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Classifications

Harrison's Part

IUIS Category

📘

Definitions

4

PIDTC 2022 typical SCID criteria

Typical SCID requires fewer than 0.05 x 10^9 autologous T cells/L on repetitive testing, plus at least one of: a pathogenic variant in a SCID-associated gene; very low or undetectable TRECs or under 20% of CD4 T cells expressing naive markers; or transplacentally engrafted maternal T cells.

DIAGNOSTIC_CRITERIA

Show evidence (1 reference)

PMID:36456361 SUPPORT Human Clinical

"Patients with typical SCID must have less than 0.05 × 109 autologous T cells/L on repetitive testing, with either pathogenic variant(s) in a SCID-associated gene, very low/undetectable T-cell receptor excision circles or less than 20% of CD4 T cells expressing naive markers, and/or..."

The PIDTC 2022 consensus definition of typical SCID quoted verbatim.

PIDTC 2022 leaky/atypical SCID criteria

Leaky/atypical SCID covers patients with less profoundly impaired autologous T-cell differentiation, requiring two or more of: low T-cell numbers, oligoclonal T cells, low TRECs, and under 20% of CD4 T cells expressing naive markers, together with either a pathogenic SCID-gene variant or reduced T-cell proliferation to certain mitogens.

DIAGNOSTIC_CRITERIA

Show evidence (1 reference)

PMID:36456361 SUPPORT Human Clinical

"Patients with less profoundly impaired autologous T-cell differentiation are designated as having leaky/atypical SCID, with 2 or more of these: low T-cell numbers, oligoclonal T cells, low T-cell receptor excision circles, and less than 20% of CD4 T cells expressing naive markers."

The PIDTC 2022 consensus definition of leaky/atypical SCID quoted verbatim.

PIDTC 2022 Omenn syndrome criteria

Omenn syndrome requires a generalized erythematous rash and absent transplacentally acquired maternal engraftment, plus two or more of eosinophilia, elevated IgE, lymphadenopathy, and hepatosplenomegaly.

DIAGNOSTIC_CRITERIA

Show evidence (1 reference)

PMID:36456361 SUPPORT Human Clinical

"Omenn syndrome requires a generalized erythematous rash, absent transplacentally acquired maternal engraftment, and 2 or more of these: eosinophilia, elevated IgE, lymphadenopathy, hepatosplenomegaly."

The PIDTC 2022 consensus definition of Omenn syndrome quoted verbatim.

PIDTC 2022 scope exclusion

Thymic stromal defects and other causes of secondary T-cell deficiency are excluded from the definition of SCID. This is why complete DiGeorge syndrome and FOXN1 athymia, which also present with profound T-cell lymphopenia and an absent thymic shadow, are not curated as SCID subtypes here.

CASE_DEFINITION

Show evidence (1 reference)

PMID:36456361 SUPPORT Human Clinical

"Thymic stromal defects and other causes of secondary T-cell deficiency are excluded from the definition of SCID."

States the boundary the consensus definition draws around SCID.

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Inheritance

2

X-linked recessive inheritance HP:0001419

The most common form of SCID in Western populations, X-linked SCID, is caused by hemizygous IL2RG variants and is inherited in an X-linked recessive pattern.

X-linked recessive inheritance

Show evidence (1 reference)

PMID:20301584 SUPPORT Human Clinical

"The diagnosis of typical and atypical X-SCID is established in a male proband with suggestive findings and a hemizygous pathogenic variant in IL2RG identified by molecular genetic testing."

X-SCID is established by a hemizygous IL2RG variant in male probands, consistent with X-linked recessive inheritance.

Autosomal recessive inheritance HP:0000007

Most non-X-linked SCID subtypes (ADA, RAG1, RAG2, IL7R, JAK3, DCLRE1C/Artemis) are inherited in an autosomal recessive pattern, and these forms predominate in populations with high consanguinity.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:32181275 SUPPORT Human Clinical

"The pattern of inheritance of SCID may be X-linked or autosomal recessive."

SCID is inherited as either X-linked or autosomal recessive, with the autosomal recessive forms covering ADA, RAG1/2, IL7R, JAK3, and Artemis deficiency.

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Subtypes

7

X-linked SCID (IL2RG deficiency, T-B+NK-) MONDO:0010315

IL2RG hgnc:6010

Caused by hemizygous loss-of-function variants in IL2RG encoding the common gamma chain. Immunophenotype is T-B+NK- (absent T and NK cells, present but non-functional B cells). Historically described as the most common form in Western populations at roughly half of cases, but that figure comes from referral-centre transplant cohorts; population-based newborn screening finds a substantially lower share (see the IL2RG case_fractions record).

Show evidence (1 reference)

PMID:25138334 SUPPORT Human Clinical

"the proportion of IL2RG deficient X-linked SCID in our study (19%) is in contrast to nearly half of cases in published cohorts from referral centers that treat SCID"

Supports the description's distinction between the referral-cohort figure of roughly half and the lower population-based share.

Adenosine deaminase deficiency (ADA-SCID, T-B-NK-) MONDO:0007064

ADA hgnc:186

A systemic purine metabolic disorder (~15% of SCID) in which deficiency of adenosine deaminase causes accumulation of toxic deoxyadenosine metabolites that are lymphotoxic, producing a T-B-NK- immunophenotype with absent humoral and cellular immunity. Unlike the other subtypes here, ADA deficiency spans a graded spectrum: about 80% present as typical infantile ADA-SCID and 15%-20% as a later-onset combined immunodeficiency (ADA-CID).

Show evidence (2 references)

PMID:32181275 SUPPORT Human Clinical

"ADA deficiency is the most severe form of SCID and is known to occur in 15% of total SCID patients."

Quantifies the ADA share of SCID cases asserted in this subtype description.

PMID:20301656 SUPPORT Human Clinical

"The ADA deficiency phenotypic spectrum includes typical early-onset severe combined immunodeficiency (ADA-SCID), diagnosed in infancy (about 80% of individuals), and less severe "delayed" or "late-onset" combined immunodeficiency (ADA-CID), diagnosed in older children and adults (15%-20% of individuals)."

Supports the 80% typical-SCID / 15%-20% delayed-onset split within ADA deficiency.

RAG1/RAG2 deficiency (T-B-NK+) MONDO:0011086

RAG1 hgnc:9831 RAG2 hgnc:9832

Autosomal recessive SCID caused by defects in the recombination-activating genes RAG1 or RAG2, which block V(D)J recombination of antigen-receptor genes. Immunophenotype is T-B-NK+; hypomorphic alleles can cause Omenn syndrome. Most common form in consanguineous populations.

IL7R alpha-chain deficiency (T-B+NK+) MONDO:0015701

IL7R hgnc:6024

Autosomal recessive SCID caused by defects in the IL-7 receptor alpha chain, impairing IL-7 signaling required for T-cell development. Immunophenotype is T-B+NK+ (B and NK cells preserved).

JAK3 deficiency (T-B+NK-) MONDO:0010938

JAK3 hgnc:6193

Autosomal recessive SCID caused by defects in Janus kinase 3, the signaling kinase coupled to the common gamma chain. The immunophenotype (T-B+NK-) mirrors X-linked SCID because JAK3 acts immediately downstream of the gamma chain.

Artemis (DCLRE1C) deficiency (radiosensitive T-B-NK+) MONDO:0011225

DCLRE1C hgnc:17642

Autosomal recessive, radiosensitive SCID caused by defects in DCLRE1C/Artemis, a nuclease required for hairpin opening during V(D)J recombination and for non-homologous end-joining DNA repair. Immunophenotype is T-B-NK+ with increased cellular radiosensitivity.

Reticular dysgenesis (AK2 deficiency, T-B-NK-)

AK2 hgnc:362

Autosomal recessive SCID caused by biallelic AK2 (adenylate kinase 2) defects, accounting for about 2% of children with SCID. Unlike the other subtypes, the block is in survival of haematopoietic precursors rather than in a lymphoid-specific signalling, recombination, or metabolic pathway, so both innate and adaptive immunity fail: profound neutropenia/absent granulocytes accompanies the lymphoid deficiency. It is the most severe SCID form, with fatal septicaemia within days of birth if untreated.

Show evidence (2 references)

PMID:32181275 SUPPORT Human Clinical

"Mutation of the AK2 gene causes reticular dysgenesis (RD), an autosomal recessive disorder occurring in 2% of children with SCID."

Establishes AK2 as the cause of reticular dysgenesis and its share of SCID cases.

PMID:32181275 SUPPORT Human Clinical

"Reticular dysgenesis is the most serious type of SCID that is associated with absent granulocytes, lymphocytes, hypoplasia of the primary and secondary lymphoid organs and fatal septicemia within days after birth."

Supports the combined myeloid-plus-lymphoid failure and the neonatal lethality distinguishing this subtype.

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Discussions and Knowledge Gaps

1

By what route do accumulating purine metabolites damage the brain, cochlea and growth plate in ADA deficiency, and is that route the same one that kills thymocytes?

KNOWLEDGE GAP OPEN ada_extraimmune_mechanism

Attached to

pathophysiology#Non-lymphoid tissue purine metabolite toxicity

The extra-immune features are established as features — they are more frequent in ADA deficiency than in other SCID subtypes receiving the same treatment, they occur in children transplanted without conditioning, and IQ correlates inversely with diagnostic dATP. What is missing is the mechanism connecting metabolite to organ. The review this node is built from says the mechanism of the neurological pathology has not been investigated, and proposes dATP neurotoxicity by analogy with the immune system as an untested possibility. The two molecular routes bound on the node — SAH hydrolase inactivation and ribonucleotide reductase inhibition — are characterised in lymphocytes and carried across on the strength of ubiquitous ADA expression, which is an inference rather than a measurement. This matters clinically because current therapies correct the immune phenotype while leaving the neurological one: six of twelve patients showed distinct neurological abnormality at a mean twelve years of follow-up despite complete immune reconstitution.

Show evidence (2 references)

PMID:27579027 SUPPORT REVIEW SYNTHESIS Other

"Current research has not, so far, investigated the mechanism of pathology. One possibility is that the accumulation of dATP causes neurotoxic effects by a similar mechanism elucidated in the immune system"

States the gap directly: the mechanism of the CNS pathology is uninvestigated, and the immune-system analogy is offered as a hypothesis.

PMID:27579027 SUPPORT REVIEW SYNTHESIS Human Clinical

"neurological abnormalities are far more prevalent in ADA-SCID than other forms of immunodeficiency"

Establishes that the gap is about a real, ADA-specific phenomenon rather than a general consequence of severe immunodeficiency or its treatment.

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Pathophysiology

9

Cytokine receptor signaling defect

In X-linked SCID, JAK3 deficiency, and IL7R deficiency, loss-of-function in the common gamma chain (IL2RG), its associated kinase JAK3, or the IL-7 receptor alpha chain abolishes IL-7-dependent JAK-STAT signaling that drives early thymocyte survival and proliferation, blocking T-cell development. IL2RG and JAK3 defects additionally abrogate NK-cell development (T-B+NK-), whereas IL7R defects spare B and NK cells (T-B+NK+).

thymocyte CL:0000893

IL2RG hgnc:6010 ↓ DECREASED

IL7R hgnc:6024 JAK3 hgnc:6193

JAK-STAT cytokine receptor signaling GO:0007259 ↓ DECREASED

Downstream

Blocked T-lymphocyte development Loss of IL-7/JAK-STAT signaling halts thymocyte survival and proliferation, blocking maturation of T lymphocytes.

Show evidence (4 references)

PMID:20301584 SUPPORT Human Clinical

"The diagnosis of typical and atypical X-SCID is established in a male proband with suggestive findings and a hemizygous pathogenic variant in IL2RG identified by molecular genetic testing."

IL2RG common gamma-chain loss underlies X-linked SCID, the cytokine-signaling form of disrupted T-cell development.

PMID:32181275 SUPPORT Human Clinical

"The gamma portion of IL2R is important for the development of T and NK cells through cytokines IL2 and IL15, respectively."

Supports the mechanism claimed by this node — that common gamma-chain cytokine signalling drives both T- and NK-cell development, so its loss gives the T-B+NK- phenotype.

PMID:32181275 SUPPORT Human Clinical

"JAK3 plays a pivotal role in cytokine receptor cell signalling."

Supports placing JAK3 in the same cytokine-receptor signalling node as IL2RG.

+ 1 more reference

Defective V(D)J recombination and DNA repair

In RAG1, RAG2, DCLRE1C (Artemis), PRKDC (DNA-PKcs), and LIG4 (DNA ligase IV) deficiency, the machinery that assembles antigen-receptor genes is impaired. RAG1/RAG2 initiate site-specific DNA cleavage during V(D)J recombination; Artemis opens the resulting DNA hairpins as part of non-homologous end-joining; DNA-PKcs activates Artemis for that step; and DNA ligase IV seals the repaired ends. Failure to recombine T-cell (and B-cell) receptor genes arrests lymphocyte development (T-B-NK+). Loss of any of the three end-joining components additionally confers cellular radiosensitivity, which is what makes the molecular diagnosis matter before transplant conditioning.

thymocyte CL:0000893

RAG1 hgnc:9831 ↓ DECREASED

RAG2 hgnc:9832 DCLRE1C hgnc:17642 PRKDC hgnc:9413 LIG4 hgnc:6601

V(D)J recombination GO:0033151 ↓ DECREASED DNA recombination GO:0006310 ↓ DECREASED

DNA-dependent protein kinase activity GO:0004677 ↓ DECREASED DNA ligase (ATP) activity GO:0003910 ↓ DECREASED

Downstream

Blocked T-lymphocyte development Failure of antigen-receptor gene recombination arrests thymocyte maturation, blocking T-cell development.

Show evidence (6 references)

PMID:32181275 SUPPORT Human Clinical

"RAG1 and RAG2, are DNA recombinases that mediate DNA recombination process and ensure the somatic diversification of immunoglobulin and TCR genes during B-cell and T-cell development, respectively."

Supports the initiating step of this node — RAG-mediated recombination of antigen-receptor genes in developing B and T cells.

PMID:32181275 SUPPORT Human Clinical

"In the absence of VDJ recombination, T cell undergoes apoptosis."

Supports the causal step from failed V(D)J recombination to loss of developing T cells.

PMID:32181275 SUPPORT Human Clinical

"DCLRE1C encodes ARTEMIS, a nuclease which is single-stranded with- 5′-3′ exonuclease potential and endonuclease activity over 5′ and 3′ ends. It is essential for V(D)J rearrangement and for DNA repair."

Supports the Artemis arm of this node, covering both hairpin processing during recombination and general DNA repair.

+ 3 more references

Toxic purine metabolite accumulation

In ADA deficiency, loss of adenosine deaminase activity causes accumulation of adenosine and especially deoxyadenosine (and intracellular dATP), which are lymphotoxic and impair lymphocyte development, viability, and function. The metabolic toxicity affects all lymphoid lineages, producing a T-B-NK- immunophenotype.

thymocyte CL:0000893

ADA hgnc:186 ↓ DECREASED

adenosine catabolic process GO:0006154 ↓ DECREASED

Downstream

Blocked T-lymphocyte development Lymphotoxic deoxyadenosine/dATP accumulation impairs thymocyte survival and blocks T-cell development.

Non-lymphoid tissue purine metabolite toxicity ADA is expressed ubiquitously rather than only in lymphoid tissue, so the same accumulating metabolites reach cells that have no immunological role. This is the branch that makes ADA deficiency the one SCID subtype in this entry whose pathology is not confined to the immune system.

Show evidence (3 references)

PMID:20301656 SUPPORT Human Clinical

"Adenosine deaminase (ADA) deficiency is a systemic purine metabolic disorder that primarily affects lymphocyte development, viability, and function."

ADA deficiency causes toxic purine-metabolite accumulation that impairs lymphocyte development, viability, and function.

PMID:32181275 SUPPORT Human Clinical

"Deficiency of ADA causes accumulation of adenosine, deoxyadenosine, and 2′-O-methyladenosine resulting in lymphocyte apoptosis, causing the absence of T cell function."

Names the accumulating metabolites bound as chemical entities on this node and supplies the intermediate step this node asserts — lymphocyte apoptosis leading to loss of T-cell function.

PMID:20301656 SUPPORT Human Clinical

"total red blood cell deoxyadenosine nucleotides (dAXP) and, if on ERT, plasma ADA activity"

Deoxyadenosine nucleotides (dAXP) are the accumulating phosphorylated species this node refers to, and are the monitored disease marker.

Non-lymphoid tissue purine metabolite toxicity

Because adenosine deaminase is ubiquitously expressed, the deoxyadenosine and dATP that accumulate in its absence are not confined to thymocytes. Two of the same molecular routes that damage developing lymphocytes operate in non-lymphoid cells: 2'-deoxyadenosine irreversibly inactivates S-adenosylhomocysteine hydrolase, so S-adenosylhomocysteine accumulates and inhibits transmethylation; and dATP inhibits ribonucleotide reductase, depleting the deoxynucleotide pool and impairing DNA synthesis in any proliferating cell. This node is the entry point for the extra-immune features of ADA deficiency — neurocognitive, auditory, skeletal, pulmonary and hepatic — which none of the other five SCID subtypes in this entry share.

transmethylation GO:0032259 ↓ DECREASED DNA replication GO:0006260 ↓ DECREASED

S-adenosylhomocysteine hydrolase activity GO:0004013 ↓ DECREASED ribonucleotide reductase activity GO:0004748 ↓ DECREASED

Downstream

Cognitive impairment Adenosine is a CNS neuromodulator and ADA-SCID patients score below both the population average and other SCID groups on IQ, with an inverse correlation between diagnostic dATP level and total IQ. The intervening steps between metabolite accumulation and the cognitive deficit are not established.

Hyperactivity The behavioural phenotype travels with the cognitive one and is reported in the same cohorts, with lower IQ accompanied by more behavioural difficulty.

Sensorineural hearing loss Bilateral sensorineural deafness occurs at roughly ten times the rate seen after transplant for immunodeficiencies confined to the immune system, in children with no structural, genetic, drug or infective cause, including children transplanted without conditioning.

Costochondral abnormalities Costochondral abnormality and skeletal dysplasia are common in ADA deficiency, and ADA-deficient mice show reduced bone formation from impaired osteoblast function. Whether the human bone phenotype follows from the purine lesion or from the immunodeficiency is explicitly unresolved, so this edge is the weakest of the five.

Elevated hepatic transaminases Hepatic involvement is the thinnest arm of the human evidence — transaminase elevation of unknown aetiology is reported but hepatic dysfunction is rare in patients, while ADA-deficient mice die perinatally of hepatocyte degeneration.

Pulmonary alveolar proteinosis Pulmonary alveolar proteinosis occurred in 43.8% of ADA-deficient patients and in none of the patients with other forms of SCID, with no clinical or immunological difference between the ADA patients who developed it and those who did not — which is what places it on this branch rather than on the infectious consequences of the immunodeficiency.

Show evidence (4 references)

PMID:27579027 SUPPORT REVIEW SYNTHESIS Other

"Adenosine deaminase (ADA) is a ubiquitously expressed metabolic enzyme that plays an integral role in numerous cellular processes"

Establishes the premise this node rests on — that the enzyme is not lymphoid-restricted, so its loss is not either.

PMID:27579027 SUPPORT REVIEW SYNTHESIS In Vitro

"2′deoxyadenosine irreversibly inactivates S-adenosyl-l-homocysteine (SAH) hydrolase"

Supports the decreased adenosylhomocysteinase activity bound on this node.

PMID:27579027 SUPPORT REVIEW SYNTHESIS In Vitro

"Inhibition of SAH hydrolase prevents hydrolysis of SAH, and the accumulated SAH inhibits transmethylation reactions"

Supports the increased S-adenosyl-L-homocysteine and the decreased methylation bound on this node.

+ 1 more reference

Defective haematopoietic precursor survival

In reticular dysgenesis, loss of adenylate kinase 2 disrupts cellular and mitochondrial energy homeostasis in haematopoietic precursors themselves. Because the lesion is bioenergetic rather than lymphoid-specific, both myeloid and lymphoid output fail: granulocytes are absent alongside lymphocytes, and innate as well as adaptive immunity is lost. This is the one SCID mechanism class in this entry whose consequences extend outside the lymphoid lineage.

hematopoietic stem cell CL:0000037

AK2 hgnc:362 ↓ DECREASED

haematopoiesis GO:0030097 ↓ DECREASED

adenylate kinase activity GO:0004017 ↓ DECREASED

Downstream

Blocked T-lymphocyte development Failure of haematopoietic precursor survival removes the progenitors from which thymocytes would derive.

Absence of circulating granulocytes The same precursor-survival defect abolishes granulocyte production, a myeloid consequence absent from the other SCID subtypes.

Hypoplasia of the thymus Absent haematopoietic precursors leave the primary and secondary lymphoid organs hypoplastic.

Show evidence (3 references)

PMID:32181275 SUPPORT Human Clinical

"Adenylate kinases are involved in cellular and mitochondrial energy homeostasis."

Supports the bioenergetic function whose loss initiates this node.

PMID:32181275 SUPPORT Human Clinical

"Deficiency of AK2 is associated with lack of innate and adaptive immunity."

Supports the claim that this mechanism removes innate immunity as well as adaptive immunity.

PMID:32181275 SUPPORT Human Clinical

"Reticular dysgenesis is the most serious type of SCID that is associated with absent granulocytes, lymphocytes, hypoplasia of the primary and secondary lymphoid organs and fatal septicemia within days after birth."

Supports the simultaneous granulocyte and lymphocyte failure and the lymphoid-organ hypoplasia this node produces.

Receptor-proximal T-cell receptor signaling defect

In CD3D and LAT deficiency signalling through the pre-T-cell receptor and T-cell receptor fails at or immediately below the receptor, by two different routes. CD3delta is an invariant chain of the complex itself, so its loss leaves no signalling-competent receptor to assemble; LAT is the transmembrane adaptor that propagates the signal from a receptor that is intact, so its loss leaves the receptor silent. Thymocyte development arrests at the double-negative to double-positive transition, giving a T-B+NK+ immunophenotype. This is a fifth mechanism class alongside cytokine receptor signaling, V(D)J recombination and DNA repair, purine metabolism, and haematopoietic precursor survival, and it is the class the CD45/PTPRC and other CD3-chain deficiencies also belong to.

thymocyte CL:0000893

CD3D hgnc:1673 LAT hgnc:18874

T cell receptor signaling pathway GO:0050852 ↓ DECREASED T cell differentiation in thymus GO:0033077 ↓ DECREASED

transmembrane signaling receptor activity GO:0004888 ⇓ LOSS OF FUNCTION signaling receptor complex adaptor activity GO:0030159 ⇓ LOSS OF FUNCTION

Downstream

Blocked T-lymphocyte development Without a signalling-competent T-cell receptor complex, or without the adaptor that carries its signal onward, beta-selection cannot be driven and thymocyte maturation arrests before the double-positive stage.

