A mutation that disrupts oligomerization and cytoskeletal association.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "CORO1A associates with the actin cytoskeleton, binds to F-actin, and localizes at sites of actin assembly."
    explanation: >-
      Grounds the molecular-function binding: coronin-1A is an F-actin-binding
      protein. The same paper shows the S401fs allele loses cytoskeletal
      association, and the other alleles remove the protein, hence DECREASED.
  - reference: PMID:18836449
    reference_title: "The actin regulator coronin 1A is mutant in a thymic egress-deficient mouse strain and in a patient with severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a T cell-deficient, B cell-sufficient and natural killer cell-sufficient patient with severe combined immunodeficiency, whom we found had mutations in both CORO1A alleles"
    explanation: The founding patient carried mutations on both CORO1A alleles.
  - reference: PMID:19097825
    reference_title: "Severe combined immunodeficiency (SCID) and attention deficit hyperactivity disorder (ADHD) associated with a Coronin-1A mutation and a chromosome 16p11.2 deletion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Molecular analysis revealed a 2 bp deletion in the paternal CORO1A coding sequence paired with a 600 kb de novo deletion encompassing CORO1A on the maternal allele."
    explanation: >-
      The genotype of the same patient: a frameshift allele in trans with a
      deletion of the whole gene.
  - reference: PMID:23522482
    reference_title: "Whole-exome sequencing identifies Coronin-1A deficiency in 3 siblings with immunodeficiency and EBV-associated B-cell lymphoproliferation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This mutation, p. V134M, results in the substitution of an evolutionarily conserved amino acid within the β-propeller domain, which abrogates almost completely the protein expression in the patients' cells."
    explanation: >-
      A missense allele that acts as loss of function by almost abolishing
      protein expression in patient cells.
  - reference: PMID:25073507
    reference_title: "Compound heterozygous CORO1A mutations in siblings with a mucocutaneous-immunodeficiency syndrome of epidermodysplasia verruciformis-HPV, molluscum contagiosum and granulomatous tuberculoid leprosy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found the compound heterozygous CORO1A variants: c.248_249delCT (p.P83RfsX10) and a novel mutation c.1077delC (p.Q360RfsX44)"
    explanation: Two frameshift alleles in trans in an affected sibship.
  - reference: PMID:26476480
    reference_title: "Recurrent viral infections associated with a homozygous CORO1A mutation that disrupts oligomerization and cytoskeletal association."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The CORO1A(S401fs) mutant was expressed in the patients' lymphocytes at a level comparable with that of wild-type CORO1A in normal lymphocytes but did not oligomerize and had impaired cytoskeletal association."
    explanation: >-
      An allele that preserves protein amount but loses oligomerization and
      cytoskeletal association, so it is functionally deficient rather than
      absent.
- name: Loss of Coronin-1A Inhibition of Arp2/3
  biological_scale: MOLECULAR
  description: >-
    Coronin-1A binds F-actin and the Arp2/3 complex and restrains
    Arp2/3-mediated actin branching; its C-terminal coiled-coil domain is
    required for that inhibition. Loss of the protein or of that domain removes
    the brake on steady-state F-actin formation.
  biological_processes:
  - preferred_term: negative regulation of Arp2/3 complex-mediated actin nucleation
    modifier: DECREASED
    term:
      id: GO:0034316
      label: negative regulation of Arp2/3 complex-mediated actin nucleation
  downstream:
  - target: Filamentous Actin Accumulation in Lymphocytes
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:16902139
      reference_title: "Requirement for coronin 1 in T lymphocyte trafficking and cellular homeostasis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We generated coronin 1-/- mice and found that coronin 1 exerted an inhibitory effect on cellular steady-state F-actin formation via an Arp2/3-dependent mechanism."
      explanation: >-
        In knockout mice, loss of coronin 1 releases an Arp2/3-dependent brake
        on F-actin formation.
  evidence:
  - reference: PMID:16902139
    reference_title: "Requirement for coronin 1 in T lymphocyte trafficking and cellular homeostasis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "coronin 1 exerted an inhibitory effect on cellular steady-state F-actin formation via an Arp2/3-dependent mechanism"
    explanation: Establishes the Arp2/3-dependent inhibitory activity that is lost.
- name: Filamentous Actin Accumulation in Lymphocytes
  biological_scale: CELLULAR
  description: >-
    T cells lacking functional coronin-1A carry excess F-actin, and at the NK
    lytic synapse the F-actin density that coronin-1A normally deconstructs is
    not cleared. Accumulated, poorly dynamic cortical actin is the shared
    cellular lesion behind the migration, survival and cytotoxicity defects
    that follow.
  biological_processes:
  - preferred_term: actin filament depolymerization
    modifier: DECREASED
    term:
      id: GO:0030042
      label: actin filament depolymerization
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  - preferred_term: natural killer cell
    term:
      id: CL:0000623
      label: natural killer cell
  downstream:
  - target: Impaired T-Cell Migration and Thymic Egress
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:16902139
      reference_title: "Requirement for coronin 1 in T lymphocyte trafficking and cellular homeostasis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Whereas coronin 1 was required for chemokine-mediated migration, it was dispensable for T cell antigen receptor functions in T cells."
      explanation: >-
        The same knockout T cells that accumulate F-actin fail
        chemokine-directed migration.
  - target: Reduced Peripheral T-Cell Survival
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:26476480
      reference_title: "Recurrent viral infections associated with a homozygous CORO1A mutation that disrupts oligomerization and cytoskeletal association."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      snippet: "In our patients, we propose that the failure of the CORO1AS401fs to oligomerize and to associate with the cytoskeleton leads to abnormal accumulation of F-actin and impaired T cell survival."
      explanation: >-
        The authors propose F-actin accumulation as the cause of the survival
        defect in their patients; this is stated as a proposal, not
        demonstrated, hence INDIRECT.
    - reference: PMID:16902139
      reference_title: "Requirement for coronin 1 in T lymphocyte trafficking and cellular homeostasis."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Moreover, actin dynamics, through a mitochondrial pathway, was linked to lymphocyte homeostasis."
      explanation: >-
        Mouse evidence linking the actin defect to lymphocyte homeostasis
        through a mitochondrial (apoptotic) pathway.
  - target: Impaired NK-Cell Lytic Synapse Function
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:24760828
      reference_title: "Lytic immune synapse function requires filamentous actin deconstruction by Coronin 1A."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "we demonstrate that Coro1A promotes the deconstruction of F-actin density that facilitates effective delivery of lytic granules to the IS"
      explanation: >-
        Without coronin-1A-mediated F-actin deconstruction, lytic granules are
        not delivered effectively to the immunological synapse.
  evidence:
  - reference: PMID:26476480
    reference_title: "Recurrent viral infections associated with a homozygous CORO1A mutation that disrupts oligomerization and cytoskeletal association."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The F-actin content of the patients’ CD4+ and CD8+ T cells was significantly higher than that of control T cells"
    explanation: Measured F-actin excess in patient CD4+ and CD8+ T cells.
  - reference: PMID:24760828
    reference_title: "Lytic immune synapse function requires filamentous actin deconstruction by Coronin 1A."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Coronin 1A (Coro1A) is the hematopoietic-specific member of the Coronin family of actin regulators that promote F-actin disassembly."
    explanation: Coronin-1A's normal role is to promote F-actin disassembly.
- name: Impaired T-Cell Migration and Thymic Egress
  biological_scale: CELLULAR
  description: >-
    Mature T cells lacking coronin-1A migrate poorly and are not efficiently
    released from the thymus, so the thymus is present but peripheral output
    is low. In patients this shows as very few recent thymic emigrants and
    low T-cell receptor excision circles.
  biological_processes:
  - preferred_term: T cell migration
    modifier: DECREASED
    term:
      id: GO:0072678
      label: T cell migration
  - preferred_term: thymocyte migration
    modifier: DECREASED
    term:
      id: GO:0072679
      label: thymocyte migration
  cell_types:
  - preferred_term: thymocyte
    term:
      id: CL:0000893
      label: thymocyte
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  downstream:
  - target: Profound Naive and Innate-Like T-Cell Deficiency
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26476480
      reference_title: "Recurrent viral infections associated with a homozygous CORO1A mutation that disrupts oligomerization and cytoskeletal association."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "indicating that the patients’ CD4+ lymphopenia stemmed from defective T cell survival as well as decreased thymic output"
      explanation: >-
        Attributes the patients' CD4+ lymphopenia in part to decreased thymic
        output.