Show evidence (3 references)

PMID:16264327 SUPPORT DIRECT Human Clinical

"Homozygous mutations in CD3D and CD3E genes lead to a complete block in T-cell development and thus to an early-onset severe combined immunodeficiency phenotype."

Supports this node's claim that loss of a CD3 invariant chain blocks T-cell development and produces SCID.

PMID:16264327 SUPPORT DIRECT Human Clinical

"Thymic studies have shown that the defect in T-cell development occurs at the transition between 'double-negative' and 'double-positive' thymocytes."

Sources the thymocyte stage at which this node places the arrest, and the thymocyte cell type bound here.

PMID:27522155 SUPPORT DIRECT BACKGROUND Model Organism

"Linker for activation of T cells (LAT) is a transmembrane adaptor signaling molecule that is part of the TCR complex and essential for T-cell development, as demonstrated by LAT-deficient mice, which show a complete lack of peripheral T cells."

Sources the T-cell receptor signaling pathway bound to this node, and LAT's position within the receptor complex.

Defective thymocyte egress

In coronin-1A deficiency the actin regulation required for thymocytes to leave the thymus and for peripheral T cells to survive is lost, so T cells do not populate the periphery. The two mouse alleles show the two halves of this separately. The Ptcd strain carries an E26K gain-of-function substitution that increases coronin-1A inhibition of Arp2/3 and blocks thymic egress; Coro1a-null mice, which match the patient's absent protein, instead lose mature thymocytes through reduced survival. Neither is a block in thymocyte development, which is the basis for placing this node beside the developmental block rather than within it.

thymocyte CL:0000893

CORO1A hgnc:2252

thymocyte migration GO:0072679 ↓ DECREASED actin cytoskeleton organization GO:0030036 ⚠ ABNORMAL

Arp2/3 complex binding GO:0071933 ⚠ ABNORMAL

Downstream

Absent adaptive immunity Thymocytes that cannot leave the thymus, and peripheral T cells that do not survive, leave the periphery without a functional T-cell compartment even though intrathymic development is not itself arrested.

Show evidence (5 references)

PMID:18836449 SUPPORT DIRECT Model Organism

"Our findings establish a function for coronin 1A in T cell egress, identify a surface of coronin involved in Arp2/3 regulation and demonstrate that actin regulation is a biological process defective in human and mouse severe combined immunodeficiency."

Sources both processes bound to this node - thymocyte egress and actin regulation - and their status as a human SCID mechanism.

PMID:18836449 SUPPORT DIRECT Human Clinical

"The discovery of another coronin 1A mutant during an N-ethyl-N-nitrosourea-mutagenesis screen for T cell-lymphopenic mice prompted us to evaluate a T cell-deficient, B cell-sufficient and natural killer cell-sufficient patient with severe combined immunodeficiency, whom we found had mutations in..."

Sources the T-B+NK+ immunophenotype this node asserts, in the index human patient.

PMID:18836449 SUPPORT INDIRECT Model Organism

"Mice carrying the recessive locus for peripheral T cell deficiency (Ptcd) have a block in thymic egress, but the mechanism responsible is undefined."

The mouse result this node's egress-rather-than-development placement rests on; recorded as model-organism evidence because the human report does not state where the block sits.

+ 2 more references

Blocked T-lymphocyte development

The convergent consequence of all SCID subtypes is failure of hematopoietic stem cells to differentiate into mature, functional T lymphocytes in the thymus, yielding absent or severely reduced autologous T cells. Depending on the genetic lesion, B and/or NK lineages are also affected.

T cell CL:0000084 hematopoietic stem cell CL:0000037

T cell differentiation in thymus GO:0033077 ↓ DECREASED

Downstream

Absent adaptive immunity Absence of functional T lymphocytes abolishes cell-mediated immunity and (directly or via loss of T-cell help) humoral immunity.

Decreased total T cell count Blocked thymic T-cell development produces profound T lymphocytopenia.

Hypoplasia of the thymus Absence of developing thymocytes leaves a small, dysplastic thymus that yields an absent thymic shadow on imaging.

Decreased total B cell count In T-B- subtypes (RAG1/RAG2, Artemis, ADA) the same developmental/metabolic block also abolishes B-lymphocyte development.

Reduced total natural killer cell count In NK-negative subtypes (IL2RG, JAK3, ADA) the gamma-chain signaling or metabolic defect also abolishes NK-cell development.

Show evidence (1 reference)

PMID:36456361 SUPPORT Human Clinical

"Severe combined immunodeficiency (SCID) results from defects in the differentiation of hematopoietic stem cells into mature T lymphocytes, with additional lymphoid lineages affected in particular genotypes."

SCID converges on failed differentiation of hematopoietic stem cells into mature T lymphocytes, with additional lineages affected by genotype.

Absent adaptive immunity

Without functional T cells (and often B cells), the patient cannot mount protective cellular or humoral adaptive immune responses, leaving the infant susceptible to overwhelming bacterial, viral, fungal, and protozoal infection.

T cell CL:0000084 B cell CL:0000236

adaptive immune response GO:0002250 ↓ DECREASED

Downstream

Severe combined immunodeficiency Loss of adaptive immunity is the defining clinical immunodeficiency.

Absent cellular immunity Loss of functional T cells abolishes cell-mediated immune responses.

Recurrent infections Without adaptive immunity, infants suffer recurrent and persistent infections from early infancy.

Recurrent fungal infections Loss of T-cell immunity predisposes to fungal infection including persistent candidiasis.

Chronic oral candidiasis Defective cellular immunity allows persistent oral Candida infection.

Pneumonia Loss of adaptive immunity predisposes to recurrent and opportunistic pneumonia (including Pneumocystis).

Chronic diarrhea Opportunistic enteric infection and immune dysfunction produce persistent diarrhea.

Failure to thrive Chronic infection and diarrhea cause poor linear growth and weight gain.

Hepatosplenomegaly Disseminated infection and immune dysregulation (e.g., Omenn syndrome) can produce hepatosplenomegaly.

Show evidence (1 reference)

PMID:20301656 SUPPORT Human Clinical

"Characteristic immune abnormalities are lymphocytopenia (low numbers of T, B, and NK cells) combined with the absence of both humoral and cellular immune function."

SCID produces absence of both humoral and cellular immune function, the loss of adaptive immunity.

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Pathograph

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Phenotypes

28

Blood 7

Decreased total T cell count VERY_FREQUENT HP:0005403

Show evidence (1 reference)

PMID:36456361 SUPPORT Human Clinical

"Patients with typical SCID must have less than 0.05 × 109 autologous T cells/L on repetitive testing"

Typical SCID is defined by profoundly low autologous T-cell counts.

Decreased total B cell count HP:0010976

Subtype tag corrected from "RAG1/RAG2 deficiency" to "ADA deficiency" to match the cited evidence, which is the ADA-deficiency GeneReviews. The T-B- immunophenotype is shared by RAG1/RAG2 and Artemis deficiency, but those subtypes are not what the quoted source documents.

Show evidence (1 reference)

PMID:20301656 SUPPORT Human Clinical

"Characteristic immune abnormalities are lymphocytopenia (low numbers of T, B, and NK cells)"

In T-B-NK- forms such as ADA-SCID, B-cell numbers are reduced along with T and NK cells.

Reduced total natural killer cell count HP:0040218

Subtype tag corrected from "X-linked SCID" to "ADA deficiency" to match the cited evidence, which is the ADA-deficiency GeneReviews. NK-negativity is also the X-linked SCID (IL2RG) and JAK3 immunophenotype, but that is not what the quoted source documents.

Show evidence (1 reference)

PMID:20301656 SUPPORT Human Clinical

"Characteristic immune abnormalities are lymphocytopenia (low numbers of T, B, and NK cells)"

NK-cell numbers are reduced in the NK-negative SCID immunophenotypes.

Increased total eosinophil count HP:0001880

Show evidence (1 reference)

PMID:32181275 SUPPORT Human Clinical

"One of the important clinical presentations of RAG defects is Omenn syndrome, characterized by significant expansion of activated oligoclonal T cells, erythroderma, diarrhoea, hepatosplenomegaly, generalized lymphadenopathy, hypereosinophilia, and elevated IgE levels."

Lists hypereosinophilia as a defining feature of the Omenn presentation of RAG deficiency.

Increased circulating IgE concentration HP:0003212

Show evidence (1 reference)

PMID:32181275 SUPPORT Human Clinical

"One of the important clinical presentations of RAG defects is Omenn syndrome, characterized by significant expansion of activated oligoclonal T cells, erythroderma, diarrhoea, hepatosplenomegaly, generalized lymphadenopathy, hypereosinophilia, and elevated IgE levels."

Lists elevated IgE among the Omenn syndrome features of RAG deficiency.

Absence of circulating granulocytes HP:0012234

Show evidence (1 reference)

PMID:32181275 SUPPORT Human Clinical

"Reticular dysgenesis is the most serious type of SCID that is associated with absent granulocytes, lymphocytes, hypoplasia of the primary and secondary lymphoid organs and fatal septicemia within days after birth."

Directly documents absent granulocytes in reticular dysgenesis.

Hemolytic anemia HP:0001878

Show evidence (1 reference)

PMID:20301656 SUPPORT Human Clinical

"Skeletal abnormalities affecting ribs and vertebra, pulmonary alveolar proteinosis, hemolytic anemia, neurologic abnormalities, and transaminitis may also suggest untreated ADA-SCID."

Lists haemolytic anaemia among the extra-immune features suggestive of untreated ADA-SCID.

Cardiovascular 3

Hypoplasia of the thymus HP:0000778

Ontology term corrected from HP:0005359 "Aplasia of the thymus" to HP:0000778 "Hypoplasia of the thymus". In typical SCID the thymic epithelial rudiment is present but hypoplastic/dysplastic because it is not populated by thymocytes; true thymic APLASIA (athymia) is the lesion of complete DiGeorge syndrome and FOXN1 deficiency, which are distinct entities. The absent thymic shadow on radiography reflects hypoplasia, not absence of the organ. This is also not a universal SCID finding - CORO1A deficiency, for example, produces T-B+ SCID with a normal-sized thymus - so no frequency band is asserted.

Show evidence (2 references)

PMID:32181275 SUPPORT Human Clinical

"hypoplasia of secondary lymphoid organs and thymus"

Documents thymic hypoplasia (rather than aplasia) as the thymic finding in SCID.

PMID:32181275 SUPPORT Human Clinical

"Deficiency of Coronin 1A known to result in T-B + SCID with a normal sized thymus."

Documents a SCID genotype with a normal-sized thymus, showing the thymic finding is genotype-dependent and not universal.

Hepatosplenomegaly HP:0001433

Show evidence (1 reference)

PMID:36456361 SUPPORT Human Clinical

"Omenn syndrome requires a generalized erythematous rash, absent transplacentally acquired maternal engraftment, and 2 or more of these: eosinophilia, elevated IgE, lymphadenopathy, hepatosplenomegaly."

Hepatosplenomegaly is a recognized feature of the Omenn syndrome presentation of leaky SCID (RAG hypomorphs).

Lymphadenopathy HP:0002716

Show evidence (1 reference)

PMID:32181275 SUPPORT Human Clinical

"One of the important clinical presentations of RAG defects is Omenn syndrome, characterized by significant expansion of activated oligoclonal T cells, erythroderma, diarrhoea, hepatosplenomegaly, generalized lymphadenopathy, hypereosinophilia, and elevated IgE levels."

Lists generalized lymphadenopathy among the Omenn syndrome features of RAG deficiency.

Digestive 1

Chronic diarrhea FREQUENT HP:0002028

Show evidence (1 reference)

PMID:20301656 SUPPORT Human Clinical

"poor linear growth and weight gain secondary to persistent diarrhea"

Persistent diarrhea is a frequent presenting feature contributing to failure to thrive in SCID.

Ear 1

Sensorineural hearing loss Sensorineural hearing impairment HP:0000407

The 58% figure comes from 12 patients assessed after transplant with no pre-transplant audiology, so it cannot establish that the deafness predated treatment; the review's argument is the comparison against the transplanted control group and the absence of any other cause, not a before-and-after measurement.

Show evidence (1 reference)

PMID:27579027 SUPPORT REVIEW SYNTHESIS Human Clinical

"a 58% incidence was reported in the 12 patients who had undergone audiologic assessment in a study by Albuquerque and Gaspar"

Quantifies the sensorineural deafness incidence in ADA-SCID that this phenotype records, and names the cohort it was measured in.

Head and Neck 1

Chronic oral candidiasis HP:0009098

Show evidence (1 reference)

PMID:32181275 SUPPORT Human Clinical

"Clinical manifestations are characterised by recurrent and severe bacterial, viral, and fungal opportunistic infections that start from early infancy period."

Persistent fungal (candidal) infection including oral thrush reflects the T-cell immune defect in SCID.

Immune 7

Severe combined immunodeficiency HP:0004430

Show evidence (1 reference)

PMID:36456361 SUPPORT Human Clinical

"Severe combined immunodeficiency (SCID) results from defects in the differentiation of hematopoietic stem cells into mature T lymphocytes, with additional lymphoid lineages affected in particular genotypes."

SCID is defined by combined defects of adaptive immunity arising from failed T-lymphocyte differentiation.

Recurrent infections VERY_FREQUENT HP:0002719

Show evidence (1 reference)

PMID:32181275 SUPPORT Human Clinical

"Clinical manifestations are characterised by recurrent and severe bacterial, viral, and fungal opportunistic infections that start from early infancy period."

Recurrent severe opportunistic infections from early infancy are the cardinal clinical feature of SCID.

Pneumonia HP:0002090

Show evidence (1 reference)

PMID:20301656 SUPPORT Human Clinical

"Untreated ADA-SCID presents as life-threatening opportunistic illnesses in the first weeks to months of life with poor linear growth and weight gain secondary to persistent diarrhea, extensive dermatitis, and recurrent pneumonia."

Recurrent pneumonia is a presenting opportunistic illness in untreated SCID.

Recurrent fungal infections HP:0002841

Show evidence (1 reference)

PMID:32181275 SUPPORT Human Clinical

"Clinical manifestations are characterised by recurrent and severe bacterial, viral, and fungal opportunistic infections that start from early infancy period."

Recurrent fungal opportunistic infections are part of the SCID clinical picture.

Erythroderma HP:0001019

Show evidence (2 references)

PMID:36456361 SUPPORT Human Clinical

"Omenn syndrome requires a generalized erythematous rash, absent transplacentally acquired maternal engraftment, and 2 or more of these: eosinophilia, elevated IgE, lymphadenopathy, hepatosplenomegaly."

A generalized erythematous rash is an obligate criterion for Omenn syndrome in the PIDTC 2022 definitions.

PMID:32181275 SUPPORT Human Clinical

"One of the important clinical presentations of RAG defects is Omenn syndrome, characterized by significant expansion of activated oligoclonal T cells, erythroderma, diarrhoea, hepatosplenomegaly, generalized lymphadenopathy, hypereosinophilia, and elevated IgE levels."

Independently lists erythroderma among the Omenn features of RAG defects and gives the oligoclonal T-cell mechanism.

Dermatitis Inflammatory abnormality of the skin HP:0011123

Bound to the general HPO skin-inflammation term rather than a specific dermatitis subtype: the cited sources say "extensive dermatitis" and "dermatitis" without characterising it as atopic, seborrhoeic, or contact dermatitis, and choosing one of those would assert more than the sources do.

Show evidence (1 reference)

PMID:20301656 SUPPORT Human Clinical

"Untreated ADA-SCID presents as life-threatening opportunistic illnesses in the first weeks to months of life with poor linear growth and weight gain secondary to persistent diarrhea, extensive dermatitis, and recurrent pneumonia."

Documents extensive dermatitis as a presenting feature of untreated ADA-SCID.

Autoimmunity HP:0002960

Show evidence (1 reference)

PMID:20301584 SUPPORT Human Clinical

"The phenotypic spectrum of X-linked severe combined immunodeficiency (X-SCID) ranges from typical X-SCID (early-onset disease in males that is fatal if not treated with hematopoietic stem cell transplantation [HSCT] or gene therapy) to atypical X-SCID (later-onset disease comprising phenotypes..."

Places immune dysregulation and autoimmunity in the atypical, later-onset end of the X-SCID spectrum.

Metabolism 1

Elevated hepatic transaminases Elevated circulating hepatic transaminase concentration HP:0002910

This is the thinnest of the extra-immune arms in humans and should not be read as equivalent to the auditory or neurocognitive evidence. The review states that hepatic dysfunction has rarely been reported in patients and that other supportive clinical data are hard to find; the strong hepatic phenotype — perinatally lethal hepatocyte degeneration — is murine and is explicitly not reproduced in patients.

Show evidence (2 references)

PMID:27579027 SUPPORT REVIEW SYNTHESIS Human Clinical

"elevated serum transaminase levels may be seen in patients with ADA deficiency: this is indicative of liver damage and often etiology is unknown"

Documents the transaminase elevation in patients that this phenotype records.

PMID:27579027 SUPPORT REVIEW SYNTHESIS Human Clinical

"the effects in ADA-deficient patients are not perinatally lethal and hepatic dysfunction has rarely been reported"

Supports the rarity qualifier this phenotype's notes record, keeping the hepatic arm from reading as an established frequent feature.

Musculoskeletal 1

Costochondral abnormalities Abnormality of the costochondral junction HP:0000919

Bound to the general costochondral-junction term rather than to HP:0000920 (enlargement): enlarged costochondral junctions are the mouse finding, while the patient finding is reported as "costochondral abnormalities" without a specified direction. Attribution is also unsettled — bony pathology described as characteristic of ADA-SCID has been found, to a lesser degree, in patients with normal ADA activity, and the review states the causal assignment is unknown. Recorded as a REFUTE item on the causal edge rather than being left out of the entry.

Show evidence (2 references)

PMID:27579027 SUPPORT REVIEW SYNTHESIS Human Clinical

"It is common for patients with ADA deficiency to display costochondral abnormalities and skeletal dysplasia"

Documents the skeletal finding in patients that this phenotype records.

PMID:20301656 SUPPORT Human Clinical

"Skeletal abnormalities affecting ribs and vertebra, pulmonary alveolar proteinosis, hemolytic anemia, neurologic abnormalities, and transaminitis may also suggest untreated ADA-SCID."

Independent GeneReviews confirmation that rib and vertebral abnormality is part of the untreated ADA-SCID picture.

Nervous System 2

Cognitive impairment HP:0100543

Bound to the general cognitive-impairment term rather than to intellectual disability: the source reports IQ distributions shifted below population and below-SCID-group averages, not a diagnosis of intellectual disability, and binding HP:0001249 would assert a threshold the source does not state.

Show evidence (1 reference)

PMID:27579027 SUPPORT REVIEW SYNTHESIS Human Clinical

"Patients with ADA-SCID consistently achieve IQ scores that are not only below the population average but also below that of other SCID groups"

Documents the cognitive deficit and its specificity to ADA deficiency within SCID, which is what makes it an extra-immune feature rather than a consequence of being a transplanted SCID patient.

Hyperactivity HP:0000752

One HPO term is bound for a cluster the source reports together (hyperactivity, attention deficits, aggressive behaviour, social problems). Hyperactivity is the element with the cleanest HPO match; the rest of the cluster is carried in preferred_term and the description rather than split into terms the source does not separately characterise.

Show evidence (1 reference)

PMID:27579027 SUPPORT REVIEW SYNTHESIS Human Clinical

"ADA-SCID patients exhibit hyperactivity, attention deficits, aggressive behavior, and social problems, scoring abnormally in all of these areas of behavior"

Names the behavioural abnormalities this phenotype records.

Respiratory 2

Pulmonary alveolar proteinosis Intraalveolar phospholipid accumulation HP:0006517

Show evidence (1 reference)

PMID:20301656 SUPPORT Human Clinical

"Skeletal abnormalities affecting ribs and vertebra, pulmonary alveolar proteinosis, hemolytic anemia, neurologic abnormalities, and transaminitis may also suggest untreated ADA-SCID."

Lists pulmonary alveolar proteinosis among the extra-immune features suggestive of untreated ADA-SCID.

Bronchiectasis HP:0002110

Show evidence (1 reference)

PMID:20301584 SUPPORT Human Clinical

"recurrent upper and lower respiratory tract infections with bronchiectasis; Omenn syndrome, a clinical phenotype caused by immune dysregulation; X-SCID combined immunodeficiency (often with recurrent infections, warts, and dermatitis); immune dysregulation and autoimmunity; or Epstein-Barr..."

Lists bronchiectasis with recurrent respiratory infection as one of the atypical X-SCID presentations.

Growth 1

Failure to thrive FREQUENT HP:0001508

Show evidence (1 reference)

PMID:20301656 SUPPORT Human Clinical

"Untreated ADA-SCID presents as life-threatening opportunistic illnesses in the first weeks to months of life with poor linear growth and weight gain secondary to persistent diarrhea"

Poor linear growth and weight gain (failure to thrive) follow chronic infection and diarrhea in untreated SCID.

Other 1

Absent cellular immunity HP:0005354

Show evidence (1 reference)

PMID:20301656 SUPPORT Human Clinical

"Characteristic immune abnormalities are lymphocytopenia (low numbers of T, B, and NK cells) combined with the absence of both humoral and cellular immune function."

SCID features absence of cellular immune function.

🧬

Genetic Associations

13

IL2RG (Causative)

Gene: IL2RG hgnc:6010 gene page

Show evidence (2 references)

PMID:20301584 SUPPORT Human Clinical

"The diagnosis of typical and atypical X-SCID is established in a male proband with suggestive findings and a hemizygous pathogenic variant in IL2RG identified by molecular genetic testing."

A hemizygous IL2RG pathogenic variant establishes the diagnosis of X-linked SCID.

PMID:32181275 SUPPORT Human Clinical

"The gamma portion of IL2R is important for the development of T and NK cells through cytokines IL2 and IL15, respectively."

Explains why common gamma-chain loss removes both T and NK lineages, giving the T-B+NK- immunophenotype.

ADA (Causative)

Gene: ADA hgnc:186

Show evidence (2 references)

PMID:20301656 SUPPORT Human Clinical

"Adenosine deaminase (ADA) deficiency is a systemic purine metabolic disorder that primarily affects lymphocyte development, viability, and function."

Biallelic ADA deficiency causes a systemic purine metabolic disorder affecting lymphocyte development, the basis of ADA-SCID.

PMID:20301656 SUPPORT Human Clinical

"The ADA deficiency phenotypic spectrum includes typical early-onset severe combined immunodeficiency (ADA-SCID), diagnosed in infancy (about 80% of individuals), and less severe "delayed" or "late-onset" combined immunodeficiency (ADA-CID), diagnosed in older children and adults (15%-20% of individuals)."

Supports the "about 80%" typical-SCID proportion stated in these features.

RAG1 (Causative)

Gene: RAG1 hgnc:9831 gene page

Show evidence (2 references)

PMID:32181275 SUPPORT Human Clinical

"Deficiency of either RAG1 or RAG2 causes T-B-NK + SCID and is inherited in an autosomal recessive pattern."

RAG1 deficiency is a well-characterized autosomal recessive cause of T-B-NK+ SCID via a V(D)J-recombination defect.

PMID:32181275 SUPPORT Human Clinical

"RAG1 and RAG2, are DNA recombinases that mediate DNA recombination process and ensure the somatic diversification of immunoglobulin and TCR genes during B-cell and T-cell development, respectively."

Supports the specific molecular role — recombinase-driven antigen-receptor gene diversification — asserted in these features.

RAG2 (Causative)

Gene: RAG2 hgnc:9832

Show evidence (1 reference)

PMID:32181275 SUPPORT Human Clinical

"Deficiency of either RAG1 or RAG2 causes T-B-NK + SCID and is inherited in an autosomal recessive pattern."

RAG2 deficiency, like RAG1, abolishes V(D)J recombination and causes autosomal recessive T-B-NK+ SCID.

IL7R (Causative)

Gene: IL7R hgnc:6024 gene page

Show evidence (2 references)

PMID:32181275 SUPPORT Human Clinical

"Deficiency of ILR7 alpha causes T-B + NK + SCID, that accounts for around 10% of the total SCID patients."

IL7R (IL7R alpha) deficiency selectively impairs T-cell development, producing a T-B+NK+ form accounting for about 10% of SCID.

PMID:32181275 SUPPORT Human Clinical

"The encoded protein is expressed on the lymphoid lineage and is required during T cell development during early stage and for proliferation and survival of T cells in the periphery."

Supports the specific requirement for IL-7 receptor alpha in early T-cell development and peripheral T-cell survival.

JAK3 (Causative)

Gene: JAK3 hgnc:6193

Show evidence (1 reference)

PMID:32181275 SUPPORT Human Clinical

"JAK3 deficiency constitutes around 6% of the total SCID patients and is inherited as an autosomal recessive trait."

JAK3 deficiency is an autosomal recessive SCID acting downstream of the common gamma chain, accounting for about 6% of cases.

DCLRE1C (Causative)

Gene: DCLRE1C hgnc:17642

Show evidence (4 references)

PMID:33628209 SUPPORT Human Clinical

"RAG2 (17), JAK3 (15), DCLRE1C (13), IL7RA (9)"

A multi-institutional cohort identifies DCLRE1C (Artemis) defects as a recurrent molecular cause of SCID.

PMID:32181275 SUPPORT Human Clinical

"DCLRE1C encodes ARTEMIS, a nuclease which is single-stranded with- 5′-3′ exonuclease potential and endonuclease activity over 5′ and 3′ ends. It is essential for V(D)J rearrangement and for DNA repair."

Supports the dual V(D)J-rearrangement and DNA-repair role asserted in these features.

PMID:32181275 SUPPORT Human Clinical

"Artemis deficiency causes early arrest in the maturation of T cells and B cell differentiation during early pre-B cell stage, resulting in T–B–NK + SCID."

Supports the T-B-NK+ immunophenotype attributed to Artemis deficiency.

+ 1 more reference

AK2 (Causative)

Gene: AK2 hgnc:362 gene page

Show evidence (3 references)

PMID:32181275 SUPPORT Human Clinical

"Mutation of the AK2 gene causes reticular dysgenesis (RD), an autosomal recessive disorder occurring in 2% of children with SCID."

Establishes AK2 as causative for reticular dysgenesis and its frequency among SCID.

PMID:32181275 SUPPORT Human Clinical

"Deficiency of AK2 is associated with lack of innate and adaptive immunity."

Supports the combined innate-plus-adaptive failure that distinguishes AK2 deficiency from the lymphoid-restricted SCID subtypes.

PMID:32181275 SUPPORT Human Clinical

"Adenylate kinases are involved in cellular and mitochondrial energy homeostasis."

Supports the non-lymphoid-specific, bioenergetic function of AK2 asserted in these features.

PRKDC (Causative)

Gene: PRKDC hgnc:9413 gene page

Show evidence (2 references)

PMID:19075392 SUPPORT DIRECT Human Clinical

"Radiosensitive T-B- severe combined immunodeficiency (RS-SCID) is caused by defects in the nonhomologous end-joining (NHEJ) DNA repair pathway, which results in failure of functional V(D)J recombination."

Places DNA-PKcs deficiency in the NHEJ/V(D)J mechanism class this entry already models, and gives the T-B-NK+ immunophenotype.

PMID:19075392 SUPPORT DIRECT Human Clinical

"Here we have identified the first human RS-SCID patient to our knowledge with a DNA-PKcs missense mutation (L3062R)."

Establishes PRKDC as a human SCID gene rather than only a mouse one.

LIG4 (Causative)

Gene: LIG4 hgnc:6601

Show evidence (4 references)

PMID:11779494 SUPPORT DIRECT Human Clinical

"DNA ligase IV functions in DNA nonhomologous end-joining and V(D)J recombination."

States the molecular step at which LIG4 acts, which is the node this gene is wired to.

PMID:11779494 SUPPORT DIRECT Human Clinical

"Cell lines from the patients show pronounced radiosensitivity."

Sources the cellular radiosensitivity that groups LIG4 with Artemis and DNA-PKcs for conditioning purposes.

PMID:26762768 SUPPORT DIRECT Human Clinical

"This study enrolled seven Chinese patients with LIG4 deficiency who presented with combined immunodeficiency, microcephaly, and growth retardation."

Sources the microcephaly and growth retardation recorded in these features, and the cohort in which the combined immunodeficiency was characterized.

+ 1 more reference

CD3D (Causative)

Gene: CD3D hgnc:1673 gene page

Show evidence (2 references)

PMID:16264327 SUPPORT DIRECT Human Clinical

"Homozygous mutations in CD3D and CD3E genes lead to a complete block in T-cell development and thus to an early-onset severe combined immunodeficiency phenotype."

Establishes CD3D as a SCID gene and states the complete developmental block this node asserts.

PMID:16264327 SUPPORT DIRECT Human Clinical

"Thymic studies have shown that the defect in T-cell development occurs at the transition between 'double-negative' and 'double-positive' thymocytes."

Locates the arrest at beta-selection, the step this node places downstream of receptor-proximal signalling failure.

LAT (Causative)

Gene: LAT hgnc:18874 gene page

Show evidence (2 references)

PMID:27522155 SUPPORT DIRECT BACKGROUND Model Organism

"Linker for activation of T cells (LAT) is a transmembrane adaptor signaling molecule that is part of the TCR complex and essential for T-cell development, as demonstrated by LAT-deficient mice, which show a complete lack of peripheral T cells."

States that LAT is a component of the TCR complex required for T-cell development, which is the mechanism this gene is bound to.

PMID:27522155 SUPPORT DIRECT Human Clinical

"We describe a pedigree affected by a severe combined immunodeficiency phenotype with absent T cells and normal B-cell and natural killer cell numbers."

Sources the human SCID phenotype and its T-B+NK+ immunophenotype.

CORO1A (Causative)

Gene: CORO1A hgnc:2252 gene page

Show evidence (2 references)

PMID:18836449 SUPPORT DIRECT Model Organism

"Our findings establish a function for coronin 1A in T cell egress, identify a surface of coronin involved in Arp2/3 regulation and demonstrate that actin regulation is a biological process defective in human and mouse severe combined immunodeficiency."

Establishes the egress mechanism and that coronin-1A loss is a human SCID mechanism distinct from the four already modelled here.

PMID:25269405 SUPPORT DIRECT Human Clinical

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

Sources the allele-dependent split recorded in these features, which is why this gene is not asserted as a uniform SCID subtype.

💊

Medical Actions

6

Hematopoietic stem cell transplantation

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

Platform: Cell therapy

Allogeneic hematopoietic stem cell transplantation is the definitive curative treatment for SCID, reconstituting a functional immune system; outcomes are best when performed early, before the onset of infections.

Mechanism Target:

RESTORES Blocked T-lymphocyte development — Donor hematopoietic stem cells reconstitute thymic T-cell development and adaptive immunity.

Show evidence (4 references)

PMID:32181275 SUPPORT Human Clinical

"Haematopoietic stem cell transplantation (HSCT) is the treatment of choice."

HSCT is the curative treatment of choice for SCID.

PMID:25138334 SUPPORT Human Clinical

"overall SCID survival was 45 of 52 (87%), while 45 of 49 treated infants (92%) survived"

Quantifies the survival achieved when SCID is detected by newborn screening and treated early, supporting the claim that outcomes are best when transplant precedes infection.

PMID:32181275 SUPPORT Human Clinical

"radiosensitive forms of SCID are prone to develop increased toxicity to alkylator-based chemotherapeutic agents used in the conditioning regimen for HSCT"

Qualifies the treatment: the conditioning regimen must be adapted in radiosensitive genotypes, so HSCT is not uniformly deliverable across SCID subtypes.

+ 1 more reference

Hematopoietic stem cell gene therapy

Action: gene therapy Ontology label: Gene Therapy NCIT:C15238

Platform: Gene therapy

Autologous hematopoietic stem cell gene therapy corrects the causative gene in the patient's own stem cells; it is an established alternative to allogeneic HSCT for ADA-SCID (Strimvelis) and has shown clinical success for X-linked and other SCID forms.

Mechanism Target:

RESTORES Blocked T-lymphocyte development — Gene-corrected autologous stem cells restore lymphocyte development and adaptive immunity.

Show evidence (3 references)

PMID:38355973 SUPPORT Human Clinical

"Long-term persistence of multilineage gene-corrected cells, metabolic detoxification, immune reconstitution and decreased infection rates were observed."

Retroviral hematopoietic stem cell gene therapy provides durable multilineage engraftment, immune reconstitution, and reduced infections in ADA-SCID.

PMID:38355973 SUPPORT Human Clinical

"2 years intervention-free survival (no need for long-term enzyme replacement therapy or allogeneic hematopoietic stem cell transplantation) of 88% (95% confidence interval 78.7-98.4%)"

Quantifies the durability of the benefit — the proportion of treated patients needing neither ongoing ERT nor rescue allogeneic transplant.

PMID:38355973 SUPPORT Human Clinical

"One patient from the named patient program developed a T cell leukemia related to treatment 4.7 years after GT and is currently in remission."

Records the insertional-oncogenesis risk of retroviral gene therapy — a treatment-related leukaemia in the long-term cohort — so the entry does not present gene therapy as risk-free.

Enzyme replacement therapy with pegademase (PEG-ADA)

Action: enzyme replacement or supplementation therapy Ontology label: Protein Replacement Therapy NCIT:C16221

Agent: pegademase bovine NCIT:C77484

For ADA deficiency, enzyme replacement therapy with PEGylated adenosine deaminase corrects the metabolic defect, providing protection against infection; it is often used to stabilize patients before curative HSCT or gene therapy.

Mechanism Target:

INHIBITS Toxic purine metabolite accumulation — Exogenous PEGylated ADA clears toxic deoxyadenosine/adenosine, correcting the lymphotoxic metabolic defect.

Show evidence (2 references)

PMID:20301656 SUPPORT Human Clinical

"enzyme replacement therapy (ERT) by intramuscular administration of PEGylated ADA"

Enzyme replacement therapy with PEGylated ADA is a targeted treatment correcting the ADA metabolic defect.

PMID:20301656 SUPPORT Human Clinical

"Often, ERT is initiated first to rapidly correct the metabolic defect and to protect against serious infections as well as neurologic/behavioral abnormalities. It is discontinued at the time HSCT or HSC-GT is performed."

Supports the bridging role asserted in this treatment's description, and specifies that ERT is stopped once curative therapy is delivered rather than continued alongside it.

Immunoglobulin replacement therapy

Action: immunoglobulin infusion therapy Ontology label: Immunoglobulin Therapy NCIT:C62710

Intravenous (or subcutaneous) immunoglobulin replacement provides passive humoral protection while patients await or recover from definitive immune reconstitution.

Target Phenotypes: Recurrent infections HP:0002719

Show evidence (1 reference)

PMID:20301656 SUPPORT Human Clinical

"use of immunoglobulin infusions and antibiotics, particularly prophylaxis against Pneumocystis jirovecii pneumonia"

Immunoglobulin infusions are an explicit part of supportive management for the profound antibody deficiency seen in SCID.

Pneumocystis jirovecii pneumonia prophylaxis

Action: antimicrobial agent therapy Ontology label: Pharmacotherapy NCIT:C15986

Antimicrobial prophylaxis, particularly against Pneumocystis jirovecii pneumonia, is a standard supportive measure to prevent opportunistic infection pending immune reconstitution.

Target Phenotypes: Pneumonia HP:0002090

Show evidence (1 reference)

PMID:20301656 SUPPORT Human Clinical

"particularly prophylaxis against Pneumocystis jirovecii pneumonia (formerly Pneumocystis carinii) and fungal infections"

Prophylaxis against Pneumocystis jirovecii pneumonia is a standard supportive measure in SCID.

Protective isolation and avoidance of live vaccines and non-irradiated blood products

Action: infection-exposure avoidance and protective isolation Ontology label: Supportive Care NCIT:C15747

Platform: Behavioral / lifestyle

Until immune reconstitution is achieved, exposure avoidance is itself treatment. Live viral vaccines — given to the infant or to household contacts — can cause disseminated vaccine-strain disease; non-irradiated blood products can cause transfusion-associated graft-versus-host disease in a patient with no T cells to reject donor lymphocytes; and breast milk is withheld pending maternal CMV status. Live rotavirus vaccine is the specific exposure that newborn-screening programmes act on first, because it is administered at the age at which screened infants are still awaiting definitive therapy.

Target Phenotypes: Recurrent infections HP:0002719

Show evidence (2 references)

PMID:20301584 SUPPORT Human Clinical

"live viral vaccines for the affected individual as well as household contacts; transfusion of non-irradiated blood products"

Names the two exposures this treatment exists to prevent, including the household-contact extension of the live-vaccine restriction.

PMID:25138334 SUPPORT Human Clinical

"All infants with T-cell lymphopenia were directed to avoid infectious exposures, transfusions (except with cytomegalovirus-negative, irradiated blood products), and live rotavirus vaccines until such time as immune compromise was no longer present."

Documents this as applied practice across 11 newborn-screening programmes, including the CMV-negative irradiated-product qualifier and the live-rotavirus-vaccine restriction.

🔬

Diagnosis

4

Lymphocyte subset flow cytometry

Flow cytometric enumeration of T, B, and NK cells — with naive/memory CD4 subsetting — is the confirmatory test after an abnormal newborn screen and the routine route to diagnosis outside screening programmes. The T/B/NK pattern also assigns the likely mechanism class before sequencing returns.

flow cytometry procedure NCIT:C16585

Show evidence (1 reference)

PMID:32181275 SUPPORT Human Clinical

"Though the diagnosis of SCID is usually established by flow cytometry-based tests, genetic diagnosis is often needed for genetic counselling, prognostication, and modification of pre-transplant chemotherapeutic agents."

Establishes flow cytometry as the usual diagnostic modality and states why genetic testing is still required.

TREC newborn screening

Quantification of T-cell receptor excision circles by PCR on Guthrie-card dried blood spots detects failed thymic T-cell output before infection begins. It is the first immune disorder accepted for population-based screening and is now universal across US states. The result is a TREC copy number per microlitre of blood, read against a beta-actin amplification control for sample quality, and the abnormal direction is low: undetectable or very low TRECs are the positive result. Cut-offs and retest rules differ by programme and assay, and several programmes set a lower first-sample threshold for preterm infants, whose TREC values are lower at birth and rise with maturation.

newborn screening NCIT:C81178

SCID newborn screening panel LOINC:62333-0 T-cell receptor excision circles (TREC), DBS LOINC:62320-7 SCID newborn screen interpretation LOINC:62321-5

Reference Ranges

T-cell receptor excision circle [#/volume] in DBS by NAA with probe detection (term newborns, Catalonia (Spain) universal SCID newborn-screening programme, EnLite Neonatal TREC assay, 2017-2023 (retest threshold as set in 2018))

Positive on first sample (< 10 {copies}/uL) Second sample requested (10–20 {copies}/uL) Retest in duplicate (20–24 {copies}/uL) Screen negative (≥ 24 {copies}/uL)

Positive on first sample: Notified to the clinical reference unit for lymphocyte phenotyping without waiting for a second sample.

Second sample requested: Retested in duplicate; if two of three values are at or below 20 copies/µL a second dried blood spot is requested, and a second sample at or below 20 copies/µL is a positive detection.

Retest in duplicate: Below the 2018 retest threshold but above the detection cut-off; the sample is re-run in duplicate and proceeds only if the repeat values fall to 20 copies/µL or below.

The programme's detection cut-off is 20 copies/µL throughout 2017-2023. Its decision algorithm, as published for 2017-2018, is tiered: a first sample at or below 10 copies/µL in a term newborn (with beta-actin at or above 50 copies/µL as the quality criterion) is a positive detection outright; a first sample at or below the retest threshold (34 copies/µL in 2017, 24 from 2018) is retested in duplicate, and if two of the three values are at or below 20 copies/µL a second sample is requested, which is positive at or below 20 copies/µL. The source's thresholds are inclusive ("at or below"), so a value of exactly 10, 20 or 24 falls one band lower in the source than in the half-open bands here; the boundaries are kept as stated rather than shifted. Preterm infants have their own first-sample threshold, recorded as a separate range. The TREC code is method-specific (nucleic acid amplification with probe detection) because LOINC's only DBS copy-number code for TRECs names the method, and quantitative PCR is the method the measurement is defined by; the Monarch KG search "T-cell receptor excision circle DBS" returned no method-less copy-number code.

Show evidence (5 references)

PMID:42079620 SUPPORT Human Clinical

"Newborns were screened for SCID using the EnLite Neonatal TREC assay (cut-off: 20 copies/μL), with confirmatory immunological and genetic testing performed in screen-positive cases."

States the programme's assay and its 20 copies/µL detection cut-off over the seven-year period.

PMID:42079620 SUPPORT Human Clinical

"This study summarizes the results of the consolidated SCID newborn screening (NBS) program in Catalonia (Spain) during the first seven years of program implementation (2017-2023)."

Names the programme and the period the cut-off applies to.

PMID:31695692 SUPPORT Human Clinical

"Samples with TRECs ≤ 5 copies/μL (preterm infants) or ≤ 10 copies/μL (term newborns) in the first sample (both with beta-actin gene ≥50 copies/μL), as well as analyses with TRECs ≤ 20 copies/μL in the second sample, were considered as positive detection (retest cutoff changed from 34 to 24..."

States the tiered first-sample and second-sample positive thresholds, the beta-actin quality criterion and the 2018 retest threshold that the bands encode.

+ 2 more references

T-cell receptor excision circle [#/volume] in DBS by NAA with probe detection (preterm infants, Catalonia (Spain) universal SCID newborn-screening programme, EnLite Neonatal TREC assay, 2017-2023 (retest threshold as set in 2018))

Positive on first sample (< 5 {copies}/uL) Second sample requested (5–20 {copies}/uL) Retest in duplicate (20–24 {copies}/uL) Screen negative (≥ 24 {copies}/uL)

Positive on first sample: Notified to the clinical reference unit for lymphocyte phenotyping without waiting for a second sample.

Second sample requested: Retested in duplicate; if two of three values are at or below 20 copies/µL a second dried blood spot is requested, which in a preterm infant is often taken at term or once birth weight exceeds 2,500 g.

Retest in duplicate: Below the 2018 retest threshold but above the detection cut-off; re-run in duplicate.

Same programme, assay, retest threshold and second-sample rule as the term-newborn range; only the first-sample positive threshold differs, at or below 5 copies/µL for preterm infants against 10 for term newborns. The source does not define "preterm" by gestational age in the sentence quoted. Inclusive thresholds in the source versus half-open bands here, as for the term range.

Show evidence (2 references)

PMID:31695692 SUPPORT Human Clinical

"Samples with TRECs ≤ 5 copies/μL (preterm infants) or ≤ 10 copies/μL (term newborns) in the first sample (both with beta-actin gene ≥50 copies/μL), as well as analyses with TRECs ≤ 20 copies/μL in the second sample, were considered as positive detection (retest cutoff changed from 34 to 24..."

States the preterm first-sample threshold of 5 copies/µL beside the term threshold.

PMID:42079620 SUPPORT Human Clinical

"Newborns were screened for SCID using the EnLite Neonatal TREC assay (cut-off: 20 copies/μL), with confirmatory immunological and genetic testing performed in screen-positive cases."

States the assay and the 20 copies/µL detection cut-off shared by both strata.

The assay measures a by-product of T-cell receptor recombination, so it is blind to defects acting *after* that step. MHC class II deficiency, ZAP70 deficiency, and late-onset ADA deficiency can all screen normal — a real false-negative class rather than an assay-quality problem. The panel code identifies the test and the TREC copy-number code carries the cut-offs; the interpretation code is the programme's reported call. Kappa-deleting recombination excision circles (KREC), which some programmes run with TREC, are not bound: the Monarch KG search "Kappa-deleting recombination excision circle" returned nothing, and the entry's screening row describes TREC alone.

Show evidence (7 references)

PMID:31695692 SUPPORT Human Clinical

"TREC quantification in DBS (1.5 mm diameter) was performed with the Enlite Neonatal TREC kit from PerkinElmer (Turku, Finland)."

Names the assay and punch size behind the Catalonian cut-offs.