  - target: Abnormally low T cell receptor excision circle level
    description: >-
      Reduced thymic output means fewer recent thymic emigrants and hence few
      T-cell receptor excision circles.
  evidence:
  - reference: PMID:18836449
    reference_title: "The actin regulator coronin 1A is mutant in a thymic egress-deficient mouse strain and in a patient with severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Our findings establish a function for coronin 1A in T cell egress"
    explanation: >-
      Coronin-1A mutant mice establish the thymic egress function, which the
      same paper connects to the human SCID patient.
  - reference: PMID:19097825
    reference_title: "Severe combined immunodeficiency (SCID) and attention deficit hyperactivity disorder (ADHD) associated with a Coronin-1A mutation and a chromosome 16p11.2 deletion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Murine Coronin-1A is essential for the release of T cells from the thymus, consistent with the paradoxically detectable thymus in our patient."
    explanation: >-
      A detectable thymus in a T-lymphopenic patient fits an egress block
      rather than failed thymopoiesis.
  - reference: PMID:26476480
    reference_title: "Recurrent viral infections associated with a homozygous CORO1A mutation that disrupts oligomerization and cytoskeletal association."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Quantification of CD4+CD31+CD45RA+ recent thymic emigrants in both patients demonstrated that CORO1ASer401fs severely impairs thymic output"
    explanation: Direct measurement of low thymic output in patients.
- name: Reduced Peripheral T-Cell Survival
  biological_scale: CELLULAR
  description: >-
    Patient CD4+ T cells show increased apoptosis at rest and after
    stimulation, and re-expressing wild-type CORO1A in Coro1a-null mouse T
    cells reduces their apoptosis. In mice the survival defect was attributed
    to defective TCR-induced calcium mobilization; in patients with the S401fs
    allele calcium flux was near normal, so calcium is not the whole
    explanation (see the discussion below).
  biological_processes:
  - preferred_term: T cell apoptotic process
    modifier: INCREASED
    term:
      id: GO:0070231
      label: T cell apoptotic process
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  downstream:
  - target: Profound Naive and Innate-Like T-Cell Deficiency
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26476480
      reference_title: "Recurrent viral infections associated with a homozygous CORO1A mutation that disrupts oligomerization and cytoskeletal association."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "indicating that the patients’ CD4+ lymphopenia stemmed from defective T cell survival as well as decreased thymic output"
      explanation: >-
        Attributes the CD4+ lymphopenia in part to defective T-cell survival.
  evidence:
  - reference: PMID:26476480
    reference_title: "Recurrent viral infections associated with a homozygous CORO1A mutation that disrupts oligomerization and cytoskeletal association."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "resting and PHA-stimulated CD4+ T cells in both siblings had increased Annexin V staining compared to control cells"
    explanation: Increased apoptosis measured in patient CD4+ T cells.
  - reference: PMID:26476480
    reference_title: "Recurrent viral infections associated with a homozygous CORO1A mutation that disrupts oligomerization and cytoskeletal association."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "lentiviral transduction with WT CORO1A, but not the CORO1ASer401fs mutant, reduced apoptosis in CORO1A−/− T cells"
    explanation: >-
      Rescue of apoptosis by wild-type CORO1A in knockout T cells ties the
      survival defect to coronin-1A function.
  - reference: PMID:18345003
    reference_title: "Regulation of T cell survival through coronin-1-mediated generation of inositol-1,4,5-trisphosphate and calcium mobilization after T cell receptor triggering."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The absence of coronin-1, although it did not affect T cell development, resulted in a profound defect in Ca2+ mobilization, interleukin-2 production, T cell proliferation and T cell survival."
    explanation: >-
      Knockout mice show the survival defect; the calcium-mobilization
      mechanism proposed here is not reproduced in patient cells with the
      S401fs allele.
- name: Impaired NK-Cell Lytic Synapse Function
  biological_scale: CELLULAR
  description: >-
    NK cells need coronin-1A to clear synaptic F-actin so that lytic granules
    reach the target. NK cells from a coronin-1A-deficient patient and a
    patient with a hemizygous missense allele had reduced cytotoxicity. The
    S401fs siblings, whose truncated protein keeps its beta-propeller domain,
    had normal NK killing, so this defect appears to depend on the allele.
  biological_processes:
  - preferred_term: natural killer cell mediated cytotoxicity
    modifier: DECREASED
    term:
      id: GO:0042267
      label: natural killer cell mediated cytotoxicity
  cellular_components:
  - preferred_term: immunological synapse
    term:
      id: GO:0001772
      label: immunological synapse
  cell_types:
  - preferred_term: natural killer cell
    term:
      id: CL:0000623
      label: natural killer cell
  downstream:
  - target: Failure of Immune Control of EBV-Infected B Cells
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:29225606
      reference_title: "Epstein-Barr Virus-Specific Immune Control by Innate Lymphocytes."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "several innate lymphocyte populations seem to target different stages of EBV infection and are compromised in primary immunodeficiencies that render individuals susceptible to symptomatic EBV infection"
      explanation: >-
        A review placing NK and other innate lymphocytes among the effectors of
        EBV control that primary immunodeficiencies disable; not specific to
        CORO1A, hence INDIRECT.
  evidence:
  - reference: PMID:24760828
    reference_title: "Lytic immune synapse function requires filamentous actin deconstruction by Coronin 1A."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here, we show that Coro1A is required for natural killer (NK) cell cytotoxic function in two human NK cell lines and ex vivo cells from a Coro1A-deficient patient."
    explanation: Reduced cytotoxicity in ex vivo NK cells from a patient.
  - reference: PMID:37915722
    reference_title: "Novel hemizygous CORO1A variant leads to combined immunodeficiency with defective platelet calcium signaling and cell mobility."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The observed mutation resulted in impaired natural killer cell cytotoxicity and platelet calcium signaling."
    explanation: A second patient allele with impaired NK cytotoxicity.
  - reference: PMID:26476480
    reference_title: "Recurrent viral infections associated with a homozygous CORO1A mutation that disrupts oligomerization and cytoskeletal association."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: "PBMCs from both patients demonstrated normal cytotoxic cell killing of K562 target cells at 4 hours"
    explanation: >-
      Contradicts a universal NK killing defect: patients with the C-terminal
      S401fs allele had normal killing. The authors attribute this to the
      retained beta-propeller domain, so the defect is allele-dependent.
- name: Profound Naive and Innate-Like T-Cell Deficiency
  biological_scale: ORGANISM
  description: >-
    The defining immunological state: very low naive CD4+ and CD8+ T cells
    with a restricted T-cell repertoire, near-absent invariant NKT cells and
    severely reduced MAIT cells, while B-cell and NK-cell numbers are
    relatively preserved in the index SCID patient. Hypomorphic alleles
    produce the same naive T-cell defect with oligoclonal expansion of memory
    T cells.
  cell_types:
  - preferred_term: naive CD4+ T cell
    term:
      id: CL:0000895
      label: naive thymus-derived CD4-positive, alpha-beta T cell
  - preferred_term: naive CD8+ T cell
    term:
      id: CL:0000900
      label: naive thymus-derived CD8-positive, alpha-beta T cell
  - preferred_term: invariant NKT cell
    term:
      id: CL:0000921
      label: type I NK T cell
  - preferred_term: mucosal-associated invariant T cell
    term:
      id: CL:0000940
      label: mucosal-associated invariant T cell
  biological_processes:
  - preferred_term: T cell homeostasis
    modifier: DECREASED
    term:
      id: GO:0043029
      label: T cell homeostasis
  downstream:
  - target: Impaired Cell-Mediated Immunity to Viruses and Intracellular Pathogens
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26476480
      reference_title: "Recurrent viral infections associated with a homozygous CORO1A mutation that disrupts oligomerization and cytoskeletal association."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Our studies demonstrate the importance of intact CORO1A C-terminal domains in thymic egress and T-cell survival, as well as in defense against viral pathogens."
      explanation: >-
        Links the thymic egress and T-cell survival defects to defective
        antiviral defence in patients.