PMID:31695692 SUPPORT Human Clinical

"In relation to gestational age, the median TREC value demonstrated a progressive increase: 70 (43–127), 96 (62–155), and 105 (68–162) copies/μL in extremely preterm, preterm, and term newborns, respectively"

Supports the statement that preterm infants have lower TREC values at birth that rise with maturation, which is why the programme stratifies its first-sample threshold.

PMID:31695692 SUPPORT Human Clinical

"cautious evaluation and a request for a second sample are needed at term and when birth weight reaches >2,500 g, respectively"

Supports the timing of the second sample in preterm and low-birth-weight infants given in the preterm band.

+ 4 more references

Molecular genetic testing

Sanger or next-generation sequencing identifies the causative gene. Beyond confirming the diagnosis, the genotype changes management: it determines genetic counselling, prognosis, and whether alkylator-based pre-transplant conditioning is safe.

molecular genetic testing NCIT:C19770

Show evidence (2 references)

PMID:32181275 SUPPORT Human Clinical

"Genetic diagnosis can be established by Sanger or Next-Generation sequencing (NGS)."

Names the sequencing modalities used for molecular diagnosis of SCID.

PMID:32181275 SUPPORT Human Clinical

"Though the diagnosis of SCID is usually established by flow cytometry-based tests, genetic diagnosis is often needed for genetic counselling, prognostication, and modification of pre-transplant chemotherapeutic agents."

Supports the three management consequences of the genotype asserted in this description.

ADA enzyme and metabolite testing

ADA deficiency has a biochemical diagnosis independent of the immune phenotype: red-cell ADA catalytic activity below 1%, or elevated adenosine and deoxyadenosine on tandem mass spectrometry. The metabolite assay also detects the later-onset ADA-CID cases that TREC screening misses.

biochemical enzyme and metabolite assay NCIT:C49236

`diagnosis_term` is bound to a generic NCIT action term because NCIT has no clinical-action term for red-cell enzyme activity or tandem mass-spectrometry metabolite quantitation specific enough to be worth asserting; the free-text `preferred_term` carries the actual test.

Show evidence (2 references)

PMID:20301656 SUPPORT Human Clinical

"The diagnosis of ADA deficiency is established in a proband with suggestive findings either by biochemical testing showing <1% of ADA catalytic activity in red blood cells or in extracts of dried blood spots (valid in untransfused individuals), or by molecular genetic testing identifying..."

Gives the biochemical diagnostic threshold and its molecular alternative.

PMID:20301656 SUPPORT Human Clinical

"Screening specific for ADA deficiency can also be performed by detection of elevated levels of adenosine (Ado) and deoxyadenosine (dAdo) by tandem mass spectrometry (TMS)."

Documents the tandem mass-spectrometry metabolite screen for ADA deficiency.

📈

Progression

5

Onset of symptoms in infancy

Age: First months of life

In a 277-child Indian multi-institutional cohort the median age of symptom onset was 2.5 months and the median age at diagnosis 5 months — a roughly 2.5-month diagnostic lag during which infants are unprotected.

Show evidence (1 reference)

PMID:33628209 SUPPORT Human Clinical

"Median (inter-quartile range) age of onset of clinical symptoms and diagnosis was 2.5 months (1, 5) and 5 months (3.5, 8), respectively."

Gives the median ages of symptom onset and of diagnosis in a large clinically ascertained SCID cohort.

Clinical presentation before newborn screening

X-linked SCID Age: Three to six months

The historical presentation, and still the presentation wherever TREC screening is not in place: infants come to attention only once recurrent, persistent, or opportunistic infection has begun.

Show evidence (1 reference)

PMID:20301584 SUPPORT Human Clinical

"Prior to universal newborn screening (NBS) for SCID most males with typical X-SCID came to medical attention between ages three and six months because of recurrent infections, persistent infections, and infections with opportunistic organisms."

Gives the pre-screening age and mode of presentation for typical X-SCID.

Presymptomatic detection by newborn screening

X-linked SCID Age: First weeks of life

Newborn screening did not just move diagnosis earlier, it changed what the disease looks like at presentation: the typical index case is now a well-appearing infant with an abnormal TREC result rather than a sick one.

Show evidence (1 reference)

PMID:20301584 SUPPORT Human Clinical

"With universal NBS for SCID, the common presentation for typical X-SCID is now an asymptomatic, healthy-appearing male infant."

Documents the shift to presymptomatic presentation under universal newborn screening.

Later-onset atypical disease

X-linked SCID Age: First years of life or later

Hypomorphic IL2RG alleles produce a later-onset spectrum that newborn screening usually does not catch, dominated by immune dysregulation rather than by the absent-immunity picture of typical SCID.

Show evidence (2 references)

PMID:20301584 SUPPORT Human Clinical

"The phenotypic spectrum of X-linked severe combined immunodeficiency (X-SCID) ranges from typical X-SCID (early-onset disease in males that is fatal if not treated with hematopoietic stem cell transplantation [HSCT] or gene therapy) to atypical X-SCID (later-onset disease comprising phenotypes..."

Defines the typical/atypical split and places atypical disease at later onset.

PMID:20301584 SUPPORT Human Clinical

"recurrent upper and lower respiratory tract infections with bronchiectasis; Omenn syndrome, a clinical phenotype caused by immune dysregulation; X-SCID combined immunodeficiency (often with recurrent infections, warts, and dermatitis); immune dysregulation and autoimmunity; or Epstein-Barr..."

Enumerates the specific later-onset atypical X-SCID presentations.

Death in infancy without immune reconstitution

Age: First one to two years

Untreated SCID is uniformly fatal in early childhood; the ADA-SCID figure below is the best-quantified example.

Show evidence (1 reference)

PMID:20301656 SUPPORT Human Clinical

"If immune function is not restored with enzyme replacement therapy (ERT), gene therapy, or hematopoietic stem cell transplantation (HSCT), children with ADA-SCID rarely survive beyond age one to two years."

States the untreated natural history and the three interventions that alter it.

📊

Prevalence

3

United States (11 TREC newborn-screening programs, 3,030,083 infants)

Birth Prevalence 1.7 per 100,000 (1.25–2.17) 1–9 per 100,000 (births)

Population-based TREC newborn screening across 11 US programs identified SCID in 1 in 58,000 infants (95% CI 1/46,000-1/80,000), i.e. 1.7 per 100,000 (CI 1.25-2.17). This is substantially higher than the ~1 in 100,000 incidence previously inferred from retrospective clinical diagnoses, reflecting under-ascertainment of infants who died of infection before diagnosis.

Show evidence (3 references)

PMID:25138334 SUPPORT Human Clinical

"Newborn screening in 11 programs in the United States identified SCID in 1 in 58 000 infants, with high survival."

Provides the population-based US birth prevalence of SCID from universal TREC newborn screening.

PMID:25138334 SUPPORT Human Clinical

"Newborn screening has provided a new, population-based incidence of SCID of 1 in 58 000 births, higher than the incidence of 1 in 100 000 suggested from retrospective clinical diagnoses."

Documents that newborn screening revised the SCID incidence upward relative to retrospective clinical ascertainment.

PMID:33551023 SUPPORT Human Clinical

"by 2019 all states in the United States had adopted versions of it in their public health programs"

Supports the universality of US TREC newborn screening (the basis for population-level ascertainment) but does not itself report an incidence figure; it was previously cited as the source of the 1/58,000 number, which it does not contain.

Navajo Nation (Navajo Area Indian Health Service TREC screening)

Birth Prevalence 28.6 per 100,000 (25.0–158.7) 1–9 per 10,000 (births)

A founder effect, not a different disease. SCID birth prevalence in the Navajo Nation is roughly 1 in 3,500 (95% CI 1/630-1/4,000), about seventeen times the overall US screened rate, driven by a frequent DCLRE1C (Artemis) founder variant estimated to cause SCID in 1 in 2,000 births. Rates converted from the reported 1-in-N figures; the confidence interval is wide because the screened denominator is small.

Show evidence (1 reference)

PMID:25138334 SUPPORT Human Clinical

"The incidence was not significantly different in any state program but as expected was higher in the Navajo Nation (1/3500; 95%CI, 1/630-1/4000), where a frequent founder mutation in DCLRE1C, encoding a DNA repair protein, causes SCID in an estimated 1 in 2000 births."

Gives the Navajo Nation birth prevalence, its confidence interval, and the DCLRE1C founder variant responsible.

Worldwide (literature estimate, per live birth)

Birth Prevalence 1.9 per 100,000 (1.33–2.5) 1–9 per 100,000 (births)

Review estimate of 1 in 40,000 to 1 in 75,000 live births (1.33-2.5 per 100,000), recorded alongside the US screened figure because it is derived from the literature rather than from a single screened population. It is consistent with the 1-in-58,000 US newborn-screening result and above the older 1-in-100,000 retrospective clinical estimate.

Show evidence (1 reference)

PMID:32181275 SUPPORT Human Clinical

"The incidence of SCID varies between 1 in 40,000 to 75,000 per live birth."

Supplies the worldwide literature range for SCID birth incidence.

⚖️

Clinical Burden

High

Untreated SCID is fatal in infancy, and the only treatments that change that are transplantation, gene therapy, or (for ADA) enzyme replacement — each of which requires specialist centres, conditioning chemotherapy, and prolonged protective isolation. Where those services are not readily accessible the burden is starkly visible: in a 277-child Indian cohort only 8.3% reached transplant and 75.8% died. Where newborn screening and transplant are available, survival exceeds 85%, so the burden is dominated by access and by time-to-diagnosis rather than by any intrinsic untreatability.

Show evidence (2 references)

PMID:33628209 SUPPORT Human Clinical

"Only 23 children (8.3%) received hematopoietic stem cell transplantation (HSCT). Of these, 11 are doing well post-HSCT. Mortality was recorded in 210 children (75.8%)."

Quantifies mortality and the low proportion reaching curative therapy in a setting without newborn screening.

PMID:25138334 SUPPORT Human Clinical

"overall SCID survival was 45 of 52 (87%), while 45 of 49 treated infants (92%) survived"

Gives the contrasting survival achievable with newborn screening and prompt definitive therapy.