  - target: Failure of Immune Control of EBV-Infected B Cells
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:25269405
      reference_title: "The expanding spectrum of human coronin 1A deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "hypomorphic mutations lead to a profound defect in naïve T cells, expansion of oligoclonal memory T cells, and exquisite susceptibility to EBV-associated B cell lymphoproliferation"
      explanation: >-
        A review pairing the naive T-cell defect with the characteristic EBV
        susceptibility in patients with hypomorphic alleles.
    - reference: PMID:26424649
      reference_title: "Primary Immunodeficiencies Associated with EBV Disease."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "EBV-infected B cells are controlled primarily by NK cells, iNKT cells, CD4 T cells, and CD8 T cells."
      explanation: >-
        General statement of which lymphocytes control EBV-infected B cells;
        the T and iNKT populations lost in this disorder are among them.
  - target: Impaired T-Cell-Dependent Humoral Immunity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:18199416
      reference_title: "The lupus-related Lmb3 locus contains a disease-suppressing Coronin-1A gene mutation."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "T-dependent humoral responses were impaired, but no intrinsic B cell defects were detected."
      explanation: >-
        In Coro1a nonsense-mutant mice the humoral defect is T-dependent, with
        no intrinsic B-cell defect, which is the basis for routing the humoral
        phenotypes through the T-cell deficiency. Mouse evidence, hence
        INDIRECT.
  - target: Severe combined immunodeficiency
  - target: Decreased total T cell count
  - target: Decreased naive CD4+ T cell proportion
  - target: Abnormal TCR repertoire
  - target: Decreased mucosal-associated invariant T cell proportion
  evidence:
  - reference: PMID:23522482
    reference_title: "Whole-exome sequencing identifies Coronin-1A deficiency in 3 siblings with immunodeficiency and EBV-associated B-cell lymphoproliferation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition to a significant diminution of naive T-cell numbers, we found impaired development of a diverse T-cell repertoire, near-to-absent invariant natural killer T cells, and severely diminished mucosal-associated invariant T cell numbers."
    explanation: >-
      Documents every component of this node: naive T-cell loss, restricted
      repertoire, and loss of iNKT and MAIT cells.
  - reference: PMID:29942301
    reference_title: "Inherited Immunodeficiencies With High Predisposition to Epstein-Barr Virus-Driven Lymphoproliferative Diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Patients with CORO1A deficiency are characterized by a profound T cell lymphopenia with strongly decreased or nearly absent naïve cells associated with defective thymic output."
    explanation: Review synthesis across the reported patients.
- name: Impaired Cell-Mediated Immunity to Viruses and Intracellular Pathogens
  biological_scale: ORGANISM
  description: >-
    With few naive T cells, patients fail to contain viruses that are normally
    held in check by T cells: varicella zoster (including vaccine strain),
    beta-human papillomaviruses, molluscum contagiosum virus and herpes
    simplex virus. One patient also developed tuberculoid leprosy, an
    intracellular bacterial infection.
  biological_processes:
  - preferred_term: T cell mediated immunity
    modifier: DECREASED
    term:
      id: GO:0002456
      label: T cell mediated immunity
  downstream:
  - target: Recurrent viral infections
  - target: Severe varicella zoster infection
  - target: Post-vaccination varicella zoster virus infection
  - target: Persistent beta-HPV infection with epidermodysplasia verruciformis-like lesions
    evidence:
    - reference: PMID:29946305
      reference_title: "Epidermodysplasia Verruciformis: Inborn Errors of Immunity to Human Beta-Papillomaviruses."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "the control of beta-HPV infections requires both EVER1/EVER2-dependent keratinocyte-intrinsic immunity and T cell-dependent adaptive immunity"
      explanation: >-
        Beta-HPV control needs T cell-dependent immunity, which this node says
        is lost; the review covers inborn errors of T-cell immunity generally,
        hence INDIRECT.
  - target: Chronic warts
  - target: Unusual molluscum contagiosum
  - target: Unusual HSV skin infection
  - target: Unusual mycobacterial skin infection
  evidence:
  - reference: PMID:26476480
    reference_title: "Recurrent viral infections associated with a homozygous CORO1A mutation that disrupts oligomerization and cytoskeletal association."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CORO1A deficiency causes T(-)B(+) natural killer-positive severe combined immunodeficiency or T-cell lymphopenia with severe viral infections."
    explanation: Severe viral infection is the clinical expression of the T-cell defect.
- name: Impaired T-Cell-Dependent Humoral Immunity
  biological_scale: ORGANISM
  description: >-
    Some patients have low memory B cells, hypogammaglobulinemia or poor
    vaccine responses, and several have high IgE. The mouse data place the
    defect in T-cell help rather than in B cells. It is not universal: the
    S401fs siblings had normal immunoglobulins and specific antibody
    responses.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  downstream:
  - target: Decreased memory B cell proportion
  - target: Decreased circulating immunoglobulin concentration
  - target: Recurrent respiratory infections
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:29942301
      reference_title: "Inherited Immunodeficiencies With High Predisposition to Epstein-Barr Virus-Driven Lymphoproliferative Diseases."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "This may be related to the hypogammaglobulinemia and/or dysgammaglobulinemia associated with low number of CD27+ memory B cells that are frequently observed in these defects."
      explanation: >-
        The review relates the recurrent lung infections of this group of
        EBV-susceptibility disorders, CORO1A deficiency among them, to their
        humoral defect. It is hedged ("may be") and group-level, hence
        INDIRECT.
  - target: Recurrent bacterial infections
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Hypogammaglobulinemia and impaired antibody responses predispose to
      recurrent bacterial infection.
    evidence:
    - reference: PMID:29942301
      reference_title: "Inherited Immunodeficiencies With High Predisposition to Epstein-Barr Virus-Driven Lymphoproliferative Diseases."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "Bacterial infections, in particular recurrent lung infections are noticed in a number of patients and can be the initial clinical presentation."
      explanation: >-
        The review notes recurrent bacterial infections in this disorder group;
        group-level and not CORO1A-specific, hence INDIRECT.
  evidence:
  - reference: PMID:18199416
    reference_title: "The lupus-related Lmb3 locus contains a disease-suppressing Coronin-1A gene mutation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "T-dependent humoral responses were impaired, but no intrinsic B cell defects were detected."
    explanation: Mouse evidence that the humoral defect is T-cell dependent.
  - reference: PMID:25073507
    reference_title: "Compound heterozygous CORO1A mutations in siblings with a mucocutaneous-immunodeficiency syndrome of epidermodysplasia verruciformis-HPV, molluscum contagiosum and granulomatous tuberculoid leprosy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "manifested as absent CD4CD45RA(+) (naïve) T and memory B cells, low NK cells"
    explanation: Patients lacking memory B cells alongside naive T cells.
- name: Failure of Immune Control of EBV-Infected B Cells
  biological_scale: ORGANISM
  description: >-
    EBV infection is normally held latent by cytotoxic T cells, NK cells and
    iNKT cells. With these compromised, EBV-infected B cells proliferate.
    Susceptibility to EBV-driven disease is the most consistent clinical
    feature across CORO1A kindreds.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  downstream:
  - target: EBV-Driven B-Cell Lymphoproliferation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29225606
      reference_title: "Epstein-Barr Virus-Specific Immune Control by Innate Lymphocytes."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "In most persistently EBV-infected individuals, potent cytotoxic lymphocyte responses prevent EBV-associated pathologies."
      explanation: >-
        General statement that cytotoxic lymphocyte control is what prevents
        EBV pathology; when that control fails, as here, EBV-associated
        pathology follows.
  - target: Unusual EBV infection
  evidence:
  - reference: PMID:23522482
    reference_title: "Whole-exome sequencing identifies Coronin-1A deficiency in 3 siblings with immunodeficiency and EBV-associated B-cell lymphoproliferation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings define a new clinical entity of a primary immunodeficiency with increased susceptibility to EBV-induced lymphoproliferation in patients associated with hypomorphic Coronin-1A mutation."
    explanation: Defines EBV susceptibility as a hallmark of the disorder.
  - reference: PMID:29942301
    reference_title: "Inherited Immunodeficiencies With High Predisposition to Epstein-Barr Virus-Driven Lymphoproliferative Diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Among them are SH2D1A (SAP), XIAP, ITK, MAGT1, CD27, CD70, CTPS1, RASGRP1, and CORO1A deficiencies."
    explanation: >-
      Lists CORO1A deficiency among the inherited disorders with a high risk of
      EBV-associated lymphoproliferative disease.