{ }

Source YAML

click to show

name: Severe Combined Immunodeficiency
category: Mendelian
creation_date: "2026-06-22T00:00:00Z"
synonyms:
- SCID
- severe combined immunodeficiency disease
- bubble boy disease
description: >-
  Severe combined immunodeficiency (SCID) is a group of inborn errors of immunity
  characterized by profound defects in T-lymphocyte development and function, with
  variable effects on B and NK cells, that abrogate adaptive immunity. The shared
  final common pathway is failure of hematopoietic stem cells to differentiate into
  mature, functional T lymphocytes, producing absent cellular and (directly or
  indirectly) humoral immunity. Distinct molecular mechanisms define the major
  subtypes: defective cytokine receptor signaling (IL2RG, JAK3, IL7R), defective
  V(D)J recombination or DNA double-strand-break repair (RAG1, RAG2, DCLRE1C/Artemis),
  and toxic metabolite accumulation from purine-salvage enzyme deficiency (ADA).
  Affected infants present in the first months of life with recurrent and
  opportunistic infections, chronic diarrhea, failure to thrive, and absent thymic
  shadow, and the condition is fatal in infancy without immune reconstitution by
  hematopoietic stem cell transplantation, gene therapy, or (for ADA) enzyme
  replacement.
disease_term:
  preferred_term: severe combined immunodeficiency
  term:
    id: MONDO:0015974
    label: severe combined immunodeficiency
parents:
- combined immunodeficiency
- primary immunodeficiency
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:32181275
      reference_title: "Genetics of severe combined immunodeficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Severe Combined Immunodeficiency (SCID) is an inherited group of rare, life-threatening disorders due to the defect in T cell development and function."
      explanation: SCID is an inherited (genetic) disorder, placing it in Harrison's genetics-and-disease Part.
  iuis_category:
    classification_value: combined immunodeficiency
    notes: >-
      IUIS 2022 classification (Tangye et al., PMID:35748970), Table 1
      (immunodeficiencies affecting cellular and humoral immunity): SCID is
      named directly by Table 1's first two section headings, "1. T-B+ Severe
      Combined Immune Deficiency (SCID)" and "2. T-B- SCID". The quoted heading
      comes from the classification tables in the cached full text rather than
      from the abstract.
    evidence:
    - reference: PMID:35748970
      reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "1. T-B+ Severe Combined Immune Deficiency (SCID)"
      explanation: >-
        Table 1 section heading naming SCID among the immunodeficiencies
        affecting cellular and humoral immunity.
    - reference: PMID:36456361
      reference_title: "The diagnosis of severe combined immunodeficiency (SCID): The Primary Immune Deficiency Treatment Consortium (PIDTC) 2022 Definitions."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Severe combined immunodeficiency (SCID) results from defects in the"
      explanation: SCID is the prototypic IUIS Table 1 immunodeficiency affecting cellular (and humoral) immunity.
inheritance:
- name: X-linked recessive inheritance
  description: >-
    The most common form of SCID in Western populations, X-linked SCID, is caused
    by hemizygous IL2RG variants and is inherited in an X-linked recessive pattern.
  inheritance_term:
    preferred_term: X-linked recessive inheritance
    term:
      id: HP:0001419
      label: X-linked recessive inheritance
  evidence:
  - reference: PMID:20301584
    reference_title: "X-Linked Severe Combined Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of typical and atypical X-SCID is established in a male proband with suggestive findings and a hemizygous pathogenic variant in IL2RG identified by molecular genetic testing."
    explanation: X-SCID is established by a hemizygous IL2RG variant in male probands, consistent with X-linked recessive inheritance.
- name: Autosomal recessive inheritance
  description: >-
    Most non-X-linked SCID subtypes (ADA, RAG1, RAG2, IL7R, JAK3, DCLRE1C/Artemis)
    are inherited in an autosomal recessive pattern, and these forms predominate in
    populations with high consanguinity.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The pattern of inheritance of SCID may be X-linked or autosomal recessive."
    explanation: SCID is inherited as either X-linked or autosomal recessive, with the autosomal recessive forms covering ADA, RAG1/2, IL7R, JAK3, and Artemis deficiency.
has_subtypes:
- name: X-linked SCID
  display_name: X-linked SCID (IL2RG deficiency, T-B+NK-)
  subtype_term:
    preferred_term: T-B+ severe combined immunodeficiency due to gamma chain deficiency
    term:
      id: MONDO:0010315
      label: T-B+ severe combined immunodeficiency due to gamma chain deficiency
  description: >-
    Caused by hemizygous loss-of-function variants in IL2RG encoding the common
    gamma chain. Immunophenotype is T-B+NK- (absent T and NK cells, present but
    non-functional B cells). Historically described as the most common form in
    Western populations at roughly half of cases, but that figure comes from
    referral-centre transplant cohorts; population-based newborn screening finds
    a substantially lower share (see the IL2RG case_fractions record).
  review_notes: >-
    The "~50% of cases" figure previously asserted here was removed as
    ascertainment-biased. PMID:25138334 found IL2RG accounted for only 19% of
    SCID detected by population-based TREC newborn screening and states
    explicitly that this is in contrast to nearly half of cases in published
    referral-centre cohorts, attributing the difference to increased
    ascertainment of autosomal recessive SCID by unbiased screening. Both
    numbers are real; they describe different populations.
  genes:
  - preferred_term: IL2RG
    term:
      id: hgnc:6010
      label: IL2RG
  evidence:
  - reference: PMID:25138334
    reference_title: "Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the proportion of IL2RG deficient X-linked SCID in our study (19%) is in contrast to nearly half of cases in published cohorts from referral centers that treat SCID"
    explanation: >-
      Supports the description's distinction between the referral-cohort figure
      of roughly half and the lower population-based share.
- name: ADA deficiency
  display_name: Adenosine deaminase deficiency (ADA-SCID, T-B-NK-)
  subtype_term:
    preferred_term: severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency
    term:
      id: MONDO:0007064
      label: severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-negative, due to adenosine deaminase deficiency
  description: >-
    A systemic purine metabolic disorder (~15% of SCID) in which deficiency of
    adenosine deaminase causes accumulation of toxic deoxyadenosine metabolites
    that are lymphotoxic, producing a T-B-NK- immunophenotype with absent humoral
    and cellular immunity. Unlike the other subtypes here, ADA deficiency spans a
    graded spectrum: about 80% present as typical infantile ADA-SCID and 15%-20%
    as a later-onset combined immunodeficiency (ADA-CID).
  genes:
  - preferred_term: ADA
    term:
      id: hgnc:186
      label: ADA
  evidence:
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ADA deficiency is the most severe form of SCID and is known to occur in 15% of total SCID patients."
    explanation: Quantifies the ADA share of SCID cases asserted in this subtype description.
  - reference: PMID:20301656
    reference_title: "Adenosine Deaminase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The ADA deficiency phenotypic spectrum includes typical early-onset severe combined immunodeficiency (ADA-SCID), diagnosed in infancy (about 80% of individuals), and less severe \"delayed\" or \"late-onset\" combined immunodeficiency (ADA-CID), diagnosed in older children and adults (15%-20% of individuals)."
    explanation: Supports the 80% typical-SCID / 15%-20% delayed-onset split within ADA deficiency.
- name: RAG1/RAG2 deficiency
  display_name: RAG1/RAG2 deficiency (T-B-NK+)
  subtype_term:
    preferred_term: severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive
    term:
      id: MONDO:0011086
      label: severe combined immunodeficiency, autosomal recessive, T cell-negative, B cell-negative, NK cell-positive
  description: >-
    Autosomal recessive SCID caused by defects in the recombination-activating
    genes RAG1 or RAG2, which block V(D)J recombination of antigen-receptor genes.
    Immunophenotype is T-B-NK+; hypomorphic alleles can cause Omenn syndrome. Most
    common form in consanguineous populations.
  genes:
  - preferred_term: RAG1
    term:
      id: hgnc:9831
      label: RAG1
  - preferred_term: RAG2
    term:
      id: hgnc:9832
      label: RAG2
- name: IL7R deficiency
  display_name: IL7R alpha-chain deficiency (T-B+NK+)
  subtype_term:
    preferred_term: T-B+ severe combined immunodeficiency due to IL-7Ralpha deficiency
    term:
      id: MONDO:0015701
      label: T-B+ severe combined immunodeficiency due to IL-7Ralpha deficiency
  description: >-
    Autosomal recessive SCID caused by defects in the IL-7 receptor alpha chain,
    impairing IL-7 signaling required for T-cell development. Immunophenotype is
    T-B+NK+ (B and NK cells preserved).
  genes:
  - preferred_term: IL7R
    term:
      id: hgnc:6024
      label: IL7R
- name: JAK3 deficiency
  display_name: JAK3 deficiency (T-B+NK-)
  subtype_term:
    preferred_term: T-B+ severe combined immunodeficiency due to JAK3 deficiency
    term:
      id: MONDO:0010938
      label: T-B+ severe combined immunodeficiency due to JAK3 deficiency
  description: >-
    Autosomal recessive SCID caused by defects in Janus kinase 3, the signaling
    kinase coupled to the common gamma chain. The immunophenotype (T-B+NK-) mirrors
    X-linked SCID because JAK3 acts immediately downstream of the gamma chain.
  genes:
  - preferred_term: JAK3
    term:
      id: hgnc:6193
      label: JAK3
- name: Artemis deficiency
  display_name: Artemis (DCLRE1C) deficiency (radiosensitive T-B-NK+)
  subtype_term:
    preferred_term: severe combined immunodeficiency due to DCLRE1C deficiency
    term:
      id: MONDO:0011225
      label: severe combined immunodeficiency due to DCLRE1C deficiency
  description: >-
    Autosomal recessive, radiosensitive SCID caused by defects in DCLRE1C/Artemis,
    a nuclease required for hairpin opening during V(D)J recombination and for
    non-homologous end-joining DNA repair. Immunophenotype is T-B-NK+ with
    increased cellular radiosensitivity.
  genes:
  - preferred_term: DCLRE1C
    term:
      id: hgnc:17642
      label: DCLRE1C
- name: Reticular dysgenesis
  display_name: Reticular dysgenesis (AK2 deficiency, T-B-NK-)
  description: >-
    Autosomal recessive SCID caused by biallelic AK2 (adenylate kinase 2) defects,
    accounting for about 2% of children with SCID. Unlike the other subtypes, the
    block is in survival of haematopoietic precursors rather than in a
    lymphoid-specific signalling, recombination, or metabolic pathway, so both
    innate and adaptive immunity fail: profound neutropenia/absent granulocytes
    accompanies the lymphoid deficiency. It is the most severe SCID form, with
    fatal septicaemia within days of birth if untreated.
  genes:
  - preferred_term: AK2
    term:
      id: hgnc:362
      label: AK2
  evidence:
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutation of the AK2 gene causes reticular dysgenesis (RD), an autosomal recessive disorder occurring in 2% of children with SCID."
    explanation: Establishes AK2 as the cause of reticular dysgenesis and its share of SCID cases.
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Reticular dysgenesis is the most serious type of SCID that is associated with absent granulocytes, lymphocytes, hypoplasia of the primary and secondary lymphoid organs and fatal septicemia within days after birth."
    explanation: Supports the combined myeloid-plus-lymphoid failure and the neonatal lethality distinguishing this subtype.
genetic:
- name: IL2RG
  subtype: X-linked SCID
  gene_term:
    preferred_term: IL2RG
    term:
      id: hgnc:6010
      label: IL2RG
  association: Causative
  features: >-
    Hemizygous loss-of-function variants in IL2RG (common cytokine-receptor gamma
    chain) cause X-linked SCID. IL2RG is the single most frequently implicated
    SCID gene in both referral cohorts and population screening, but its share of
    cases differs sharply by ascertainment (see case_fractions).
  case_fractions:
  - population: United States, 11 TREC newborn-screening programs (52 screened SCID cases)
    case_fraction_percent: 19.0
    cohort_size: 52
    notes: >-
      Population-based ascertainment. The same paper contrasts this with the
      roughly one-half share seen in referral-centre transplant cohorts and
      attributes the gap to better detection of autosomal recessive SCID by
      unbiased newborn screening rather than to a real difference in IL2RG
      frequency.
    evidence:
    - reference: PMID:25138334
      reference_title: "Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Mutations in the X chromosome–linked IL2RG gene, encoding the cytokine receptor common γ chain, accounted for only 19% of cases."
      explanation: Gives the population-based IL2RG share of screened SCID cases.
    - reference: PMID:25138334
      reference_title: "Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "our lower proportion of IL2RG-deficient SCID is likely to reflect increased ascertainment of autosomal recessive SCID cases by population-based screening"
      explanation: The authors' own explanation for why the screened share is below the referral-cohort figure.
  - population: Indian multi-institutional SCID cohort (162 patients with a molecular diagnosis)
    case_fraction_percent: 22.2
    cohort_size: 162
    notes: >-
      Derived: IL2RG in 36 of 162 molecularly diagnosed patients. Consanguinity
      is common in this cohort, so autosomal recessive forms (RAG1, ADA, RAG2)
      together substantially outnumber IL2RG.
    evidence:
    - reference: PMID:33628209
      reference_title: "Clinical, Immunological, and Molecular Features of Severe Combined Immune Deficiency: A Multi-Institutional Experience From India."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Molecular diagnosis was obtained in 162 patients - IL2RG (36), RAG1 (26), ADA (19), RAG2 (17), JAK3 (15), DCLRE1C (13), IL7RA (9)"
      explanation: Gives the IL2RG count and cohort denominator behind this case fraction.
  evidence:
  - reference: PMID:20301584
    reference_title: "X-Linked Severe Combined Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of typical and atypical X-SCID is established in a male proband with suggestive findings and a hemizygous pathogenic variant in IL2RG identified by molecular genetic testing."
    explanation: A hemizygous IL2RG pathogenic variant establishes the diagnosis of X-linked SCID.
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The gamma portion of IL2R is important for the development of T and NK cells through cytokines IL2 and IL15, respectively."
    explanation: Explains why common gamma-chain loss removes both T and NK lineages, giving the T-B+NK- immunophenotype.
- name: ADA
  subtype: ADA deficiency
  gene_term:
    preferred_term: ADA
    term:
      id: hgnc:186
      label: ADA
  association: Causative
  features: >-
    Biallelic ADA variants cause adenosine deaminase deficiency, a systemic purine
    metabolic disorder that primarily affects lymphocyte development, viability, and
    function, producing T-B-NK- SCID in about 80% of affected individuals.
  case_fractions:
  - population: United States, 11 TREC newborn-screening programs (52 screened SCID cases)
    case_fraction_percent: 11.0
    cohort_size: 52
    notes: Population-based newborn-screening ascertainment.
    evidence:
    - reference: PMID:25138334
      reference_title: "Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Interleukin-7 defects and adenosine deaminase deficiency contributed 12% and 11%, respectively."
      explanation: Gives the ADA share of population-screened SCID cases.
  evidence:
  - reference: PMID:20301656
    reference_title: "Adenosine Deaminase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Adenosine deaminase (ADA) deficiency is a systemic purine metabolic disorder that primarily affects lymphocyte development, viability, and function."
    explanation: Biallelic ADA deficiency causes a systemic purine metabolic disorder affecting lymphocyte development, the basis of ADA-SCID.
  - reference: PMID:20301656
    reference_title: "Adenosine Deaminase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The ADA deficiency phenotypic spectrum includes typical early-onset severe combined immunodeficiency (ADA-SCID), diagnosed in infancy (about 80% of individuals), and less severe \"delayed\" or \"late-onset\" combined immunodeficiency (ADA-CID), diagnosed in older children and adults (15%-20% of individuals)."
    explanation: Supports the "about 80%" typical-SCID proportion stated in these features.
- name: RAG1
  subtype: RAG1/RAG2 deficiency
  gene_term:
    preferred_term: RAG1
    term:
      id: hgnc:9831
      label: RAG1
  association: Causative
  features: >-
    Biallelic RAG1 variants impair V(D)J recombination, blocking T- and B-cell
    receptor assembly; RAG1 defects are among the most common autosomal recessive
    causes of SCID, especially in consanguineous populations.
  case_fractions:
  - population: United States, 11 TREC newborn-screening programs (52 screened SCID cases)
    case_fraction_percent: 15.0
    cohort_size: 52
    notes: >-
      Includes both typical and leaky SCID presentations; one of the leaky cases
      was Omenn syndrome, illustrating the hypomorphic-allele spectrum.
    evidence:
    - reference: PMID:25138334
      reference_title: "Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Recombinase activating gene 1 (RAG1) defects, causing impairment of V(D) J lymphocyte antigen receptor recombination, were detected in 4 typical and 4 leaky SCID cases, 1 of the latter with Omenn syndrome, accounting for 15% of all 52 cases."
      explanation: Gives the RAG1 share of population-screened SCID cases and its typical/leaky split.
  evidence:
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Deficiency of either RAG1 or RAG2 causes T-B-NK + SCID and is inherited in an autosomal recessive pattern."
    explanation: RAG1 deficiency is a well-characterized autosomal recessive cause of T-B-NK+ SCID via a V(D)J-recombination defect.
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "RAG1 and RAG2, are DNA recombinases that mediate DNA recombination process and ensure the somatic diversification of immunoglobulin and TCR genes during B-cell and T-cell development, respectively."
    explanation: Supports the specific molecular role — recombinase-driven antigen-receptor gene diversification — asserted in these features.
- name: RAG2
  subtype: RAG1/RAG2 deficiency
  gene_term:
    preferred_term: RAG2
    term:
      id: hgnc:9832
      label: RAG2
  association: Causative
  features: >-
    Biallelic RAG2 variants, like RAG1, abolish V(D)J recombination and cause
    T-B-NK+ SCID; hypomorphic RAG variants can produce Omenn syndrome.
  evidence:
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Deficiency of either RAG1 or RAG2 causes T-B-NK + SCID and is inherited in an autosomal recessive pattern."
    explanation: RAG2 deficiency, like RAG1, abolishes V(D)J recombination and causes autosomal recessive T-B-NK+ SCID.
- name: IL7R
  subtype: IL7R deficiency
  gene_term:
    preferred_term: IL7R
    term:
      id: hgnc:6024
      label: IL7R
  association: Causative
  features: >-
    Biallelic IL7R variants disrupt IL-7 receptor alpha-chain signaling required
    for T-cell development, producing T-B+NK+ SCID with preserved B and NK cells.
  case_fractions:
  - population: United States, 11 TREC newborn-screening programs (52 screened SCID cases)
    case_fraction_percent: 12.0
    cohort_size: 52
    notes: Population-based newborn-screening ascertainment; consistent with the ~10% literature estimate.
    evidence:
    - reference: PMID:25138334
      reference_title: "Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Interleukin-7 defects and adenosine deaminase deficiency contributed 12% and 11%, respectively."
      explanation: Gives the IL-7 receptor share of population-screened SCID cases.
  evidence:
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Deficiency of ILR7 alpha causes T-B + NK + SCID, that accounts for around 10% of the total SCID patients."
    explanation: IL7R (IL7R alpha) deficiency selectively impairs T-cell development, producing a T-B+NK+ form accounting for about 10% of SCID.
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The encoded protein is expressed on the lymphoid lineage and is required during T cell development during early stage and for proliferation and survival of T cells in the periphery."
    explanation: Supports the specific requirement for IL-7 receptor alpha in early T-cell development and peripheral T-cell survival.
- name: JAK3
  subtype: JAK3 deficiency
  gene_term:
    preferred_term: JAK3
    term:
      id: hgnc:6193
      label: JAK3
  association: Causative
  features: >-
    Biallelic JAK3 variants disrupt the Janus kinase coupled to the common gamma
    chain, producing a T-B+NK- immunophenotype that phenocopies X-linked SCID.
  evidence:
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "JAK3 deficiency constitutes around 6% of the total SCID patients and is inherited as an autosomal recessive trait."
    explanation: JAK3 deficiency is an autosomal recessive SCID acting downstream of the common gamma chain, accounting for about 6% of cases.
- name: DCLRE1C
  subtype: Artemis deficiency
  gene_term:
    preferred_term: DCLRE1C
    term:
      id: hgnc:17642
      label: DCLRE1C
  association: Causative
  features: >-
    Biallelic DCLRE1C (Artemis) variants impair hairpin opening during V(D)J
    recombination and non-homologous end-joining DNA repair, producing a
    radiosensitive T-B-NK+ SCID. Radiosensitivity is not an incidental label: it
    changes management, because these patients tolerate alkylator-based
    pre-transplant conditioning poorly.
  evidence:
  - reference: PMID:33628209
    reference_title: "Clinical, Immunological, and Molecular Features of Severe Combined Immune Deficiency: A Multi-Institutional Experience From India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "RAG2 (17), JAK3 (15), DCLRE1C (13), IL7RA (9)"
    explanation: A multi-institutional cohort identifies DCLRE1C (Artemis) defects as a recurrent molecular cause of SCID.
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DCLRE1C encodes ARTEMIS, a nuclease which is single-stranded with- 5′-3′ exonuclease potential and endonuclease activity over 5′ and 3′ ends. It is essential for V(D)J rearrangement and for DNA repair."
    explanation: Supports the dual V(D)J-rearrangement and DNA-repair role asserted in these features.
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Artemis deficiency causes early arrest in the maturation of T cells and B cell differentiation during early pre-B cell stage, resulting in T–B–NK + SCID."
    explanation: Supports the T-B-NK+ immunophenotype attributed to Artemis deficiency.
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with this form of SCID are sensitive to ionizing radiation and chemotherapeutic agents."
    explanation: >-
      Directly supports the radiosensitivity claim, which the previously cited
      gene-count snippet did not address.
- name: AK2
  subtype: Reticular dysgenesis
  gene_term:
    preferred_term: AK2
    term:
      id: hgnc:362
      label: AK2
  association: Causative
  features: >-
    Biallelic AK2 (adenylate kinase 2) variants cause reticular dysgenesis. AK2
    acts in cellular and mitochondrial energy homeostasis rather than in any
    lymphoid-specific pathway, so its loss compromises survival of haematopoietic
    precursors generally and abolishes innate as well as adaptive immunity.
  evidence:
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutation of the AK2 gene causes reticular dysgenesis (RD), an autosomal recessive disorder occurring in 2% of children with SCID."
    explanation: Establishes AK2 as causative for reticular dysgenesis and its frequency among SCID.
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Deficiency of AK2 is associated with lack of innate and adaptive immunity."
    explanation: Supports the combined innate-plus-adaptive failure that distinguishes AK2 deficiency from the lymphoid-restricted SCID subtypes.
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Adenylate kinases are involved in cellular and mitochondrial energy homeostasis."
    explanation: Supports the non-lymphoid-specific, bioenergetic function of AK2 asserted in these features.
- name: PRKDC
  gene_term:
    preferred_term: PRKDC
    term:
      id: hgnc:9413
      label: PRKDC
  association: Causative
  features: >-
    Biallelic PRKDC variants abolish or cripple DNA-dependent protein kinase
    catalytic subunit (DNA-PKcs), which activates Artemis during hairpin opening
    in V(D)J recombination and is required for non-homologous end-joining. The
    resulting disease is radiosensitive T-B-NK+ SCID, the same mechanism class and
    the same conditioning problem as DCLRE1C/Artemis deficiency. No separate
    has_subtypes row is asserted: this gene acts at the V(D)J recombination and
    DNA repair node the Artemis subtype already models.
  evidence:
  - reference: PMID:19075392
    reference_title: "A DNA-PKcs mutation in a radiosensitive T-B- SCID patient inhibits Artemis activation and nonhomologous end-joining."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Radiosensitive T-B- severe combined immunodeficiency (RS-SCID) is caused by defects in the nonhomologous end-joining (NHEJ) DNA repair pathway, which results in failure of functional V(D)J recombination."
    explanation: Places DNA-PKcs deficiency in the NHEJ/V(D)J mechanism class this entry already models, and gives the T-B-NK+ immunophenotype.
  - reference: PMID:19075392
    reference_title: "A DNA-PKcs mutation in a radiosensitive T-B- SCID patient inhibits Artemis activation and nonhomologous end-joining."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we have identified the first human RS-SCID patient to our knowledge with a DNA-PKcs missense mutation (L3062R)."
    explanation: Establishes PRKDC as a human SCID gene rather than only a mouse one.
- name: LIG4
  gene_term:
    preferred_term: LIG4
    term:
      id: hgnc:6601
      label: LIG4
  association: Causative
  features: >-
    Biallelic hypomorphic LIG4 variants impair DNA ligase IV, the ligase that seals
    double-strand breaks during non-homologous end-joining and V(D)J recombination,
    and cause LIG4 syndrome. The immune phenotype is a spectrum rather than a fixed
    one, running from near-normal to radiosensitive T-B-NK+ SCID, and it is
    accompanied by microcephaly and growth retardation that the lymphoid-restricted
    SCID subtypes do not share.
  notes: >-
    Bound here as a gene acting at the V(D)J recombination and DNA repair node, not
    as a subtype row. The IUIS 2022 classification lists DNA ligase IV deficiency in
    the T-B- SCID table, but the disease-specific review describes a phenotypic range
    from normal to severe combined immunodeficiency, so treating LIG4 syndrome as a
    SCID subtype in its own right would overstate a variable immune phenotype in a
    disorder whose defining features are radiosensitivity and microcephaly. The review
    cited below states that range directly.
  evidence:
  - reference: PMID:11779494
    reference_title: "DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "DNA ligase IV functions in DNA nonhomologous end-joining and V(D)J recombination."
    explanation: States the molecular step at which LIG4 acts, which is the node this gene is wired to.
  - reference: PMID:11779494
    reference_title: "DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cell lines from the patients show pronounced radiosensitivity."
    explanation: Sources the cellular radiosensitivity that groups LIG4 with Artemis and DNA-PKcs for conditioning purposes.
  - reference: PMID:26762768
    reference_title: "Molecular and immunological characterization of DNA ligase IV deficiency."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study enrolled seven Chinese patients with LIG4 deficiency who presented with combined immunodeficiency, microcephaly, and growth retardation."
    explanation: Sources the microcephaly and growth retardation recorded in these features, and the cohort in which the combined immunodeficiency was characterized.
  - reference: PMID:27717373
    reference_title: "DNA ligase IV syndrome; a review."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with hypomorphic mutations in LIG4 present with a range of phenotypes, from normal to severe combined immunodeficiency."
    explanation: Sources the phenotypic range recorded in these notes, which is why LIG4 is bound as a gene at the DNA repair node rather than asserted as a SCID subtype.
- name: CD3D
  gene_term:
    preferred_term: CD3D
    term:
      id: hgnc:1673
      label: CD3D
  association: Causative
  features: >-
    Biallelic CD3D loss-of-function variants remove the CD3delta invariant chain of
    the pre-T-cell receptor and T-cell receptor complex, arresting thymocyte
    development at the double-negative to double-positive transition and producing
    T-B+NK+ SCID. The mechanism is failure of signal transduction through an
    assembled receptor, not failure of cytokine signalling, of antigen-receptor gene
    recombination, of purine metabolism, or of precursor survival.
  evidence:
  - reference: PMID:16264327
    reference_title: "CD3 deficiencies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Homozygous mutations in CD3D and CD3E genes lead to a complete block in T-cell development and thus to an early-onset severe combined immunodeficiency phenotype."
    explanation: Establishes CD3D as a SCID gene and states the complete developmental block this node asserts.
  - reference: PMID:16264327
    reference_title: "CD3 deficiencies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thymic studies have shown that the defect in T-cell development occurs at the transition between 'double-negative' and 'double-positive' thymocytes."
    explanation: Locates the arrest at beta-selection, the step this node places downstream of receptor-proximal signalling failure.
- name: LAT
  gene_term:
    preferred_term: LAT
    term:
      id: hgnc:18874
      label: LAT
  association: Causative
  features: >-
    Biallelic LAT loss-of-function variants remove the transmembrane adaptor that
    propagates signalling from the engaged T-cell receptor complex. The reported
    phenotypes span typical SCID with absent T cells and a combined immunodeficiency
    with severe autoimmunity, so LAT is wired here to the receptor-proximal
    signalling node rather than recorded as a uniform SCID subtype.
  evidence:
  - reference: PMID:27522155
    reference_title: "Mutations in linker for activation of T cells (LAT) lead to a novel form of severe combined immunodeficiency."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: MODEL_ORGANISM
    snippet: "Linker for activation of T cells (LAT) is a transmembrane adaptor signaling molecule that is part of the TCR complex and essential for T-cell development, as demonstrated by LAT-deficient mice, which show a complete lack of peripheral T cells."
    explanation: States that LAT is a component of the TCR complex required for T-cell development, which is the mechanism this gene is bound to.
  - reference: PMID:27522155
    reference_title: "Mutations in linker for activation of T cells (LAT) lead to a novel form of severe combined immunodeficiency."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a pedigree affected by a severe combined immunodeficiency phenotype with absent T cells and normal B-cell and natural killer cell numbers."
    explanation: Sources the human SCID phenotype and its T-B+NK+ immunophenotype.
- name: CORO1A
  gene_term:
    preferred_term: CORO1A
    term:
      id: hgnc:2252
      label: CORO1A
  association: Causative
  features: >-
    Biallelic CORO1A variants remove coronin-1A, an actin regulator required for
    thymocyte egress from the thymus and for peripheral T-cell survival. Complete
    absence causes T-B+NK+ SCID, in which T cells fail to populate the periphery.
    The two mouse alleles split that picture: the Ptcd E26K substitution increases
    coronin-1A inhibition of Arp2/3 and blocks egress from the thymus, while
    Coro1a-null mice, which match the patient's absent protein, lose mature
    thymocytes through reduced survival. Hypomorphic alleles instead give a
    combined immunodeficiency with Epstein-Barr-virus-associated B-cell
    lymphoproliferation.
  notes: >-
    Neither cited report states the size of the human thymus, so no thymic-size
    claim is made for this gene.
  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
    directness: DIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Our findings establish a function for coronin 1A in T cell egress, identify a surface of coronin involved in Arp2/3 regulation and demonstrate that actin regulation is a biological process defective in human and mouse severe combined immunodeficiency."
    explanation: Establishes the egress mechanism and that coronin-1A loss is a human SCID mechanism distinct from the four already modelled here.
  - reference: PMID:25269405
    reference_title: "The expanding spectrum of human coronin 1A deficiency."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whereas complete absence of coronin 1A is associated with severe combined immunodeficiency in humans, 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: Sources the allele-dependent split recorded in these features, which is why this gene is not asserted as a uniform SCID subtype.
pathophysiology:
- name: Cytokine receptor signaling defect
  description: >-
    In X-linked SCID, JAK3 deficiency, and IL7R deficiency, loss-of-function in the
    common gamma chain (IL2RG), its associated kinase JAK3, or the IL-7 receptor
    alpha chain abolishes IL-7-dependent JAK-STAT signaling that drives early
    thymocyte survival and proliferation, blocking T-cell development. IL2RG and
    JAK3 defects additionally abrogate NK-cell development (T-B+NK-), whereas IL7R
    defects spare B and NK cells (T-B+NK+).
  genes:
  - preferred_term: IL7R
    term:
      id: hgnc:6024
      label: IL7R
  - preferred_term: JAK3
    term:
      id: hgnc:6193
      label: JAK3
  gene:
    preferred_term: IL2RG
    modifier: DECREASED
    term:
      id: hgnc:6010
      label: IL2RG
  biological_processes:
  - preferred_term: JAK-STAT cytokine receptor signaling
    modifier: DECREASED
    term:
      id: GO:0007259
      label: cell surface receptor signaling pathway via JAK-STAT
  cell_types:
  - preferred_term: thymocyte
    term:
      id: CL:0000893
      label: thymocyte
  evidence:
  - reference: PMID:20301584
    reference_title: "X-Linked Severe Combined Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of typical and atypical X-SCID is established in a male proband with suggestive findings and a hemizygous pathogenic variant in IL2RG identified by molecular genetic testing."
    explanation: IL2RG common gamma-chain loss underlies X-linked SCID, the cytokine-signaling form of disrupted T-cell development.
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The gamma portion of IL2R is important for the development of T and NK cells through cytokines IL2 and IL15, respectively."
    explanation: >-
      Supports the mechanism claimed by this node — that common gamma-chain
      cytokine signalling drives both T- and NK-cell development, so its loss
      gives the T-B+NK- phenotype.
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "JAK3 plays a pivotal role in cytokine receptor cell signalling."
    explanation: Supports placing JAK3 in the same cytokine-receptor signalling node as IL2RG.
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The encoded protein is expressed on the lymphoid lineage and is required during T cell development during early stage and for proliferation and survival of T cells in the periphery."
    explanation: >-
      Supports the IL-7 receptor arm of this node, and specifically the claim
      that the signal drives early thymocyte survival and proliferation.
  downstream:
  - target: Blocked T-lymphocyte development
    description: Loss of IL-7/JAK-STAT signaling halts thymocyte survival and proliferation, blocking maturation of T lymphocytes.
    causal_link_type: DIRECT
- name: Defective V(D)J recombination and DNA repair
  description: >-
    In RAG1, RAG2, DCLRE1C (Artemis), PRKDC (DNA-PKcs), and LIG4 (DNA ligase IV)
    deficiency, the machinery that assembles antigen-receptor genes is impaired.
    RAG1/RAG2 initiate site-specific DNA cleavage during V(D)J recombination; Artemis
    opens the resulting DNA hairpins as part of non-homologous end-joining; DNA-PKcs
    activates Artemis for that step; and DNA ligase IV seals the repaired ends.
    Failure to recombine T-cell (and B-cell) receptor genes arrests lymphocyte
    development (T-B-NK+). Loss of any of the three end-joining components
    additionally confers cellular radiosensitivity, which is what makes the molecular
    diagnosis matter before transplant conditioning.
  genes:
  - preferred_term: RAG2
    term:
      id: hgnc:9832
      label: RAG2
  - preferred_term: DCLRE1C
    term:
      id: hgnc:17642
      label: DCLRE1C
  - preferred_term: PRKDC
    term:
      id: hgnc:9413
      label: PRKDC
  - preferred_term: LIG4
    term:
      id: hgnc:6601
      label: LIG4
  gene:
    preferred_term: RAG1
    modifier: DECREASED
    term:
      id: hgnc:9831
      label: RAG1
  biological_processes:
  - preferred_term: V(D)J recombination
    modifier: DECREASED
    term:
      id: GO:0033151
      label: V(D)J recombination
  - preferred_term: DNA recombination
    modifier: DECREASED
    term:
      id: GO:0006310
      label: DNA recombination
  molecular_functions:
  - preferred_term: DNA-dependent protein kinase activity
    modifier: DECREASED
    term:
      id: GO:0004677
      label: DNA-dependent protein kinase activity
  - preferred_term: DNA ligase (ATP) activity
    modifier: DECREASED
    term:
      id: GO:0003910
      label: DNA ligase (ATP) activity
  cell_types:
  - preferred_term: thymocyte
    term:
      id: CL:0000893
      label: thymocyte
  evidence:
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "RAG1 and RAG2, are DNA recombinases that mediate DNA recombination process and ensure the somatic diversification of immunoglobulin and TCR genes during B-cell and T-cell development, respectively."
    explanation: Supports the initiating step of this node — RAG-mediated recombination of antigen-receptor genes in developing B and T cells.
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the absence of VDJ recombination, T cell undergoes apoptosis."
    explanation: Supports the causal step from failed V(D)J recombination to loss of developing T cells.
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "DCLRE1C encodes ARTEMIS, a nuclease which is single-stranded with- 5′-3′ exonuclease potential and endonuclease activity over 5′ and 3′ ends. It is essential for V(D)J rearrangement and for DNA repair."
    explanation: Supports the Artemis arm of this node, covering both hairpin processing during recombination and general DNA repair.
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with this form of SCID are sensitive to ionizing radiation and chemotherapeutic agents."
    explanation: Supports the cellular radiosensitivity this node attributes specifically to Artemis loss.
  - reference: PMID:19075392
    reference_title: "A DNA-PKcs mutation in a radiosensitive T-B- SCID patient inhibits Artemis activation and nonhomologous end-joining."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Radiosensitive T-B- severe combined immunodeficiency (RS-SCID) is caused by defects in the nonhomologous end-joining (NHEJ) DNA repair pathway, which results in failure of functional V(D)J recombination."
    explanation: Supports extending this node to the end-joining components, and the T-B-NK+ immunophenotype they share with Artemis deficiency.
  - reference: PMID:11779494
    reference_title: "DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "DNA ligase IV functions in DNA nonhomologous end-joining and V(D)J recombination."
    explanation: Supports placing LIG4 at the ligation step of the same end-joining pathway this node models.
  downstream:
  - target: Blocked T-lymphocyte development
    description: Failure of antigen-receptor gene recombination arrests thymocyte maturation, blocking T-cell development.
    causal_link_type: DIRECT
- name: Toxic purine metabolite accumulation
  description: >-
    In ADA deficiency, loss of adenosine deaminase activity causes accumulation of
    adenosine and especially deoxyadenosine (and intracellular dATP), which are
    lymphotoxic and impair lymphocyte development, viability, and function. The
    metabolic toxicity affects all lymphoid lineages, producing a
    T-B-NK- immunophenotype.
  gene:
    preferred_term: ADA
    modifier: DECREASED
    term:
      id: hgnc:186
      label: ADA
  biological_processes:
  - preferred_term: adenosine catabolic process
    modifier: DECREASED
    term:
      id: GO:0006154
      label: adenosine catabolic process
  chemical_entities:
  - preferred_term: 2'-deoxyadenosine
    modifier: INCREASED
    term:
      id: CHEBI:17256
      label: 2'-deoxyadenosine
  - preferred_term: adenosine
    modifier: INCREASED
    term:
      id: CHEBI:16335
      label: adenosine
  cell_types:
  - preferred_term: thymocyte
    term:
      id: CL:0000893
      label: thymocyte
  evidence:
  - reference: PMID:20301656
    reference_title: "Adenosine Deaminase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Adenosine deaminase (ADA) deficiency is a systemic purine metabolic disorder that primarily affects lymphocyte development, viability, and function."
    explanation: ADA deficiency causes toxic purine-metabolite accumulation that impairs lymphocyte development, viability, and function.
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Deficiency of ADA causes accumulation of adenosine, deoxyadenosine, and 2′-O-methyladenosine resulting in lymphocyte apoptosis, causing the absence of T cell function."
    explanation: >-
      Names the accumulating metabolites bound as chemical entities on this node
      and supplies the intermediate step this node asserts — lymphocyte
      apoptosis leading to loss of T-cell function.
  - reference: PMID:20301656
    reference_title: "Adenosine Deaminase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "total red blood cell deoxyadenosine nucleotides (dAXP) and, if on ERT, plasma ADA activity"
    explanation: >-
      Deoxyadenosine nucleotides (dAXP) are the accumulating phosphorylated
      species this node refers to, and are the monitored disease marker.
  downstream:
  - target: Blocked T-lymphocyte development
    description: Lymphotoxic deoxyadenosine/dATP accumulation impairs thymocyte survival and blocks T-cell development.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - deoxyadenosine and intracellular dATP accumulation; lymphocyte apoptosis
  - target: Non-lymphoid tissue purine metabolite toxicity
    description: >-
      ADA is expressed ubiquitously rather than only in lymphoid tissue, so the
      same accumulating metabolites reach cells that have no immunological role.
      This is the branch that makes ADA deficiency the one SCID subtype in this
      entry whose pathology is not confined to the immune system.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27579027
      reference_title: "Adenosine Deaminase Deficiency - More Than Just an Immunodeficiency."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "there is now a growing body of evidence that deficiency of ADA has significant impact on non-immunological organ systems"
      explanation: >-
        States the review's central claim, which is what this edge asserts: that
        the metabolic lesion has consequences outside the immune system.
    - reference: PMID:20301656
      reference_title: "Adenosine Deaminase Deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Skeletal abnormalities affecting ribs and vertebra, pulmonary alveolar proteinosis, hemolytic anemia, neurologic abnormalities, and transaminitis may also suggest untreated ADA-SCID."
      explanation: >-
        Enumerates the non-lymphoid organ systems this branch leads to, from the
        GeneReviews clinical description rather than from the review.
- name: Non-lymphoid tissue purine metabolite toxicity
  biological_scale: CELLULAR
  description: >-
    Because adenosine deaminase is ubiquitously expressed, the deoxyadenosine and
    dATP that accumulate in its absence are not confined to thymocytes. Two of the
    same molecular routes that damage developing lymphocytes operate in
    non-lymphoid cells: 2'-deoxyadenosine irreversibly inactivates
    S-adenosylhomocysteine hydrolase, so S-adenosylhomocysteine accumulates and
    inhibits transmethylation; and dATP inhibits ribonucleotide reductase,
    depleting the deoxynucleotide pool and impairing DNA synthesis in any
    proliferating cell. This node is the entry point for the extra-immune
    features of ADA deficiency — neurocognitive, auditory, skeletal, pulmonary
    and hepatic — which none of the other five SCID subtypes in this entry share.
  molecular_functions:
  - preferred_term: S-adenosylhomocysteine hydrolase activity
    modifier: DECREASED
    term:
      id: GO:0004013
      label: adenosylhomocysteinase activity
  - preferred_term: ribonucleotide reductase activity
    modifier: DECREASED
    term:
      id: GO:0004748
      label: "ribonucleoside-diphosphate reductase activity, thioredoxin disulfide as acceptor"
  biological_processes:
  - preferred_term: transmethylation
    modifier: DECREASED
    term:
      id: GO:0032259
      label: methylation
  - preferred_term: DNA replication
    modifier: DECREASED
    term:
      id: GO:0006260
      label: DNA replication
  chemical_entities:
  - preferred_term: S-adenosyl-L-homocysteine
    modifier: INCREASED
    term:
      id: CHEBI:16680
      label: S-adenosyl-L-homocysteine
  - preferred_term: dATP
    modifier: INCREASED
    term:
      id: CHEBI:16284
      label: dATP
  notes: >-
    The two molecular routes bound here are characterised in the lymphoid
    compartment, where they were worked out; the review's argument for extending
    them to non-lymphoid tissue is the ubiquity of ADA expression plus the
    organ-specific patient findings downstream, not a direct measurement of
    transmethylation or deoxynucleotide pools in cochlea, brain or bone. The
    causal_link_type on each downstream edge records how far that inference
    reaches for the organ concerned.
  evidence:
  - reference: PMID:27579027
    reference_title: "Adenosine Deaminase Deficiency - More Than Just an Immunodeficiency."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Adenosine deaminase (ADA) is a ubiquitously expressed metabolic enzyme that plays an integral role in numerous cellular processes"
    explanation: >-
      Establishes the premise this node rests on — that the enzyme is not
      lymphoid-restricted, so its loss is not either.
  - reference: PMID:27579027
    reference_title: "Adenosine Deaminase Deficiency - More Than Just an Immunodeficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "2′deoxyadenosine irreversibly inactivates S-adenosyl-l-homocysteine (SAH) hydrolase"
    explanation: >-
      Supports the decreased adenosylhomocysteinase activity bound on this node.
  - reference: PMID:27579027
    reference_title: "Adenosine Deaminase Deficiency - More Than Just an Immunodeficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "Inhibition of SAH hydrolase prevents hydrolysis of SAH, and the accumulated SAH inhibits transmethylation reactions"
    explanation: >-
      Supports the increased S-adenosyl-L-homocysteine and the decreased
      methylation bound on this node.
  - reference: PMID:27579027
    reference_title: "Adenosine Deaminase Deficiency - More Than Just an Immunodeficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: REVIEW_SYNTHESIS
    snippet: "dATP is an inhibitor of ribonucleotide reductase that is necessary for deoxynucleotide synthesis, and its inhibition depletes the intracellular deoxynucleotide pool"
    explanation: >-
      Supports the decreased ribonucleotide reductase activity and the impaired
      DNA replication bound on this node.
  downstream:
  - target: Cognitive impairment
    description: >-
      Adenosine is a CNS neuromodulator and ADA-SCID patients score below both the
      population average and other SCID groups on IQ, with an inverse correlation
      between diagnostic dATP level and total IQ. The intervening steps between
      metabolite accumulation and the cognitive deficit are not established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27579027
      reference_title: "Adenosine Deaminase Deficiency - More Than Just an Immunodeficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "a significant inverse correlation between dATP levels at diagnosis and total IQ has been demonstrated"
      explanation: >-
        Ties the cognitive outcome to the accumulating metabolite rather than to
        treatment, which is what makes this a causal edge from this node.
  - target: Hyperactivity
    description: >-
      The behavioural phenotype travels with the cognitive one and is reported in
      the same cohorts, with lower IQ accompanied by more behavioural difficulty.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27579027
      reference_title: "Adenosine Deaminase Deficiency - More Than Just an Immunodeficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "ADA-SCID patients exhibit hyperactivity, attention deficits, aggressive behavior, and social problems, scoring abnormally in all of these areas of behavior"
      explanation: >-
        Reports the behavioural abnormalities this edge terminates in.
  - target: Sensorineural hearing loss
    description: >-
      Bilateral sensorineural deafness occurs at roughly ten times the rate seen
      after transplant for immunodeficiencies confined to the immune system, in
      children with no structural, genetic, drug or infective cause, including
      children transplanted without conditioning.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27579027
      reference_title: "Adenosine Deaminase Deficiency - More Than Just an Immunodeficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "bilateral sensorineural deafness has been investigated as a non-immunological manifestation of ADA deficiency"
      explanation: >-
        States the attribution of the auditory phenotype to the metabolic lesion
        rather than to the immunodeficiency or its treatment.
  - target: Costochondral abnormalities
    description: >-
      Costochondral abnormality and skeletal dysplasia are common in ADA
      deficiency, and ADA-deficient mice show reduced bone formation from impaired
      osteoblast function. Whether the human bone phenotype follows from the
      purine lesion or from the immunodeficiency is explicitly unresolved, so this
      edge is the weakest of the five.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27579027
      reference_title: "Adenosine Deaminase Deficiency - More Than Just an Immunodeficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "It is common for patients with ADA deficiency to display costochondral abnormalities and skeletal dysplasia"
      explanation: >-
        Reports the skeletal phenotype in patients that this edge terminates in.
    - reference: PMID:27579027
      reference_title: "Adenosine Deaminase Deficiency - More Than Just an Immunodeficiency."
      supports: REFUTE
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "it is unknown whether these bony defects are caused by the disrupted purine metabolism or the underlying immunodeficiency"
      explanation: >-
        Withholds the attribution this edge makes: the same review states the
        causal assignment to purine metabolism is not settled for bone.
  - target: Elevated hepatic transaminases
    description: >-
      Hepatic involvement is the thinnest arm of the human evidence — transaminase
      elevation of unknown aetiology is reported but hepatic dysfunction is rare in
      patients, while ADA-deficient mice die perinatally of hepatocyte degeneration.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27579027
      reference_title: "Adenosine Deaminase Deficiency - More Than Just an Immunodeficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "elevated serum transaminase levels may be seen in patients with ADA deficiency: this is indicative of liver damage and often etiology is unknown"
      explanation: >-
        Reports the hepatic laboratory abnormality in patients that this edge
        terminates in, and records that its aetiology is often unestablished.
  - target: Pulmonary alveolar proteinosis
    description: >-
      Pulmonary alveolar proteinosis occurred in 43.8% of ADA-deficient patients
      and in none of the patients with other forms of SCID, with no clinical or
      immunological difference between the ADA patients who developed it and those
      who did not — which is what places it on this branch rather than on the
      infectious consequences of the immunodeficiency.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27579027
      reference_title: "Adenosine Deaminase Deficiency - More Than Just an Immunodeficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: REVIEW_SYNTHESIS
      snippet: "The incidence of ADA-deficient patients with PAP was reported to be 43.8% in this Grunebaum study"
      explanation: >-
        Quantifies the PAP incidence specific to ADA deficiency that this edge
        asserts follows from the metabolic lesion.
- name: Defective haematopoietic precursor survival
  description: >-
    In reticular dysgenesis, loss of adenylate kinase 2 disrupts cellular and
    mitochondrial energy homeostasis in haematopoietic precursors themselves.
    Because the lesion is bioenergetic rather than lymphoid-specific, both
    myeloid and lymphoid output fail: granulocytes are absent alongside
    lymphocytes, and innate as well as adaptive immunity is lost. This is the
    one SCID mechanism class in this entry whose consequences extend outside the
    lymphoid lineage.
  gene:
    preferred_term: AK2
    modifier: DECREASED
    term:
      id: hgnc:362
      label: AK2
  molecular_functions:
  - preferred_term: adenylate kinase activity
    modifier: DECREASED
    term:
      id: GO:0004017
      label: AMP kinase activity
  biological_processes:
  - preferred_term: haematopoiesis
    modifier: DECREASED
    term:
      id: GO:0030097
      label: hemopoiesis
  cell_types:
  - preferred_term: hematopoietic stem cell
    term:
      id: CL:0000037
      label: hematopoietic stem cell
  evidence:
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Adenylate kinases are involved in cellular and mitochondrial energy homeostasis."
    explanation: Supports the bioenergetic function whose loss initiates this node.
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Deficiency of AK2 is associated with lack of innate and adaptive immunity."
    explanation: Supports the claim that this mechanism removes innate immunity as well as adaptive immunity.
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Reticular dysgenesis is the most serious type of SCID that is associated with absent granulocytes, lymphocytes, hypoplasia of the primary and secondary lymphoid organs and fatal septicemia within days after birth."
    explanation: Supports the simultaneous granulocyte and lymphocyte failure and the lymphoid-organ hypoplasia this node produces.
  downstream:
  - target: Blocked T-lymphocyte development
    description: Failure of haematopoietic precursor survival removes the progenitors from which thymocytes would derive.
    causal_link_type: DIRECT
  - target: Absence of circulating granulocytes
    description: The same precursor-survival defect abolishes granulocyte production, a myeloid consequence absent from the other SCID subtypes.
    causal_link_type: DIRECT
  - target: Hypoplasia of the thymus
    description: Absent haematopoietic precursors leave the primary and secondary lymphoid organs hypoplastic.
    causal_link_type: DIRECT
- name: Receptor-proximal T-cell receptor signaling defect
  description: >-
    In CD3D and LAT deficiency signalling through the pre-T-cell receptor and T-cell
    receptor fails at or immediately below the receptor, by two different routes.
    CD3delta is an invariant chain of the complex itself, so its loss leaves no
    signalling-competent receptor to assemble; LAT is the transmembrane adaptor that
    propagates the signal from a receptor that is intact, so its loss leaves the
    receptor silent. Thymocyte development arrests at the
    double-negative to double-positive transition, giving a T-B+NK+ immunophenotype.
    This is a fifth mechanism class alongside cytokine receptor signaling, V(D)J
    recombination and DNA repair, purine metabolism, and haematopoietic precursor
    survival, and it is the class the CD45/PTPRC and other CD3-chain deficiencies
    also belong to.
  biological_scale: CELLULAR
  genes:
  - preferred_term: CD3D
    term:
      id: hgnc:1673
      label: CD3D
  - preferred_term: LAT
    term:
      id: hgnc:18874
      label: LAT
  biological_processes:
  - preferred_term: T cell receptor signaling pathway
    modifier: DECREASED
    term:
      id: GO:0050852
      label: T cell receptor signaling pathway
  - preferred_term: T cell differentiation in thymus
    modifier: DECREASED
    term:
      id: GO:0033077
      label: T cell differentiation in thymus
  molecular_functions:
  - preferred_term: transmembrane signaling receptor activity
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0004888
      label: transmembrane signaling receptor activity
  - preferred_term: signaling receptor complex adaptor activity
    modifier: LOSS_OF_FUNCTION
    term:
      id: GO:0030159
      label: signaling receptor complex adaptor activity
  cell_types:
  - preferred_term: thymocyte