- name: EBV-Driven B-Cell Lymphoproliferation
  biological_scale: TISSUE
  description: >-
    EBV-positive B-cell lymphoproliferative disease and B-cell lymphoma, often
    in early childhood and in several cases fatal.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  downstream:
  - target: Lymphoproliferative disorder
  - target: B-cell lymphoma
  evidence:
  - reference: PMID:23522482
    reference_title: "Whole-exome sequencing identifies Coronin-1A deficiency in 3 siblings with immunodeficiency and EBV-associated B-cell lymphoproliferation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We evaluated 3 siblings from a consanguineous family presenting with EBV-associated B-cell lymphoproliferation at an early age"
    explanation: EBV-associated B-cell lymphoproliferation in three affected siblings.
  - reference: PMID:25073507
    reference_title: "Compound heterozygous CORO1A mutations in siblings with a mucocutaneous-immunodeficiency syndrome of epidermodysplasia verruciformis-HPV, molluscum contagiosum and granulomatous tuberculoid leprosy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the female died of EBV+ lymphomas at age 16 years"
    explanation: A fatal EBV-positive lymphoma in a second kindred.
- name: Co-occurring 16p11.2 Contiguous Gene Deletion
  biological_scale: MOLECULAR
  description: >-
    In at least two patients the second CORO1A allele was removed by a
    16p11.2 microdeletion that also deletes neighbouring genes. The
    neurodevelopmental features of the deletion are a contiguous-gene effect
    and are not attributed to coronin-1A loss.
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  downstream:
  - target: Biallelic CORO1A Loss-of-Function Variants
    causal_link_type: DIRECT
    description: >-
      The deletion removes CORO1A on one chromosome and so supplies one of the
      two deficient alleles.
  - target: Cognitive impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Candidate explanation only. At least two patients carried the 16p11.2
      deletion, but the review reporting cognitive impairment in 3 of 9 patients
      does not say which patients were affected, so the contribution of the
      deletion versus coronin-1A loss is not established.
  - target: Attention deficit hyperactivity disorder
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:19097825
      reference_title: "Severe combined immunodeficiency (SCID) and attention deficit hyperactivity disorder (ADHD) associated with a Coronin-1A mutation and a chromosome 16p11.2 deletion."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This genomic region at 16p11.2 is subject to recurrent copy number variations associated with autism spectrum disorders, including attention deficit and hyperactivity, present in our patient."
      explanation: >-
        The authors link the patient's attention deficit and hyperactivity to
        the 16p11.2 copy number variation.
  evidence:
  - reference: PMID:19097825
    reference_title: "Severe combined immunodeficiency (SCID) and attention deficit hyperactivity disorder (ADHD) associated with a Coronin-1A mutation and a chromosome 16p11.2 deletion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a 600 kb de novo deletion encompassing CORO1A on the maternal allele"
    explanation: The deletion that forms one CORO1A allele in the first reported patient.
  - reference: PMID:37915722
    reference_title: "Novel hemizygous CORO1A variant leads to combined immunodeficiency with defective platelet calcium signaling and cell mobility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in combination with a de novo heterozygous microdeletion of chromosome 16p11.2"
    explanation: A second patient in whom a 16p11.2 microdeletion accompanies the CORO1A variant.
phenotypes:
- category: Immune
  name: Severe combined immunodeficiency
  description: >-
    The index patient had T-B+NK+ SCID. Later patients with hypomorphic or
    C-terminal alleles have a combined immunodeficiency presenting later in
    childhood or young adulthood, so SCID is the severe end of the spectrum
    rather than a constant feature.
  phenotype_term:
    preferred_term: T-B+NK+ severe combined immunodeficiency
    term:
      id: HP:0004430
      label: Severe combined immunodeficiency
  evidence:
  - reference: PMID:19097825
    reference_title: "Severe combined immunodeficiency (SCID) and attention deficit hyperactivity disorder (ADHD) associated with a Coronin-1A mutation and a chromosome 16p11.2 deletion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified absence of Coronin-1A in a girl with T-B+NK+ SCID who suffered recurrent infections including severe post-vaccination varicella at age 13 months"
    explanation: The founding patient's T-B+NK+ SCID phenotype.
  - reference: DOI:10.14785/lymphosign-2019-0004
    reference_title: "Successful hematopoietic stem cell transplantation in a patient with a novel mutation in coronin 1A"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Null mutations in coronin 1A result in severe combined immunodeficiency, whereas hypomorphic mutations have been associated with a somewhat milder immunological phenotype."
    explanation: >-
      States the allele-dependent spectrum: SCID with null alleles, milder
      combined immunodeficiency with hypomorphic ones.
- category: Immune
  name: Decreased total T cell count
  phenotype_term:
    preferred_term: T-cell lymphopenia
    term:
      id: HP:0005403
      label: Decreased total T cell count
  evidence:
  - reference: PMID:18836449
    reference_title: "The actin regulator coronin 1A is mutant in a thymic egress-deficient mouse strain and in a patient with severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a T cell-deficient, B cell-sufficient and natural killer cell-sufficient patient with severe combined immunodeficiency"
    explanation: T-cell deficiency with preserved B and NK cells in the index patient.
- category: Immune
  name: Decreased total CD4+ T cell count
  frequency: VERY_FREQUENT
  description: >-
    Reduced CD4+ T cells were recorded in 8 of 9 patients in a 2018 review
    table.
  phenotype_term:
    preferred_term: CD4+ T-cell lymphopenia
    term:
      id: HP:5210418
      label: Decreased total CD4+ T cell count
  reports_on:
  - target: Profound Naive and Innate-Like T-Cell Deficiency
    relationship: READOUT_OF
    description: The CD4+ count is a direct laboratory readout of the T-cell deficiency.
  evidence:
  - reference: PMID:26476480
    reference_title: "Recurrent viral infections associated with a homozygous CORO1A mutation that disrupts oligomerization and cytoskeletal association."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both patients had CD4(+) T-cell lymphopenia and decreased lymphocyte proliferation to mitogens."
    explanation: CD4+ lymphopenia in both affected siblings.
  - reference: PMID:29942301
    reference_title: "Inherited Immunodeficiencies With High Predisposition to Epstein-Barr Virus-Driven Lymphoproliferative Diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "↓ CD4+ 8/9 ↓ MAIT 1/1 ↓ iNKT 1/1"
    explanation: >-
      From the CORO1A row of the review's Table 1 (n = 9): reduced CD4+ T cells
      in 8 of 9, supporting VERY_FREQUENT.
- category: Immune
  name: Decreased naive CD4+ T cell proportion
  phenotype_term:
    preferred_term: Absent or reduced naive CD4+ T cells
    term:
      id: HP:0410378
      label: Decreased naive CD4+ T cell proportion
  evidence:
  - reference: PMID:25073507
    reference_title: "Compound heterozygous CORO1A mutations in siblings with a mucocutaneous-immunodeficiency syndrome of epidermodysplasia verruciformis-HPV, molluscum contagiosum and granulomatous tuberculoid leprosy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "manifested as absent CD4CD45RA(+) (naïve) T and memory B cells, low NK cells"
    explanation: Absent naive (CD45RA+) CD4+ T cells in both siblings.
  - reference: DOI:10.14785/lymphosign-2019-0001
    reference_title: "Coronin 1A deficiency identified by newborn screening for severe combined immunodeficiency"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient presented with T cell lymphopenia, reduction in CD4+CD45Ra+ cells and hypogammaglobulinemia."
    explanation: Reduced naive CD4+ T cells in a newborn-screened patient.
- category: Immune
  name: Abnormally low T cell receptor excision circle level
  description: Low TRECs make the disorder detectable by TREC-based newborn SCID screening.
  phenotype_term:
    preferred_term: Low T-cell receptor excision circles
    term:
      id: HP:0031545
      label: Abnormally low T cell receptor excision circle level
  diagnostic: true
  evidence:
  - reference: DOI:10.14785/lymphosign-2019-0004
    reference_title: "Successful hematopoietic stem cell transplantation in a patient with a novel mutation in coronin 1A"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lymphocyte responses to mitogens and T cell receptor excision circle levels were markedly reduced, consistent with the diagnosis of severe combined immunodeficiency."
    explanation: Markedly reduced TRECs in a patient.