    term:
      id: CL:0000893
      label: thymocyte
  evidence:
  - reference: PMID:16264327
    reference_title: "CD3 deficiencies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Homozygous mutations in CD3D and CD3E genes lead to a complete block in T-cell development and thus to an early-onset severe combined immunodeficiency phenotype."
    explanation: Supports this node's claim that loss of a CD3 invariant chain blocks T-cell development and produces SCID.
  - reference: PMID:16264327
    reference_title: "CD3 deficiencies."
    supports: SUPPORT
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thymic studies have shown that the defect in T-cell development occurs at the transition between 'double-negative' and 'double-positive' thymocytes."
    explanation: Sources the thymocyte stage at which this node places the arrest, and the thymocyte cell type bound here.
  - reference: PMID:27522155
    reference_title: "Mutations in linker for activation of T cells (LAT) lead to a novel form of severe combined immunodeficiency."
    supports: SUPPORT
    directness: DIRECT
    quote_role: BACKGROUND
    evidence_source: MODEL_ORGANISM
    snippet: "Linker for activation of T cells (LAT) is a transmembrane adaptor signaling molecule that is part of the TCR complex and essential for T-cell development, as demonstrated by LAT-deficient mice, which show a complete lack of peripheral T cells."
    explanation: Sources the T-cell receptor signaling pathway bound to this node, and LAT's position within the receptor complex.
  downstream:
  - target: Blocked T-lymphocyte development
    description: >-
      Without a signalling-competent T-cell receptor complex, or without the adaptor
      that carries its signal onward, beta-selection cannot be driven and thymocyte
      maturation arrests before the double-positive stage.
    causal_link_type: DIRECT
- name: Defective thymocyte egress
  description: >-
    In coronin-1A deficiency the actin regulation required for thymocytes to leave the
    thymus and for peripheral T cells to survive is lost, so T cells do not populate
    the periphery. The two mouse alleles show the two halves of this separately. The
    Ptcd strain carries an E26K gain-of-function substitution that increases
    coronin-1A inhibition of Arp2/3 and blocks thymic egress; Coro1a-null mice, which
    match the patient's absent protein, instead lose mature thymocytes through reduced
    survival. Neither is a block in thymocyte development, which is the basis for
    placing this node beside the developmental block rather than within it.
  biological_scale: CELLULAR
  genes:
  - preferred_term: CORO1A
    term:
      id: hgnc:2252
      label: CORO1A
  biological_processes:
  - preferred_term: thymocyte migration
    modifier: DECREASED
    term:
      id: GO:0072679
      label: thymocyte migration
  - preferred_term: actin cytoskeleton organization
    modifier: ABNORMAL
    term:
      id: GO:0030036
      label: actin cytoskeleton organization
  molecular_functions:
  - preferred_term: Arp2/3 complex binding
    modifier: ABNORMAL
    term:
      id: GO:0071933
      label: Arp2/3 complex binding
  cell_types:
  - preferred_term: thymocyte
    term:
      id: CL:0000893
      label: thymocyte
  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
    directness: DIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Our findings establish a function for coronin 1A in T cell egress, identify a surface of coronin involved in Arp2/3 regulation and demonstrate that actin regulation is a biological process defective in human and mouse severe combined immunodeficiency."
    explanation: Sources both processes bound to this node - thymocyte egress and actin regulation - and their status as a human SCID mechanism.
  - 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
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The discovery of another coronin 1A mutant during an N-ethyl-N-nitrosourea-mutagenesis screen for T cell-lymphopenic mice prompted us to evaluate 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: Sources the T-B+NK+ immunophenotype this node asserts, in the index human patient.
  - 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
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Mice carrying the recessive locus for peripheral T cell deficiency (Ptcd) have a block in thymic egress, but the mechanism responsible is undefined."
    explanation: The mouse result this node's egress-rather-than-development placement rests on; recorded as model-organism evidence because the human report does not state where the block sits.
  - 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
    directness: DIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "the E26K mutation does not phenocopy the Coro1A deficient state"
    explanation: >-
      Distinguishes the gain-of-function Ptcd allele from the null state, which in
      mice reduces mature thymocyte survival; the node's description and its
      ABNORMAL Arp2/3 binding modifier cover both alleles for this reason.
  - 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
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "The identification of a patient with a peripheral T cell deficiency who lacks expression of Coro1A strongly suggests that Coro1A has similar functions in humans as in mice."
    explanation: Establishes that the human disease is the null state, not the Ptcd gain-of-function allele.
  downstream:
  - target: Absent adaptive immunity
    description: >-
      Thymocytes that cannot leave the thymus, and peripheral T cells that do not
      survive, leave the periphery without a functional T-cell compartment even
      though intrathymic development is not itself arrested.
    causal_link_type: DIRECT
- name: Blocked T-lymphocyte development
  description: >-
    The convergent consequence of all SCID subtypes is failure of hematopoietic
    stem cells to differentiate into mature, functional T lymphocytes in the thymus,
    yielding absent or severely reduced autologous T cells. Depending on the genetic
    lesion, B and/or NK lineages are also affected.
  biological_processes:
  - preferred_term: T cell differentiation in thymus
    modifier: DECREASED
    term:
      id: GO:0033077
      label: T cell differentiation in thymus
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  - preferred_term: hematopoietic stem cell
    term:
      id: CL:0000037
      label: hematopoietic stem cell
  evidence:
  - reference: PMID:36456361
    reference_title: "The diagnosis of severe combined immunodeficiency (SCID): The Primary Immune Deficiency Treatment Consortium (PIDTC) 2022 Definitions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Severe combined immunodeficiency (SCID) results from defects in the differentiation of hematopoietic stem cells into mature T lymphocytes, with additional lymphoid lineages affected in particular genotypes."
    explanation: SCID converges on failed differentiation of hematopoietic stem cells into mature T lymphocytes, with additional lineages affected by genotype.
  downstream:
  - target: Absent adaptive immunity
    description: Absence of functional T lymphocytes abolishes cell-mediated immunity and (directly or via loss of T-cell help) humoral immunity.
    causal_link_type: DIRECT
  - target: Decreased total T cell count
    description: Blocked thymic T-cell development produces profound T lymphocytopenia.
    causal_link_type: DIRECT
  - target: Hypoplasia of the thymus
    description: Absence of developing thymocytes leaves a small, dysplastic thymus that yields an absent thymic shadow on imaging.
    causal_link_type: DIRECT
  - target: Decreased total B cell count
    description: In T-B- subtypes (RAG1/RAG2, Artemis, ADA) the same developmental/metabolic block also abolishes B-lymphocyte development.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - shared V(D)J recombination or metabolic block affecting the B-lymphoid lineage
  - target: Reduced total natural killer cell count
    description: In NK-negative subtypes (IL2RG, JAK3, ADA) the gamma-chain signaling or metabolic defect also abolishes NK-cell development.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - shared common gamma-chain signaling or metabolic defect affecting the NK lineage
- name: Absent adaptive immunity
  description: >-
    Without functional T cells (and often B cells), the patient cannot mount
    protective cellular or humoral adaptive immune responses, leaving the infant
    susceptible to overwhelming bacterial, viral, fungal, and protozoal infection.
  biological_processes:
  - preferred_term: adaptive immune response
    modifier: DECREASED
    term:
      id: GO:0002250
      label: adaptive immune response
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  evidence:
  - reference: PMID:20301656
    reference_title: "Adenosine Deaminase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Characteristic immune abnormalities are lymphocytopenia (low numbers of T, B, and NK cells) combined with the absence of both humoral and cellular immune function."
    explanation: SCID produces absence of both humoral and cellular immune function, the loss of adaptive immunity.
  downstream:
  - target: Severe combined immunodeficiency
    description: Loss of adaptive immunity is the defining clinical immunodeficiency.
    causal_link_type: DIRECT
  - target: Absent cellular immunity
    description: Loss of functional T cells abolishes cell-mediated immune responses.
    causal_link_type: DIRECT
  - target: Recurrent infections
    description: Without adaptive immunity, infants suffer recurrent and persistent infections from early infancy.
    causal_link_type: DIRECT
  - target: Recurrent fungal infections
    description: Loss of T-cell immunity predisposes to fungal infection including persistent candidiasis.
    causal_link_type: DIRECT
  - target: Chronic oral candidiasis
    description: Defective cellular immunity allows persistent oral Candida infection.
    causal_link_type: DIRECT
  - target: Pneumonia
    description: Loss of adaptive immunity predisposes to recurrent and opportunistic pneumonia (including Pneumocystis).
    causal_link_type: DIRECT
  - target: Chronic diarrhea
    description: Opportunistic enteric infection and immune dysfunction produce persistent diarrhea.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - opportunistic enteric and viral gastrointestinal infection
  - target: Failure to thrive
    description: Chronic infection and diarrhea cause poor linear growth and weight gain.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - chronic infection and persistent diarrhea with poor weight gain
  - target: Hepatosplenomegaly
    description: Disseminated infection and immune dysregulation (e.g., Omenn syndrome) can produce hepatosplenomegaly.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- category: Clinical
  name: Severe combined immunodeficiency
  description: Profound combined defect of cellular and humoral adaptive immunity is the defining feature.
  phenotype_term:
    preferred_term: Severe combined immunodeficiency
    term:
      id: HP:0004430
      label: Severe combined immunodeficiency
  evidence:
  - reference: PMID:36456361
    reference_title: "The diagnosis of severe combined immunodeficiency (SCID): The Primary Immune Deficiency Treatment Consortium (PIDTC) 2022 Definitions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Severe combined immunodeficiency (SCID) results from defects in the differentiation of hematopoietic stem cells into mature T lymphocytes, with additional lymphoid lineages affected in particular genotypes."
    explanation: SCID is defined by combined defects of adaptive immunity arising from failed T-lymphocyte differentiation.
- category: Clinical
  name: Absent cellular immunity
  description: Cell-mediated immune responses are absent owing to loss of functional T lymphocytes.
  phenotype_term:
    preferred_term: Absent cellular immunity
    term:
      id: HP:0005354
      label: Absent cellular immunity
  evidence:
  - reference: PMID:20301656
    reference_title: "Adenosine Deaminase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Characteristic immune abnormalities are lymphocytopenia (low numbers of T, B, and NK cells) combined with the absence of both humoral and cellular immune function."
    explanation: SCID features absence of cellular immune function.
- category: Clinical
  name: Recurrent infections
  description: >-
    Recurrent, severe, and opportunistic bacterial, viral, fungal, and protozoal
    infections beginning in early infancy.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical manifestations are characterised by recurrent and severe bacterial, viral, and fungal opportunistic infections that start from early infancy period."
    explanation: Recurrent severe opportunistic infections from early infancy are the cardinal clinical feature of SCID.
- category: Clinical
  name: Pneumonia
  description: Recurrent and opportunistic pneumonia, including Pneumocystis jirovecii pneumonia, is common.
  phenotype_term:
    preferred_term: Pneumonia
    term:
      id: HP:0002090
      label: Pneumonia
  evidence:
  - reference: PMID:20301656
    reference_title: "Adenosine Deaminase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Untreated ADA-SCID presents as life-threatening opportunistic illnesses in the first weeks to months of life with poor linear growth and weight gain secondary to persistent diarrhea, extensive dermatitis, and recurrent pneumonia."
    explanation: Recurrent pneumonia is a presenting opportunistic illness in untreated SCID.
- category: Clinical
  name: Recurrent fungal infections
  description: Persistent fungal infection, especially mucocutaneous candidiasis, reflects loss of T-cell immunity.
  phenotype_term:
    preferred_term: Recurrent fungal infections
    term:
      id: HP:0002841
      label: Recurrent fungal infections
  evidence:
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical manifestations are characterised by recurrent and severe bacterial, viral, and fungal opportunistic infections that start from early infancy period."
    explanation: Recurrent fungal opportunistic infections are part of the SCID clinical picture.
- category: Clinical
  name: Chronic oral candidiasis
  description: Persistent oral thrush is a frequent early manifestation of defective cellular immunity.
  phenotype_term:
    preferred_term: Chronic oral candidiasis
    term:
      id: HP:0009098
      label: Chronic oral candidiasis
  evidence:
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical manifestations are characterised by recurrent and severe bacterial, viral, and fungal opportunistic infections that start from early infancy period."
    explanation: Persistent fungal (candidal) infection including oral thrush reflects the T-cell immune defect in SCID.
- category: Clinical
  name: Chronic diarrhea
  description: Persistent diarrhea, often from opportunistic enteric infection, is a common presenting feature.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Chronic diarrhea
    term:
      id: HP:0002028
      label: Chronic diarrhea
  evidence:
  - reference: PMID:20301656
    reference_title: "Adenosine Deaminase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "poor linear growth and weight gain secondary to persistent diarrhea"
    explanation: Persistent diarrhea is a frequent presenting feature contributing to failure to thrive in SCID.
- category: Clinical
  name: Failure to thrive
  description: Poor linear growth and weight gain secondary to chronic infection and persistent diarrhea.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:20301656
    reference_title: "Adenosine Deaminase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Untreated ADA-SCID presents as life-threatening opportunistic illnesses in the first weeks to months of life with poor linear growth and weight gain secondary to persistent diarrhea"
    explanation: Poor linear growth and weight gain (failure to thrive) follow chronic infection and diarrhea in untreated SCID.
- category: Laboratory
  name: Decreased total T cell count
  description: Profound T lymphocytopenia (<0.05 x 10^9 autologous T cells/L in typical SCID).
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Decreased total T cell count
    term:
      id: HP:0005403
      label: Decreased total T cell count
  evidence:
  - reference: PMID:36456361
    reference_title: "The diagnosis of severe combined immunodeficiency (SCID): The Primary Immune Deficiency Treatment Consortium (PIDTC) 2022 Definitions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with typical SCID must have less than 0.05 × 109 autologous T cells/L on repetitive testing"
    explanation: Typical SCID is defined by profoundly low autologous T-cell counts.
- category: Laboratory
  name: Decreased total B cell count
  description: B lymphocytes are absent in T-B- forms (RAG1/RAG2, ADA, Artemis) and preserved in T-B+ forms.
  subtype: ADA deficiency
  notes: >-
    Subtype tag corrected from "RAG1/RAG2 deficiency" to "ADA deficiency" to
    match the cited evidence, which is the ADA-deficiency GeneReviews. The
    T-B- immunophenotype is shared by RAG1/RAG2 and Artemis deficiency, but
    those subtypes are not what the quoted source documents.
  phenotype_term:
    preferred_term: Decreased total B cell count
    term:
      id: HP:0010976
      label: Decreased total B cell count
  evidence:
  - reference: PMID:20301656
    reference_title: "Adenosine Deaminase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Characteristic immune abnormalities are lymphocytopenia (low numbers of T, B, and NK cells)"
    explanation: In T-B-NK- forms such as ADA-SCID, B-cell numbers are reduced along with T and NK cells.
- category: Laboratory
  name: Reduced total natural killer cell count
  description: NK cells are absent in T-B+NK- forms (IL2RG, JAK3) and in T-B-NK- ADA deficiency.
  subtype: ADA deficiency
  notes: >-
    Subtype tag corrected from "X-linked SCID" to "ADA deficiency" to match the
    cited evidence, which is the ADA-deficiency GeneReviews. NK-negativity is
    also the X-linked SCID (IL2RG) and JAK3 immunophenotype, but that is not
    what the quoted source documents.
  phenotype_term:
    preferred_term: Reduced total natural killer cell count
    term:
      id: HP:0040218
      label: Reduced total natural killer cell count
  evidence:
  - reference: PMID:20301656
    reference_title: "Adenosine Deaminase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Characteristic immune abnormalities are lymphocytopenia (low numbers of T, B, and NK cells)"
    explanation: NK-cell numbers are reduced in the NK-negative SCID immunophenotypes.
- category: Imaging
  name: Hypoplasia of the thymus
  description: >-
    A small, dysplastic thymus depleted of developing thymocytes produces the
    characteristic absent thymic shadow on chest imaging.
  notes: >-
    Ontology term corrected from HP:0005359 "Aplasia of the thymus" to
    HP:0000778 "Hypoplasia of the thymus". In typical SCID the thymic
    epithelial rudiment is present but hypoplastic/dysplastic because it is not
    populated by thymocytes; true thymic APLASIA (athymia) is the lesion of
    complete DiGeorge syndrome and FOXN1 deficiency, which are distinct
    entities. The absent thymic shadow on radiography reflects hypoplasia, not
    absence of the organ. This is also not a universal SCID finding - CORO1A
    deficiency, for example, produces T-B+ SCID with a normal-sized thymus - so
    no frequency band is asserted.
  phenotype_term:
    preferred_term: Thymic hypoplasia (absent thymic shadow)
    term:
      id: HP:0000778
      label: Hypoplasia of the thymus
  evidence:
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "hypoplasia of secondary lymphoid organs and thymus"
    explanation: Documents thymic hypoplasia (rather than aplasia) as the thymic finding in SCID.
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Deficiency of Coronin 1A known to result in T-B + SCID with a normal sized thymus."
    explanation: >-
      Documents a SCID genotype with a normal-sized thymus, showing the thymic
      finding is genotype-dependent and not universal.
- category: Clinical
  name: Hepatosplenomegaly
  description: Hepatosplenomegaly occurs particularly in Omenn syndrome and with disseminated infection.
  subtype: RAG1/RAG2 deficiency
  phenotype_term:
    preferred_term: Hepatosplenomegaly
    term:
      id: HP:0001433
      label: Hepatosplenomegaly
  evidence:
  - reference: PMID:36456361
    reference_title: "The diagnosis of severe combined immunodeficiency (SCID): The Primary Immune Deficiency Treatment Consortium (PIDTC) 2022 Definitions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Omenn syndrome requires a generalized erythematous rash, absent transplacentally acquired maternal engraftment, and 2 or more of these: eosinophilia, elevated IgE, lymphadenopathy, hepatosplenomegaly."
    explanation: Hepatosplenomegaly is a recognized feature of the Omenn syndrome presentation of leaky SCID (RAG hypomorphs).
- category: Clinical
  name: Erythroderma
  description: >-
    A generalized erythematous rash (erythroderma) is a required feature of the
    Omenn syndrome presentation, in which hypomorphic RAG alleles permit
    expansion of activated oligoclonal autoreactive T cells.
  subtype: RAG1/RAG2 deficiency
  phenotype_term:
    preferred_term: Generalized erythematous rash (erythroderma)
    term:
      id: HP:0001019
      label: Erythroderma
  evidence:
  - reference: PMID:36456361
    reference_title: "The diagnosis of severe combined immunodeficiency (SCID): The Primary Immune Deficiency Treatment Consortium (PIDTC) 2022 Definitions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Omenn syndrome requires a generalized erythematous rash, absent transplacentally acquired maternal engraftment, and 2 or more of these: eosinophilia, elevated IgE, lymphadenopathy, hepatosplenomegaly."
    explanation: A generalized erythematous rash is an obligate criterion for Omenn syndrome in the PIDTC 2022 definitions.
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One of the important clinical presentations of RAG defects is Omenn syndrome, characterized by significant expansion of activated oligoclonal T cells, erythroderma, diarrhoea, hepatosplenomegaly, generalized lymphadenopathy, hypereosinophilia, and elevated IgE levels."
    explanation: Independently lists erythroderma among the Omenn features of RAG defects and gives the oligoclonal T-cell mechanism.
- category: Laboratory
  name: Increased total eosinophil count
  description: >-
    Eosinophilia (hypereosinophilia) accompanies the immune-dysregulation
    presentation of leaky SCID / Omenn syndrome.
  subtype: RAG1/RAG2 deficiency
  phenotype_term:
    preferred_term: Eosinophilia
    term:
      id: HP:0001880
      label: Increased total eosinophil count
  evidence:
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One of the important clinical presentations of RAG defects is Omenn syndrome, characterized by significant expansion of activated oligoclonal T cells, erythroderma, diarrhoea, hepatosplenomegaly, generalized lymphadenopathy, hypereosinophilia, and elevated IgE levels."
    explanation: Lists hypereosinophilia as a defining feature of the Omenn presentation of RAG deficiency.
- category: Laboratory
  name: Increased circulating IgE concentration
  description: >-
    Elevated serum IgE is part of the Omenn syndrome immune-dysregulation
    profile, and contrasts with the panhypogammaglobulinaemia of typical SCID.
  subtype: RAG1/RAG2 deficiency
  phenotype_term:
    preferred_term: Elevated IgE
    term:
      id: HP:0003212
      label: Increased circulating IgE concentration
  evidence:
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One of the important clinical presentations of RAG defects is Omenn syndrome, characterized by significant expansion of activated oligoclonal T cells, erythroderma, diarrhoea, hepatosplenomegaly, generalized lymphadenopathy, hypereosinophilia, and elevated IgE levels."
    explanation: Lists elevated IgE among the Omenn syndrome features of RAG deficiency.
- category: Clinical
  name: Lymphadenopathy
  description: >-
    Generalized lymphadenopathy occurs in Omenn syndrome, where oligoclonal
    activated T cells expand — the opposite of the absent lymphoid tissue of
    typical SCID.
  subtype: RAG1/RAG2 deficiency
  phenotype_term:
    preferred_term: Generalized lymphadenopathy
    term:
      id: HP:0002716
      label: Lymphadenopathy
  evidence:
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One of the important clinical presentations of RAG defects is Omenn syndrome, characterized by significant expansion of activated oligoclonal T cells, erythroderma, diarrhoea, hepatosplenomegaly, generalized lymphadenopathy, hypereosinophilia, and elevated IgE levels."
    explanation: Lists generalized lymphadenopathy among the Omenn syndrome features of RAG deficiency.
- category: Laboratory
  name: Absence of circulating granulocytes
  description: >-
    Absent granulocytes with profound neutropenia is the feature that separates
    reticular dysgenesis from every other SCID subtype, and follows from the
    haematopoietic-precursor rather than lymphoid-specific block.
  subtype: Reticular dysgenesis
  phenotype_term:
    preferred_term: Absent granulocytes
    term:
      id: HP:0012234
      label: Absence of circulating granulocytes
  evidence:
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Reticular dysgenesis is the most serious type of SCID that is associated with absent granulocytes, lymphocytes, hypoplasia of the primary and secondary lymphoid organs and fatal septicemia within days after birth."
    explanation: Directly documents absent granulocytes in reticular dysgenesis.
- category: Clinical
  name: Dermatitis
  description: >-
    Extensive dermatitis is a presenting feature of untreated ADA-SCID, and
    recurrent dermatitis is also reported in the atypical X-SCID combined
    immunodeficiency phenotype.
  phenotype_term:
    preferred_term: Extensive dermatitis
    term:
      id: HP:0011123
      label: Inflammatory abnormality of the skin
  notes: >-
    Bound to the general HPO skin-inflammation term rather than a specific
    dermatitis subtype: the cited sources say "extensive dermatitis" and
    "dermatitis" without characterising it as atopic, seborrhoeic, or
    contact dermatitis, and choosing one of those would assert more than the
    sources do.
  evidence:
  - reference: PMID:20301656
    reference_title: "Adenosine Deaminase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Untreated ADA-SCID presents as life-threatening opportunistic illnesses in the first weeks to months of life with poor linear growth and weight gain secondary to persistent diarrhea, extensive dermatitis, and recurrent pneumonia."
    explanation: Documents extensive dermatitis as a presenting feature of untreated ADA-SCID.
- category: Laboratory
  name: Hemolytic anemia
  description: >-
    Haemolytic anaemia is one of the non-immunological features that can point
    to untreated ADA deficiency, reflecting the systemic (not lymphoid-restricted)
    nature of the metabolic defect.
  subtype: ADA deficiency
  phenotype_term:
    preferred_term: Hemolytic anemia
    term:
      id: HP:0001878
      label: Hemolytic anemia
  evidence:
  - reference: PMID:20301656
    reference_title: "Adenosine Deaminase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skeletal abnormalities affecting ribs and vertebra, pulmonary alveolar proteinosis, hemolytic anemia, neurologic abnormalities, and transaminitis may also suggest untreated ADA-SCID."
    explanation: Lists haemolytic anaemia among the extra-immune features suggestive of untreated ADA-SCID.
- category: Imaging
  name: Pulmonary alveolar proteinosis
  description: >-
    Pulmonary alveolar proteinosis is a recognized non-infectious pulmonary
    complication of untreated ADA deficiency.
  subtype: ADA deficiency
  phenotype_term:
    preferred_term: Pulmonary alveolar proteinosis
    term:
      id: HP:0006517
      label: Intraalveolar phospholipid accumulation
  evidence:
  - reference: PMID:20301656
    reference_title: "Adenosine Deaminase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skeletal abnormalities affecting ribs and vertebra, pulmonary alveolar proteinosis, hemolytic anemia, neurologic abnormalities, and transaminitis may also suggest untreated ADA-SCID."
    explanation: Lists pulmonary alveolar proteinosis among the extra-immune features suggestive of untreated ADA-SCID.
- category: Clinical
  name: Cognitive impairment
  description: >-
    ADA-SCID patients score below the population average on IQ testing and also
    below other SCID groups receiving the same transplant treatment, and total IQ
    correlates inversely with the dATP level measured at diagnosis. That
    dissociation from the shared treatment is the argument that the deficit is
    metabolic rather than an artefact of transplantation.
  subtype: ADA deficiency
  phenotype_term:
    preferred_term: Below-average IQ
    term:
      id: HP:0100543
      label: Cognitive impairment
  notes: >-
    Bound to the general cognitive-impairment term rather than to intellectual
    disability: the source reports IQ distributions shifted below population and