  - reference: DOI:10.14785/lymphosign-2019-0001
    reference_title: "Coronin 1A deficiency identified by newborn screening for severe combined immunodeficiency"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Coronin 1A deficiency can be detected after birth by T cell receptor excision circle-based newborn screening."
    explanation: Low TRECs led to detection by newborn screening.
- category: Immune
  name: Abnormal TCR repertoire
  phenotype_term:
    preferred_term: Restricted T-cell receptor repertoire
    term:
      id: HP:0025845
      label: Abnormal TCR repertoire
  evidence:
  - reference: PMID:23522482
    reference_title: "Whole-exome sequencing identifies Coronin-1A deficiency in 3 siblings with immunodeficiency and EBV-associated B-cell lymphoproliferation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we found impaired development of a diverse T-cell repertoire"
    explanation: Impaired T-cell repertoire diversity in patients.
- category: Immune
  name: Decreased mucosal-associated invariant T cell proportion
  description: >-
    MAIT cells are severely reduced and invariant NKT cells near-absent. HPO
    has no term for iNKT deficiency, so the iNKT loss is carried in this
    description and in the pathophysiology node's cell types.
  phenotype_term:
    preferred_term: Decreased MAIT and iNKT cells
    term:
      id: HP:4000039
      label: Decreased mucosal-associated invariant T cell proportion
  evidence:
  - reference: PMID:23522482
    reference_title: "Whole-exome sequencing identifies Coronin-1A deficiency in 3 siblings with immunodeficiency and EBV-associated B-cell lymphoproliferation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "near-to-absent invariant natural killer T cells, and severely diminished mucosal-associated invariant T cell numbers"
    explanation: Loss of both innate-like T-cell populations.
- category: Immune
  name: Decreased mitogen-induced T-cell proliferation
  phenotype_term:
    preferred_term: Decreased T-cell proliferation to mitogens
    term:
      id: HP:0031381
      label: Decreased mitogen-induced T-cell proliferation
  reports_on:
  - target: Profound Naive and Innate-Like T-Cell Deficiency
    relationship: READOUT_OF
    description: A functional laboratory readout of the T-cell compartment.
  evidence:
  - reference: PMID:26476480
    reference_title: "Recurrent viral infections associated with a homozygous CORO1A mutation that disrupts oligomerization and cytoskeletal association."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both patients had CD4(+) T-cell lymphopenia and decreased lymphocyte proliferation to mitogens."
    explanation: Reduced mitogen proliferation in both siblings.
- category: Immune
  name: Increased double-negative T cell number
  phenotype_term:
    preferred_term: Increased double-negative gamma-delta T cells
    term:
      id: HP:0002851
      label: Increased double-negative T cell number
  reports_on:
  - target: Profound Naive and Innate-Like T-Cell Deficiency
    relationship: READOUT_OF
    description: A feature of the disturbed T-cell compartment.
  evidence:
  - reference: PMID:25073507
    reference_title: "Compound heterozygous CORO1A mutations in siblings with a mucocutaneous-immunodeficiency syndrome of epidermodysplasia verruciformis-HPV, molluscum contagiosum and granulomatous tuberculoid leprosy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "low NK cells and abnormally increased double-negative (DN)"
    explanation: >-
      Increased double-negative T cells (gamma-delta, per the full sentence) in
      the compound heterozygous siblings.
- category: Immune
  name: Decreased memory B cell proportion
  phenotype_term:
    preferred_term: Absent memory B cells
    term:
      id: HP:0030374
      label: Decreased memory B cell proportion
  evidence:
  - reference: PMID:25073507
    reference_title: "Compound heterozygous CORO1A mutations in siblings with a mucocutaneous-immunodeficiency syndrome of epidermodysplasia verruciformis-HPV, molluscum contagiosum and granulomatous tuberculoid leprosy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "manifested as absent CD4CD45RA(+) (naïve) T and memory B cells"
    explanation: Absent memory B cells in the compound heterozygous siblings.
- category: Immune
  name: Decreased circulating immunoglobulin concentration
  description: >-
    Hypogammaglobulinemia is reported in several patients but not all; the
    S401fs siblings had normal IgG, IgM, IgA and specific antibody responses.
  phenotype_term:
    preferred_term: Hypogammaglobulinemia
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  evidence:
  - reference: DOI:10.14785/lymphosign-2019-0001
    reference_title: "Coronin 1A deficiency identified by newborn screening for severe combined immunodeficiency"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient presented with T cell lymphopenia, reduction in CD4+CD45Ra+ cells and hypogammaglobulinemia."
    explanation: Hypogammaglobulinemia in a newborn-screened patient.
  - reference: PMID:40464874
    reference_title: "A rare case of coronin-1A deficiency with IgM dominant membranoproliferative glomerulonephritis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "This condition presents with lymphopenia, hypogammaglobulinemia, recurrent Epstein-Barr virus (EBV) infections, EBV-associated B-cell lymphoma and epidermodysplasia verruciformis."
    explanation: >-
      Background summary of the disorder in a case report, listing
      hypogammaglobulinemia among its features.
- category: Immune
  name: Increased circulating IgE concentration
  frequency: VERY_FREQUENT
  description: >-
    High IgE in 4 of the 5 patients in whom it was recorded in a 2018 review
    table; the denominator is small.
  phenotype_term:
    preferred_term: Elevated IgE
    term:
      id: HP:0003212
      label: Increased circulating IgE concentration
  reports_on:
  - target: Impaired T-Cell-Dependent Humoral Immunity
    relationship: READOUT_OF
    description: A marker of disturbed B-cell regulation; the mechanism is not established.
  evidence:
  - reference: PMID:29942301
    reference_title: "Inherited Immunodeficiencies With High Predisposition to Epstein-Barr Virus-Driven Lymphoproliferative Diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "↓ iNKT 1/1 | High IgE level 4/5"
    explanation: >-
      CORO1A row of the review's Table 1: high IgE in 4 of 5 patients tested.
- category: Immune
  name: Decreased natural killer cell-induced killing of target cells
  description: >-
    Reduced NK cytotoxicity in a coronin-1A-deficient patient and a
    hemizygous-variant patient; normal in the S401fs siblings.
  phenotype_term:
    preferred_term: Impaired NK-cell cytotoxicity
    term:
      id: HP:0025808
      label: Decreased natural killer cell-induced killing of target cells
  reports_on:
  - target: Impaired NK-Cell Lytic Synapse Function
    relationship: READOUT_OF
    description: The cytotoxicity assay is the direct readout of this node.
  evidence:
  - reference: PMID:24760828
    reference_title: "Lytic immune synapse function requires filamentous actin deconstruction by Coronin 1A."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here, we show that Coro1A is required for natural killer (NK) cell cytotoxic function in two human NK cell lines and ex vivo cells from a Coro1A-deficient patient."
    explanation: Defective killing by ex vivo patient NK cells.
- category: Immune
  name: Recurrent viral infections
  phenotype_term:
    preferred_term: Severe and recurrent viral infections
    term:
      id: HP:0004429
      label: Recurrent viral infections
  evidence:
  - reference: PMID:26476480
    reference_title: "Recurrent viral infections associated with a homozygous CORO1A mutation that disrupts oligomerization and cytoskeletal association."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CORO1A deficiency causes T(-)B(+) natural killer-positive severe combined immunodeficiency or T-cell lymphopenia with severe viral infections."
    explanation: Severe viral infection is a defining feature.
- category: Immune
  name: Severe varicella zoster infection
  frequency: FREQUENT
  description: Disseminated varicella; VZV infection in 5 of 9 patients in a 2018 review table.
  phenotype_term:
    preferred_term: Severe or disseminated varicella
    term:
      id: HP:0032170
      label: Severe varicella zoster infection
  evidence:
  - reference: PMID:26476480
    reference_title: "Recurrent viral infections associated with a homozygous CORO1A mutation that disrupts oligomerization and cytoskeletal association."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "2 young adult siblings with a history of disseminated varicella, cutaneous warts, and CD4(+) T-cell lymphopenia"
    explanation: Disseminated varicella in the S401fs sibship.
  - reference: PMID:29942301
    reference_title: "Inherited Immunodeficiencies With High Predisposition to Epstein-Barr Virus-Driven Lymphoproliferative Diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "EBV 5/9 HPV 4/9, VZV 5/9 HSV 2/9 Parvovirus B19 1/9"
    explanation: >-
      CORO1A row of the review's Table 1: VZV infection in 5 of 9 patients,
      supporting the FREQUENT band.
- category: Immune
  name: Post-vaccination varicella zoster virus infection
  phenotype_term:
    preferred_term: Severe post-vaccination varicella
    term:
      id: HP:4000166
      label: Post-vaccination varicella zoster virus infection
  evidence:
  - reference: PMID:19097825
    reference_title: "Severe combined immunodeficiency (SCID) and attention deficit hyperactivity disorder (ADHD) associated with a Coronin-1A mutation and a chromosome 16p11.2 deletion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "severe post-vaccination varicella at age 13 months"
    explanation: The index patient's severe reaction to varicella vaccine.
- category: Integument
  name: Persistent beta-HPV infection with epidermodysplasia verruciformis-like lesions
  frequency: FREQUENT
  description: >-
    An epidermodysplasia verruciformis-like syndrome with disseminated flat
    warts and pityriasis versicolor-like lesions from beta-HPV, particularly in
    patients with hypomorphic or compound heterozygous alleles; HPV in 4 of 9
    patients in a 2018 review table.
  phenotype_term:
    preferred_term: Persistent human papillomavirus infection
    term:
      id: HP:0020114
      label: Persistent human papillomavirus infection
  evidence:
  - reference: PMID:25073507
    reference_title: "Compound heterozygous CORO1A mutations in siblings with a mucocutaneous-immunodeficiency syndrome of epidermodysplasia verruciformis-HPV, molluscum contagiosum and granulomatous tuberculoid leprosy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Distinguishing characteristics were late clinical debut with an unusual mucocutaneous syndrome of epidermodysplasia verruciformis-human papilloma virus (EV-HPV)"
    explanation: The EV-HPV mucocutaneous syndrome in the compound heterozygous siblings.
  - reference: PMID:29942301
    reference_title: "Inherited Immunodeficiencies With High Predisposition to Epstein-Barr Virus-Driven Lymphoproliferative Diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Four patients had severe mucocutaneous-immunodeficiency manifestations including epidermodysplasia verruciformis-HPV (EV-HPV)"
    explanation: EV-HPV in 4 patients in the review, supporting FREQUENT.
- category: Integument
  name: Chronic warts
  phenotype_term:
    preferred_term: Chronic cutaneous warts
    term:
      id: HP:5210306
      label: Chronic warts
  evidence:
  - reference: PMID:26476480
    reference_title: "Recurrent viral infections associated with a homozygous CORO1A mutation that disrupts oligomerization and cytoskeletal association."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "2 young adult siblings with a history of disseminated varicella, cutaneous warts, and CD4(+) T-cell lymphopenia"
    explanation: Chronic cutaneous warts in the S401fs siblings.
- category: Integument
  name: Unusual molluscum contagiosum
  phenotype_term:
    preferred_term: Molluscum contagiosum
    term:
      id: HP:0032163
      label: Unusual molluscum contagiosum
  evidence:
  - reference: PMID:25073507
    reference_title: "Compound heterozygous CORO1A mutations in siblings with a mucocutaneous-immunodeficiency syndrome of epidermodysplasia verruciformis-HPV, molluscum contagiosum and granulomatous tuberculoid leprosy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "an unusual mucocutaneous syndrome of epidermodysplasia verruciformis-human papilloma virus (EV-HPV), molluscum contagiosum and oral-cutaneous herpetic ulcers"
    explanation: Molluscum contagiosum in the compound heterozygous siblings.
- category: Integument
  name: Unusual HSV skin infection
  phenotype_term:
    preferred_term: Oral-cutaneous herpes simplex ulcers
    term:
      id: HP:5210233
      label: Unusual HSV skin infection
  evidence:
  - reference: PMID:25073507
    reference_title: "Compound heterozygous CORO1A mutations in siblings with a mucocutaneous-immunodeficiency syndrome of epidermodysplasia verruciformis-HPV, molluscum contagiosum and granulomatous tuberculoid leprosy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "molluscum contagiosum and oral-cutaneous herpetic ulcers"
    explanation: Oral-cutaneous HSV-1 ulcers in the compound heterozygous siblings.
- category: Integument
  name: Unusual mycobacterial skin infection
  description: >-
    A single patient developed granulomatous tuberculoid leprosy; recorded as
    an isolated observation.
  phenotype_term:
    preferred_term: Granulomatous tuberculoid leprosy
    term:
      id: HP:5210242
      label: Unusual mycobacterial skin infection
  evidence:
  - reference: PMID:25073507
    reference_title: "Compound heterozygous CORO1A mutations in siblings with a mucocutaneous-immunodeficiency syndrome of epidermodysplasia verruciformis-HPV, molluscum contagiosum and granulomatous tuberculoid leprosy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the older female sibling also had a disfiguring granulomatous tuberculoid leprosy"
    explanation: Tuberculoid leprosy in one sibling.
- category: Immune
  name: Unusual EBV infection
  description: >-
    Inability to control EBV, with chronic infection preceding lymphoproliferative
    disease.
  phenotype_term:
    preferred_term: Uncontrolled EBV infection
    term:
      id: HP:5210286
      label: Unusual EBV infection
  evidence:
  - reference: PMID:29942301
    reference_title: "Inherited Immunodeficiencies With High Predisposition to Epstein-Barr Virus-Driven Lymphoproliferative Diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "EBV 5/9 HPV 4/9, VZV 5/9 HSV 2/9 Parvovirus B19 1/9"
    explanation: EBV infection in 5 of 9 patients in the review's CORO1A row.
- category: Neoplasm
  name: Lymphoproliferative disorder
  phenotype_term:
    preferred_term: EBV-associated lymphoproliferative disorder
    term:
      id: HP:0005523
      label: Lymphoproliferative disorder
  evidence:
  - reference: PMID:23522482
    reference_title: "Whole-exome sequencing identifies Coronin-1A deficiency in 3 siblings with immunodeficiency and EBV-associated B-cell lymphoproliferation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "EBV-associated B-cell lymphoproliferation at an early age"
    explanation: EBV-associated lymphoproliferation in the affected siblings.
- category: Neoplasm
  name: B-cell lymphoma
  frequency: FREQUENT
  description: >-
    EBV-positive B-cell lymphoma; lymphoproliferative disorder or B lymphoma in
    5 of 9 patients in a 2018 review table.
  phenotype_term:
    preferred_term: EBV-positive B-cell lymphoma
    term:
      id: HP:0012191
      label: B-cell lymphoma
  evidence:
  - reference: PMID:25073507
    reference_title: "Compound heterozygous CORO1A mutations in siblings with a mucocutaneous-immunodeficiency syndrome of epidermodysplasia verruciformis-HPV, molluscum contagiosum and granulomatous tuberculoid leprosy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the female died of EBV+ lymphomas at age 16 years"
    explanation: A fatal EBV-positive B-cell lymphoma.
  - reference: PMID:29942301
    reference_title: "Inherited Immunodeficiencies With High Predisposition to Epstein-Barr Virus-Driven Lymphoproliferative Diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Patients presented with severe infections, and five developed EBV-driven B cell lymphoma."
    explanation: >-
      Review statement that 5 of the 9 reported CORO1A patients developed
      EBV-driven B-cell lymphoma, supporting the FREQUENT band.
- category: Respiratory
  name: Recurrent respiratory infections
  frequency: FREQUENT
  description: >-
    Recurrent respiratory and ENT infections; lung infections in 7 of 9
    patients in a 2018 review table.
  phenotype_term:
    preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  sequelae:
  - target: Bronchiectasis
    causal_link_type: DIRECT
    description: >-
      Repeated lower respiratory infection causes the structural airway damage
      of bronchiectasis.
  evidence:
  - reference: PMID:29942301
    reference_title: "Inherited Immunodeficiencies With High Predisposition to Epstein-Barr Virus-Driven Lymphoproliferative Diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Lung infections 7/9 Cutaneous leprosy 1/9 Visceral leishmaniasis 1/9"
    explanation: Lung infections in 7 of 9 patients in the review's CORO1A row.
- category: Respiratory
  name: Bronchiectasis
  description: Structural lung damage from recurrent respiratory infection.
  phenotype_term:
    preferred_term: Bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
  evidence:
  - reference: PMID:25073507
    reference_title: "Compound heterozygous CORO1A mutations in siblings with a mucocutaneous-immunodeficiency syndrome of epidermodysplasia verruciformis-HPV, molluscum contagiosum and granulomatous tuberculoid leprosy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both had bilateral bronchiectasis and the female died of EBV+ lymphomas at age 16 years."
    explanation: Bilateral bronchiectasis in both compound heterozygous siblings.
- category: Immune
  name: Recurrent bacterial infections
  description: >-
    Recurrent bacterial infections, including recurrent pneumonia, in some
    patients.
  phenotype_term:
    preferred_term: Recurrent bacterial infections
    term:
      id: HP:0002718
      label: Recurrent bacterial infections
  evidence:
  - reference: PMID:42318436
    reference_title: "A Novel Variant of CORO1A Gene Contributing to the Development of Primary Immunodeficiency in Children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Her past medical history was remarkable for multiple hospital admissions secondary to community-acquired pneumonia and urinary tract infections"
    explanation: Recurrent bacterial infections in a patient with a novel CORO1A variant.
- category: Blood
  name: Decreased total neutrophil count
  description: >-
    Neutropenia is an unusual finding, reported in a newborn-screened patient.
  phenotype_term:
    preferred_term: Neutropenia
    term:
      id: HP:0001875
      label: Decreased total neutrophil count
  evidence:
  - reference: DOI:10.14785/lymphosign-2019-0001
    reference_title: "Coronin 1A deficiency identified by newborn screening for severe combined immunodeficiency"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Uniquely, she also had persistent severe neutropenia."
    explanation: Persistent severe neutropenia, described as a unique finding.
- category: Nervous System
  name: Attention deficit hyperactivity disorder
  description: >-
    Reported in one patient and attributed by the authors to her 16p11.2
    contiguous-gene deletion rather than to coronin-1A loss; modeled through the
    contiguous-gene deletion node.
  phenotype_term:
    preferred_term: Attention deficit hyperactivity disorder
    term:
      id: HP:0007018
      label: Attention deficit hyperactivity disorder
  evidence:
  - reference: PMID:19097825
    reference_title: "Severe combined immunodeficiency (SCID) and attention deficit hyperactivity disorder (ADHD) associated with a Coronin-1A mutation and a chromosome 16p11.2 deletion."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This genomic region at 16p11.2 is subject to recurrent copy number variations associated with autism spectrum disorders, including attention deficit and hyperactivity, present in our patient."
    explanation: ADHD attributed to the 16p11.2 copy number variation.
- category: Nervous System
  name: Cognitive impairment
  description: >-
    Neurological involvement, reported as cognitive impairment, in 3 of the 9
    patients summarised in a 2018 review, including autism-like symptoms. The
    review does not identify which patients were affected, and at least two
    reported patients carry a 16p11.2 contiguous-gene deletion that is itself
    associated with neurodevelopmental disorders, so whether coronin-1A loss
    contributes is unresolved.
  phenotype_term:
    preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  frequency: FREQUENT
  evidence:
  - reference: PMID:29942301
    reference_title: "Inherited Immunodeficiencies With High Predisposition to Epstein-Barr Virus-Driven Lymphoproliferative Diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Neurological involvement (cognitive impairment) 3/9"
    explanation: >-
      The review's CORO1A table row: cognitive impairment in 3 of 9 patients
      (33%), supporting the FREQUENT band.
  - reference: PMID:29942301
    reference_title: "Inherited Immunodeficiencies With High Predisposition to Epstein-Barr Virus-Driven Lymphoproliferative Diseases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Three patients also exhibited neurological abnormalities including autism-like symptoms."
    explanation: The review's text on the same three patients, including autism-like features.
- category: Blood
  name: Short telomere length
  description: >-
    Very short telomeres were found in one surviving patient; a single
    observation not previously reported in CORO1A deficiency.
  phenotype_term:
    preferred_term: Short telomeres
    term:
      id: HP:0031413
      label: Short telomere length
  evidence:
  - reference: PMID:25073507
    reference_title: "Compound heterozygous CORO1A mutations in siblings with a mucocutaneous-immunodeficiency syndrome of epidermodysplasia verruciformis-HPV, molluscum contagiosum and granulomatous tuberculoid leprosy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The younger surviving male, without malignancy, had reproducibly very short telomere lengths, not before appreciated in CORO1A mutations."
    explanation: Very short telomeres in one patient, noted as a novel finding.
genetic:
- name: CORO1A
  gene_term:
    preferred_term: CORO1A
    term:
      id: hgnc:2252
      label: CORO1A
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  notes: >-
    CORO1A (16p11.2) encodes coronin-1A, an actin regulator expressed mainly in
    haematopoietic cells. Reported disease alleles are frameshift truncations
    (p.P83RfsX10, p.Q360RfsX44), a beta-propeller missense that abolishes
    expression (p.V134M), whole-gene deletion within a 16p11.2 microdeletion,
    and a C-terminal frameshift (p.S401fs) that is expressed but cannot
    oligomerize. All are loss of function; heterozygous carriers are unaffected.
  evidence:
  - reference: PMID:18836449
    reference_title: "The actin regulator coronin 1A is mutant in a thymic egress-deficient mouse strain and in a patient with severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a T cell-deficient, B cell-sufficient and natural killer cell-sufficient patient with severe combined immunodeficiency, whom we found had mutations in both CORO1A alleles"
    explanation: Establishes CORO1A as the causative gene in the index patient.
  - reference: PMID:23522482
    reference_title: "Whole-exome sequencing identifies Coronin-1A deficiency in 3 siblings with immunodeficiency and EBV-associated B-cell lymphoproliferation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a homozygous inherited missense mutation in the gene encoding Coronin-1A (CORO1A) in the 3 siblings."
    explanation: Independent identification of a causative CORO1A allele.
animal_models:
- name: Coronin-1A knockout mouse
  species: Mouse
  genotype: Coro1a-/-
  publication: PMID:16902139
  description: >-
    Germline Coro1a-null mice have profound peripheral T-cell lymphopenia with
    impaired chemokine-directed migration and disturbed lymphocyte homeostasis,
    while T-cell receptor functions are relatively spared. The model reproduces
    the human peripheral T-cell deficiency and the migration lesion.
  modeled_mechanisms:
  - target: Impaired T-Cell Migration and Thymic Egress
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Coronin 1-deficient T cells fail chemokine-mediated migration, the same
      defect proposed to block thymic egress in patients.
    limitations: >-
      The mouse reproduces the T-cell migration and homeostasis defect but not
      the human-specific viral complications (EBV lymphoproliferation, beta-HPV
      disease), whose viruses do not infect mice.
    readouts:
    - name: Chemokine-mediated T-cell migration
      target: Impaired T-Cell Migration and Thymic Egress
      direction: DECREASED
      interpretation: Migration defect corresponding to the human egress block.
      evidence:
      - reference: PMID:16902139
        reference_title: "Requirement for coronin 1 in T lymphocyte trafficking and cellular homeostasis."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "coronin 1 was required for chemokine-mediated migration"
        explanation: The measured migration defect in knockout T cells.
    evidence:
    - reference: PMID:16902139
      reference_title: "Requirement for coronin 1 in T lymphocyte trafficking and cellular homeostasis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "coronin 1 was required for chemokine-mediated migration, it was dispensable for T cell antigen receptor functions in T cells"
      explanation: >-
        Establishes the model as informative for the migration node, with the
        TCR-sparing pattern seen in patients.
  - target: Reduced Peripheral T-Cell Survival
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Coro1a-null T cells survive poorly; the defect was attributed to impaired
      TCR-induced calcium mobilization, which is where the mouse and the human
      S401fs data diverge (see the discussion).
    limitations: >-
      The calcium-mobilization mechanism proposed in mice is not reproduced in
      patients with the C-terminal S401fs allele, whose calcium flux is near
      normal. The mouse mechanism may therefore be allele- or species-specific.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Coro1a-null mouse T cells show a profound calcium-mobilization defect
        driving apoptosis, whereas patient T cells carrying the S401fs allele
        have near-normal calcium flux with the same survival defect, so the
        murine calcium mechanism does not transfer to that human allele.
    evidence:
    - reference: PMID:18345003
      reference_title: "Regulation of T cell survival through coronin-1-mediated generation of inositol-1,4,5-trisphosphate and calcium mobilization after T cell receptor triggering."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The absence of coronin-1, although it did not affect T cell development, resulted in a profound defect in Ca2+ mobilization, interleukin-2 production, T cell proliferation and T cell survival."
      explanation: The murine survival defect and its proposed calcium mechanism.
  evidence:
  - reference: PMID:16902139
    reference_title: "Requirement for coronin 1 in T lymphocyte trafficking and cellular homeostasis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We generated coronin 1-/- mice and found that coronin 1 exerted an inhibitory effect on cellular steady-state F-actin formation via an Arp2/3-dependent mechanism."
    explanation: Attests the model recapitulates the core actin-regulatory lesion.
treatments:
- name: Allogeneic hematopoietic stem cell transplantation
  description: >-
    The only curative therapy. Because the defect is intrinsic to
    haematopoietic cells, donor stem cells reconstitute T-cell numbers and
    function; two long-term successful transplants are documented, and it is
    proposed as an immunologic cure.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: hematopoietic stem cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: Biallelic CORO1A Loss-of-Function Variants
    description: >-
      Replaces CORO1A-deficient haematopoietic cells with donor cells carrying
      functional CORO1A.
  evidence:
  - reference: DOI:10.14785/lymphosign-2019-0004
    reference_title: "Successful hematopoietic stem cell transplantation in a patient with a novel mutation in coronin 1A"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HSCT using a HLA-matched unrelated donor resulted in long term engraftment and solid immune reconstitution."
    explanation: A documented successful transplant with long-term immune reconstitution.
  - reference: PMID:25269405
    reference_title: "The expanding spectrum of human coronin 1A deficiency."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "complete absence of coronin 1A is associated with severe combined immunodeficiency in humans"
    explanation: >-
      Review confirming the SCID phenotype that transplantation is intended to
      correct; the transplant outcome itself is cited from the case report
      above.
- name: Immunoglobulin replacement and anti-infective prophylaxis
  description: >-
    Supportive care while awaiting or in place of transplant: immunoglobulin
    replacement for hypogammaglobulinemia and poor vaccine responses, plus
    antibacterial and antiviral prophylaxis. Live vaccines are contraindicated,
    given severe post-vaccination varicella.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
    therapeutic_agent:
    - preferred_term: immunoglobulin replacement (IgG)
      term:
        id: NCIT:C80829
        label: Human Immunoglobulin G
  target_mechanisms:
  - target: Impaired Cell-Mediated Immunity to Viruses and Intracellular Pathogens
    description: >-
      Prophylaxis and passive antibody reduce the infection burden that follows
      from the immune defect; they do not correct it.
  evidence:
  - reference: PMID:19097825
    reference_title: "Severe combined immunodeficiency (SCID) and attention deficit hyperactivity disorder (ADHD) associated with a Coronin-1A mutation and a chromosome 16p11.2 deletion."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "severe post-vaccination varicella at age 13 months"
    explanation: >-
      The severe reaction to live varicella vaccine is why live vaccines are
      avoided; cited as the basis for the safety caveat rather than for a
      prophylaxis trial.
  - reference: PMID:42318436
    reference_title: "A Novel Variant of CORO1A Gene Contributing to the Development of Primary Immunodeficiency in Children."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Given the immunological findings, subcutaneous immunoglobulin therapy was initiated at a dosing schedule of every 2 weeks in the daycare unit."
    explanation: >-
      Immunoglobulin replacement given to a CORO1A-deficient child, the basis
      for the immunoglobulin part of this treatment.
discussions:
- discussion_id: coro1a_calcium_flux_mouse_human_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Does defective TCR-induced calcium mobilization explain the T-cell survival
    defect in CORO1A-deficient patients, or is that mechanism specific to the
    mouse and to null alleles?
  attaches_to:
  - pathophysiology#Reduced Peripheral T-Cell Survival
  rationale: >-
    Coro1a-null mice have a profound defect in TCR-induced calcium mobilization
    that was proposed to cause their T-cell death. Patients with the C-terminal
    p.S401fs allele have the same poor T-cell survival but near-normal calcium
    flux, and their F-actin accumulation was proposed instead as the survival
    mechanism. The mouse mechanism therefore does not transfer to at least one
    human allele, leaving open whether calcium signalling matters in patients
    with null alleles, or whether F-actin accumulation is the common route.
  evidence:
  - reference: PMID:18345003
    reference_title: "Regulation of T cell survival through coronin-1-mediated generation of inositol-1,4,5-trisphosphate and calcium mobilization after T cell receptor triggering."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "resulted in a profound defect in Ca2+ mobilization, interleukin-2 production, T cell proliferation and T cell survival"
    explanation: The murine calcium-dependent survival mechanism.
  - reference: PMID:26476480
    reference_title: "Recurrent viral infections associated with a homozygous CORO1A mutation that disrupts oligomerization and cytoskeletal association."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "calcium flux in our patients’ CD4+ and CD8+ T cells after anti-CD3 stimulation was minimally decreased, indicating that calcium flux is not the sole mechanism by which CORO1A regulates T cell survival"
    explanation: >-
      The human data that contradict the murine calcium mechanism, which is the
      substance of this mismatch.
references:
- reference: PMID:18836449
  title: "The actin regulator coronin 1A is mutant in a thymic egress-deficient mouse strain and in a patient with severe combined immunodeficiency."
- reference: PMID:19097825
  title: "Severe combined immunodeficiency (SCID) and attention deficit hyperactivity disorder (ADHD) associated with a Coronin-1A mutation and a chromosome 16p11.2 deletion."
- reference: PMID:23522482
  title: "Whole-exome sequencing identifies Coronin-1A deficiency in 3 siblings with immunodeficiency and EBV-associated B-cell lymphoproliferation."
- reference: PMID:25073507
  title: "Compound heterozygous CORO1A mutations in siblings with a mucocutaneous-immunodeficiency syndrome of epidermodysplasia verruciformis-HPV, molluscum contagiosum and granulomatous tuberculoid leprosy."
- reference: PMID:25269405
  title: "The expanding spectrum of human coronin 1A deficiency."
- reference: PMID:26476480
  title: "Recurrent viral infections associated with a homozygous CORO1A mutation that disrupts oligomerization and cytoskeletal association."
- reference: PMID:16902139
  title: "Requirement for coronin 1 in T lymphocyte trafficking and cellular homeostasis."
- reference: PMID:18345003
  title: "Regulation of T cell survival through coronin-1-mediated generation of inositol-1,4,5-trisphosphate and calcium mobilization after T cell receptor triggering."
- reference: PMID:24760828
  title: "Lytic immune synapse function requires filamentous actin deconstruction by Coronin 1A."
- reference: PMID:18199416
  title: "The lupus-related Lmb3 locus contains a disease-suppressing Coronin-1A gene mutation."
- reference: PMID:29942301
  title: "Inherited Immunodeficiencies With High Predisposition to Epstein-Barr Virus-Driven Lymphoproliferative Diseases."
- reference: PMID:26424649
  title: "Primary Immunodeficiencies Associated with EBV Disease."
- reference: PMID:29225606
  title: "Epstein-Barr Virus-Specific Immune Control by Innate Lymphocytes."
- reference: PMID:29946305
  title: "Epidermodysplasia Verruciformis: Inborn Errors of Immunity to Human Beta-Papillomaviruses."
- reference: PMID:37915722
  title: "Novel hemizygous CORO1A variant leads to combined immunodeficiency with defective platelet calcium signaling and cell mobility."
- reference: PMID:40464874
  title: "A rare case of coronin-1A deficiency with IgM dominant membranoproliferative glomerulonephritis."
- reference: PMID:42318436
  title: "A Novel Variant of CORO1A Gene Contributing to the Development of Primary Immunodeficiency in Children."
- reference: DOI:10.14785/lymphosign-2019-0001
  title: "Coronin 1A deficiency identified by newborn screening for severe combined immunodeficiency"
- reference: DOI:10.14785/lymphosign-2019-0004
  title: "Successful hematopoietic stem cell transplantation in a patient with a novel mutation in coronin 1A"

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References & Deep Research

References

PMID:18836449

The actin regulator coronin 1A is mutant in a thymic egress-deficient mouse strain and in a patient with severe combined immunodeficiency.