    below-SCID-group averages, not a diagnosis of intellectual disability, and
    binding HP:0001249 would assert a threshold the source does not state.
  evidence:
  - reference: PMID:27579027
    reference_title: "Adenosine Deaminase Deficiency - More Than Just an Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Patients with ADA-SCID consistently achieve IQ scores that are not only below the population average but also below that of other SCID groups"
    explanation: >-
      Documents the cognitive deficit and its specificity to ADA deficiency
      within SCID, which is what makes it an extra-immune feature rather than a
      consequence of being a transplanted SCID patient.
- category: Clinical
  name: Hyperactivity
  description: >-
    Hyperactivity, attention deficit, aggression and social difficulty are
    reported across ADA-SCID cohorts, and track with the cognitive deficit:
    patients with lower IQ show more emotional and behavioural difficulty.
  subtype: ADA deficiency
  phenotype_term:
    preferred_term: Hyperactivity with attention deficit and behavioural difficulty
    term:
      id: HP:0000752
      label: Hyperactivity
  notes: >-
    One HPO term is bound for a cluster the source reports together
    (hyperactivity, attention deficits, aggressive behaviour, social problems).
    Hyperactivity is the element with the cleanest HPO match; the rest of the
    cluster is carried in preferred_term and the description rather than split
    into terms the source does not separately characterise.
  evidence:
  - reference: PMID:27579027
    reference_title: "Adenosine Deaminase Deficiency - More Than Just an Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "ADA-SCID patients exhibit hyperactivity, attention deficits, aggressive behavior, and social problems, scoring abnormally in all of these areas of behavior"
    explanation: >-
      Names the behavioural abnormalities this phenotype records.
- category: Clinical
  name: Sensorineural hearing loss
  description: >-
    Bilateral sensorineural deafness is reported as a non-immunological
    manifestation of ADA deficiency. In an audiologically assessed ADA-SCID
    transplant cohort the incidence was 58%, against 6% in patients transplanted
    for immunodeficiencies confined to the immune system; affected children had no
    identifiable genetic, structural, drug or infective cause, and some were
    transplanted without conditioning.
  subtype: ADA deficiency
  phenotype_term:
    preferred_term: Bilateral sensorineural deafness
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  notes: >-
    The 58% figure comes from 12 patients assessed after transplant with no
    pre-transplant audiology, so it cannot establish that the deafness predated
    treatment; the review's argument is the comparison against the transplanted
    control group and the absence of any other cause, not a before-and-after
    measurement.
  evidence:
  - reference: PMID:27579027
    reference_title: "Adenosine Deaminase Deficiency - More Than Just an Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "a 58% incidence was reported in the 12 patients who had undergone audiologic assessment in a study by Albuquerque and Gaspar"
    explanation: >-
      Quantifies the sensorineural deafness incidence in ADA-SCID that this
      phenotype records, and names the cohort it was measured in.
- category: Imaging
  name: Costochondral abnormalities
  description: >-
    Costochondral abnormality and skeletal dysplasia are commonly seen in ADA
    deficiency. Autopsy shows short growth plates with few proliferating and some
    hypertrophic chondrocytes, and ADA-deficient mice show reduced bone formation
    from impaired osteoblast function that neonatal enzyme replacement, transplant
    or gene therapy can correct.
  subtype: ADA deficiency
  phenotype_term:
    preferred_term: Costochondral abnormalities and skeletal dysplasia
    term:
      id: HP:0000919
      label: Abnormality of the costochondral junction
  notes: >-
    Bound to the general costochondral-junction term rather than to
    HP:0000920 (enlargement): enlarged costochondral junctions are the mouse
    finding, while the patient finding is reported as "costochondral
    abnormalities" without a specified direction. Attribution is also unsettled —
    bony pathology described as characteristic of ADA-SCID has been found, to a
    lesser degree, in patients with normal ADA activity, and the review states
    the causal assignment is unknown. Recorded as a REFUTE item on the causal
    edge rather than being left out of the entry.
  evidence:
  - reference: PMID:27579027
    reference_title: "Adenosine Deaminase Deficiency - More Than Just an Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "It is common for patients with ADA deficiency to display costochondral abnormalities and skeletal dysplasia"
    explanation: >-
      Documents the skeletal finding in patients that this phenotype records.
  - reference: PMID:20301656
    reference_title: "Adenosine Deaminase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skeletal abnormalities affecting ribs and vertebra, pulmonary alveolar proteinosis, hemolytic anemia, neurologic abnormalities, and transaminitis may also suggest untreated ADA-SCID."
    explanation: >-
      Independent GeneReviews confirmation that rib and vertebral abnormality is
      part of the untreated ADA-SCID picture.
- category: Laboratory
  name: Elevated hepatic transaminases
  description: >-
    Elevated serum transaminases of frequently unknown aetiology are reported in
    ADA deficiency, and hyperbilirubinaemia, hepatitis, liver stiffness, fatty
    liver and hepatomegaly have each been described in individual patients, with
    resolution on enzyme replacement.
  subtype: ADA deficiency
  phenotype_term:
    preferred_term: Elevated serum transaminases
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  notes: >-
    This is the thinnest of the extra-immune arms in humans and should not be read
    as equivalent to the auditory or neurocognitive evidence. The review states
    that hepatic dysfunction has rarely been reported in patients and that other
    supportive clinical data are hard to find; the strong hepatic phenotype —
    perinatally lethal hepatocyte degeneration — is murine and is explicitly not
    reproduced in patients.
  evidence:
  - reference: PMID:27579027
    reference_title: "Adenosine Deaminase Deficiency - More Than Just an Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "elevated serum transaminase levels may be seen in patients with ADA deficiency: this is indicative of liver damage and often etiology is unknown"
    explanation: >-
      Documents the transaminase elevation in patients that this phenotype
      records.
  - reference: PMID:27579027
    reference_title: "Adenosine Deaminase Deficiency - More Than Just an Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "the effects in ADA-deficient patients are not perinatally lethal and hepatic dysfunction has rarely been reported"
    explanation: >-
      Supports the rarity qualifier this phenotype's notes record, keeping the
      hepatic arm from reading as an established frequent feature.
- category: Clinical
  name: Autoimmunity
  description: >-
    Autoimmunity and immune dysregulation dominate the atypical (hypomorphic)
    end of the SCID spectrum rather than the typical infantile presentation:
    residual T-cell development permits autoreactivity that complete blocks do
    not.
  subtype: X-linked SCID
  phenotype_term:
    preferred_term: Autoimmunity
    term:
      id: HP:0002960
      label: Autoimmunity
  evidence:
  - reference: PMID:20301584
    reference_title: "X-Linked Severe Combined Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The phenotypic spectrum of X-linked severe combined immunodeficiency (X-SCID) ranges from typical X-SCID (early-onset disease in males that is fatal if not treated with hematopoietic stem cell transplantation [HSCT] or gene therapy) to atypical X-SCID (later-onset disease comprising phenotypes caused by variable immunodeficiency, immune dysregulation, and/or autoimmunity)."
    explanation: Places immune dysregulation and autoimmunity in the atypical, later-onset end of the X-SCID spectrum.
- category: Imaging
  name: Bronchiectasis
  description: >-
    Bronchiectasis follows years of recurrent upper and lower respiratory tract
    infection in atypical (later-onset) X-SCID, and is not a feature of typical
    infantile SCID, which is fatal before such damage accrues.
  subtype: X-linked SCID
  phenotype_term:
    preferred_term: Bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
  evidence:
  - reference: PMID:20301584
    reference_title: "X-Linked Severe Combined Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "recurrent upper and lower respiratory tract infections with bronchiectasis; Omenn syndrome, a clinical phenotype caused by immune dysregulation; X-SCID combined immunodeficiency (often with recurrent infections, warts, and dermatitis); immune dysregulation and autoimmunity; or Epstein-Barr virus-related lymphoproliferative complications."
    explanation: Lists bronchiectasis with recurrent respiratory infection as one of the atypical X-SCID presentations.
treatments:
- name: Hematopoietic stem cell transplantation
  description: >-
    Allogeneic hematopoietic stem cell transplantation is the definitive curative
    treatment for SCID, reconstituting a functional immune system; outcomes are best
    when performed early, before the onset of infections.
  therapeutic_modality: CELL_THERAPY
  treatment_term:
    preferred_term: hematopoietic stem cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: Blocked T-lymphocyte development
    treatment_effect: RESTORES
    description: Donor hematopoietic stem cells reconstitute thymic T-cell development and adaptive immunity.
  notes: >-
    Conditioning is genotype-dependent, not one protocol for all SCID. In the
    radiosensitive DNA-repair subtypes (Artemis/DCLRE1C, and by the same logic
    LIG4, NHEJ1, PRKDC) alkylator-based conditioning carries increased toxicity
    and is preferably avoided, which is one of the practical reasons a molecular
    diagnosis is sought before transplant rather than after.
  evidence:
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Haematopoietic stem cell transplantation (HSCT) is the treatment of choice."
    explanation: HSCT is the curative treatment of choice for SCID.
  - reference: PMID:25138334
    reference_title: "Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "overall SCID survival was 45 of 52 (87%), while 45 of 49 treated infants (92%) survived"
    explanation: >-
      Quantifies the survival achieved when SCID is detected by newborn
      screening and treated early, supporting the claim that outcomes are best
      when transplant precedes infection.
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "radiosensitive forms of SCID are prone to develop increased toxicity to alkylator-based chemotherapeutic agents used in the conditioning regimen for HSCT"
    explanation: >-
      Qualifies the treatment: the conditioning regimen must be adapted in
      radiosensitive genotypes, so HSCT is not uniformly deliverable across SCID
      subtypes.
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pre-transplant conditioning regimens are preferably avoided in patients with radiosensitive forms of SCID."
    explanation: States the genotype-specific management consequence recorded in this treatment's notes.
- name: Hematopoietic stem cell gene therapy
  description: >-
    Autologous hematopoietic stem cell gene therapy corrects the causative gene in
    the patient's own stem cells; it is an established alternative to allogeneic HSCT
    for ADA-SCID (Strimvelis) and has shown clinical success for X-linked and other
    SCID forms.
  treatment_term:
    preferred_term: gene therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  therapeutic_modality: GENE_THERAPY
  target_mechanisms:
  - target: Blocked T-lymphocyte development
    treatment_effect: RESTORES
    description: Gene-corrected autologous stem cells restore lymphocyte development and adaptive immunity.
  evidence:
  - reference: PMID:38355973
    reference_title: "Long-term and real-world safety and efficacy of retroviral gene therapy for adenosine deaminase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Long-term persistence of multilineage gene-corrected cells, metabolic detoxification, immune reconstitution and decreased infection rates were observed."
    explanation: Retroviral hematopoietic stem cell gene therapy provides durable multilineage engraftment, immune reconstitution, and reduced infections in ADA-SCID.
  - reference: PMID:38355973
    reference_title: "Long-term and real-world safety and efficacy of retroviral gene therapy for adenosine deaminase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "2 years intervention-free survival (no need for long-term enzyme replacement therapy or allogeneic hematopoietic stem cell transplantation) of 88% (95% confidence interval 78.7-98.4%)"
    explanation: >-
      Quantifies the durability of the benefit — the proportion of treated
      patients needing neither ongoing ERT nor rescue allogeneic transplant.
  - reference: PMID:38355973
    reference_title: "Long-term and real-world safety and efficacy of retroviral gene therapy for adenosine deaminase deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One patient from the named patient program developed a T cell leukemia related to treatment 4.7 years after GT and is currently in remission."
    explanation: >-
      Records the insertional-oncogenesis risk of retroviral gene therapy — a
      treatment-related leukaemia in the long-term cohort — so the entry does
      not present gene therapy as risk-free.
  notes: >-
    Retroviral vectors carry an insertional-oncogenesis risk that is not
    hypothetical: one treatment-related T-cell leukaemia occurred in the 43-patient
    long-term ADA-SCID cohort. The authors nonetheless judge the risk-benefit
    balance favourable and call for continued long-term safety monitoring.
- name: Enzyme replacement therapy with pegademase (PEG-ADA)
  description: >-
    For ADA deficiency, enzyme replacement therapy with PEGylated adenosine
    deaminase corrects the metabolic defect, providing protection against infection;
    it is often used to stabilize patients before curative HSCT or gene therapy.
  treatment_term:
    preferred_term: enzyme replacement or supplementation therapy
    term:
      id: NCIT:C16221
      label: Protein Replacement Therapy
    therapeutic_agent:
    - preferred_term: pegademase bovine
      term:
        id: NCIT:C77484
        label: Pegademase Bovine
  target_mechanisms:
  - target: Toxic purine metabolite accumulation
    treatment_effect: INHIBITS
    description: Exogenous PEGylated ADA clears toxic deoxyadenosine/adenosine, correcting the lymphotoxic metabolic defect.
  evidence:
  - reference: PMID:20301656
    reference_title: "Adenosine Deaminase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "enzyme replacement therapy (ERT) by intramuscular administration of PEGylated ADA"
    explanation: Enzyme replacement therapy with PEGylated ADA is a targeted treatment correcting the ADA metabolic defect.
  - reference: PMID:20301656
    reference_title: "Adenosine Deaminase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Often, ERT is initiated first to rapidly correct the metabolic defect and to protect against serious infections as well as neurologic/behavioral abnormalities. It is discontinued at the time HSCT or HSC-GT is performed."
    explanation: >-
      Supports the bridging role asserted in this treatment's description, and
      specifies that ERT is stopped once curative therapy is delivered rather
      than continued alongside it.
  notes: >-
    ERT is a bridge, not an endpoint: it is started to correct the metabolite
    burden quickly and is discontinued when HSCT or gene therapy is performed.
    Prolonged ERT with declining lymphocyte counts is itself a trigger for
    lymphoma surveillance.
- name: Immunoglobulin replacement therapy
  description: >-
    Intravenous (or subcutaneous) immunoglobulin replacement provides passive humoral
    protection while patients await or recover from definitive immune reconstitution.
  treatment_term:
    preferred_term: immunoglobulin infusion therapy
    term:
      id: NCIT:C62710
      label: Immunoglobulin Therapy
  target_phenotypes:
  - preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: PMID:20301656
    reference_title: "Adenosine Deaminase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "use of immunoglobulin infusions and antibiotics, particularly prophylaxis against Pneumocystis jirovecii pneumonia"
    explanation: Immunoglobulin infusions are an explicit part of supportive management for the profound antibody deficiency seen in SCID.
- name: Pneumocystis jirovecii pneumonia prophylaxis
  description: >-
    Antimicrobial prophylaxis, particularly against Pneumocystis jirovecii pneumonia,
    is a standard supportive measure to prevent opportunistic infection pending
    immune reconstitution.
  treatment_term:
    preferred_term: antimicrobial agent therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_phenotypes:
  - preferred_term: Pneumonia
    term:
      id: HP:0002090
      label: Pneumonia
  evidence:
  - reference: PMID:20301656
    reference_title: "Adenosine Deaminase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "particularly prophylaxis against Pneumocystis jirovecii pneumonia (formerly Pneumocystis carinii) and fungal infections"
    explanation: Prophylaxis against Pneumocystis jirovecii pneumonia is a standard supportive measure in SCID.
- name: Protective isolation and avoidance of live vaccines and non-irradiated blood products
  description: >-
    Until immune reconstitution is achieved, exposure avoidance is itself
    treatment. Live viral vaccines — given to the infant or to household contacts
    — can cause disseminated vaccine-strain disease; non-irradiated blood products
    can cause transfusion-associated graft-versus-host disease in a patient with
    no T cells to reject donor lymphocytes; and breast milk is withheld pending
    maternal CMV status. Live rotavirus vaccine is the specific exposure that
    newborn-screening programmes act on first, because it is administered at the
    age at which screened infants are still awaiting definitive therapy.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: infection-exposure avoidance and protective isolation
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: PMID:20301584
    reference_title: "X-Linked Severe Combined Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "live viral vaccines for the affected individual as well as household contacts; transfusion of non-irradiated blood products"
    explanation: >-
      Names the two exposures this treatment exists to prevent, including the
      household-contact extension of the live-vaccine restriction.
  - reference: PMID:25138334
    reference_title: "Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All infants with T-cell lymphopenia were directed to avoid infectious exposures, transfusions (except with cytomegalovirus-negative, irradiated blood products), and live rotavirus vaccines until such time as immune compromise was no longer present."
    explanation: >-
      Documents this as applied practice across 11 newborn-screening programmes,
      including the CMV-negative irradiated-product qualifier and the
      live-rotavirus-vaccine restriction.
prevalence:
- population: United States (11 TREC newborn-screening programs, 3,030,083 infants)
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 1.7
  rate_low: 1.25
  rate_high: 2.17
  notes: >-
    Population-based TREC newborn screening across 11 US programs identified
    SCID in 1 in 58,000 infants (95% CI 1/46,000-1/80,000), i.e. 1.7 per
    100,000 (CI 1.25-2.17). This is substantially higher than the ~1 in 100,000
    incidence previously inferred from retrospective clinical diagnoses,
    reflecting under-ascertainment of infants who died of infection before
    diagnosis.
  evidence:
  - reference: PMID:25138334
    reference_title: "Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Newborn screening in 11 programs in the United States identified SCID in 1 in 58 000 infants, with high survival."
    explanation: Provides the population-based US birth prevalence of SCID from universal TREC newborn screening.
  - reference: PMID:25138334
    reference_title: "Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Newborn screening has provided a new, population-based incidence of SCID of 1 in 58 000 births, higher than the incidence of 1 in 100 000 suggested from retrospective clinical diagnoses."
    explanation: Documents that newborn screening revised the SCID incidence upward relative to retrospective clinical ascertainment.
  - reference: PMID:33551023
    reference_title: "SCID newborn screening: What we've learned."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "by 2019 all states in the United States had adopted versions of it in their public health programs"
    explanation: >-
      Supports the universality of US TREC newborn screening (the basis for
      population-level ascertainment) but does not itself report an incidence
      figure; it was previously cited as the source of the 1/58,000 number,
      which it does not contain.
- population: Navajo Nation (Navajo Area Indian Health Service TREC screening)
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 28.6
  rate_low: 25.0
  rate_high: 158.7
  notes: >-
    A founder effect, not a different disease. SCID birth prevalence in the
    Navajo Nation is roughly 1 in 3,500 (95% CI 1/630-1/4,000), about seventeen
    times the overall US screened rate, driven by a frequent DCLRE1C (Artemis)
    founder variant estimated to cause SCID in 1 in 2,000 births. Rates
    converted from the reported 1-in-N figures; the confidence interval is wide
    because the screened denominator is small.
  evidence:
  - reference: PMID:25138334
    reference_title: "Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The incidence was not significantly different in any state program but as expected was higher in the Navajo Nation (1/3500; 95%CI, 1/630-1/4000), where a frequent founder mutation in DCLRE1C, encoding a DNA repair protein, causes SCID in an estimated 1 in 2000 births."
    explanation: Gives the Navajo Nation birth prevalence, its confidence interval, and the DCLRE1C founder variant responsible.
- population: Worldwide (literature estimate, per live birth)
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 1.9
  rate_low: 1.33
  rate_high: 2.5
  notes: >-
    Review estimate of 1 in 40,000 to 1 in 75,000 live births (1.33-2.5 per
    100,000), recorded alongside the US screened figure because it is derived
    from the literature rather than from a single screened population. It is
    consistent with the 1-in-58,000 US newborn-screening result and above the
    older 1-in-100,000 retrospective clinical estimate.
  evidence:
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The incidence of SCID varies between 1 in 40,000 to 75,000 per live birth."
    explanation: Supplies the worldwide literature range for SCID birth incidence.
progression:
- phase: Onset of symptoms in infancy
  age_range: First months of life
  notes: >-
    In a 277-child Indian multi-institutional cohort the median age of symptom
    onset was 2.5 months and the median age at diagnosis 5 months — a roughly
    2.5-month diagnostic lag during which infants are unprotected.
  evidence:
  - reference: PMID:33628209
    reference_title: "Clinical, Immunological, and Molecular Features of Severe Combined Immune Deficiency: A Multi-Institutional Experience From India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Median (inter-quartile range) age of onset of clinical symptoms and diagnosis was 2.5 months (1, 5) and 5 months (3.5, 8), respectively."
    explanation: Gives the median ages of symptom onset and of diagnosis in a large clinically ascertained SCID cohort.
- phase: Clinical presentation before newborn screening
  subtype: X-linked SCID
  age_range: Three to six months
  notes: >-
    The historical presentation, and still the presentation wherever TREC
    screening is not in place: infants come to attention only once recurrent,
    persistent, or opportunistic infection has begun.
  evidence:
  - reference: PMID:20301584
    reference_title: "X-Linked Severe Combined Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prior to universal newborn screening (NBS) for SCID most males with typical X-SCID came to medical attention between ages three and six months because of recurrent infections, persistent infections, and infections with opportunistic organisms."
    explanation: Gives the pre-screening age and mode of presentation for typical X-SCID.
- phase: Presymptomatic detection by newborn screening
  subtype: X-linked SCID
  age_range: First weeks of life
  notes: >-
    Newborn screening did not just move diagnosis earlier, it changed what the
    disease looks like at presentation: the typical index case is now a
    well-appearing infant with an abnormal TREC result rather than a sick one.
  evidence:
  - reference: PMID:20301584
    reference_title: "X-Linked Severe Combined Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "With universal NBS for SCID, the common presentation for typical X-SCID is now an asymptomatic, healthy-appearing male infant."
    explanation: Documents the shift to presymptomatic presentation under universal newborn screening.
- phase: Later-onset atypical disease
  subtype: X-linked SCID
  age_range: First years of life or later
  notes: >-
    Hypomorphic IL2RG alleles produce a later-onset spectrum that newborn
    screening usually does not catch, dominated by immune dysregulation rather
    than by the absent-immunity picture of typical SCID.
  evidence:
  - reference: PMID:20301584
    reference_title: "X-Linked Severe Combined Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The phenotypic spectrum of X-linked severe combined immunodeficiency (X-SCID) ranges from typical X-SCID (early-onset disease in males that is fatal if not treated with hematopoietic stem cell transplantation [HSCT] or gene therapy) to atypical X-SCID (later-onset disease comprising phenotypes caused by variable immunodeficiency, immune dysregulation, and/or autoimmunity)."
    explanation: Defines the typical/atypical split and places atypical disease at later onset.
  - reference: PMID:20301584
    reference_title: "X-Linked Severe Combined Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "recurrent upper and lower respiratory tract infections with bronchiectasis; Omenn syndrome, a clinical phenotype caused by immune dysregulation; X-SCID combined immunodeficiency (often with recurrent infections, warts, and dermatitis); immune dysregulation and autoimmunity; or Epstein-Barr virus-related lymphoproliferative complications."
    explanation: Enumerates the specific later-onset atypical X-SCID presentations.
- phase: Death in infancy without immune reconstitution
  age_range: First one to two years
  notes: >-
    Untreated SCID is uniformly fatal in early childhood; the ADA-SCID figure
    below is the best-quantified example.
  evidence:
  - reference: PMID:20301656
    reference_title: "Adenosine Deaminase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "If immune function is not restored with enzyme replacement therapy (ERT), gene therapy, or hematopoietic stem cell transplantation (HSCT), children with ADA-SCID rarely survive beyond age one to two years."
    explanation: States the untreated natural history and the three interventions that alter it.
clinical_burden:
  burden_level: HIGH
  rationale: >-
    Untreated SCID is fatal in infancy, and the only treatments that change that
    are transplantation, gene therapy, or (for ADA) enzyme replacement — each of
    which requires specialist centres, conditioning chemotherapy, and prolonged
    protective isolation. Where those services are not readily accessible the
    burden is starkly visible: in a 277-child Indian cohort only 8.3% reached
    transplant and 75.8% died. Where newborn screening and transplant are
    available, survival exceeds 85%, so the burden is dominated by access and by
    time-to-diagnosis rather than by any intrinsic untreatability.
  evidence:
  - reference: PMID:33628209
    reference_title: "Clinical, Immunological, and Molecular Features of Severe Combined Immune Deficiency: A Multi-Institutional Experience From India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Only 23 children (8.3%) received hematopoietic stem cell transplantation (HSCT). Of these, 11 are doing well post-HSCT. Mortality was recorded in 210 children (75.8%)."
    explanation: Quantifies mortality and the low proportion reaching curative therapy in a setting without newborn screening.
  - reference: PMID:25138334
    reference_title: "Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "overall SCID survival was 45 of 52 (87%), while 45 of 49 treated infants (92%) survived"
    explanation: Gives the contrasting survival achievable with newborn screening and prompt definitive therapy.
diagnosis:
- name: Lymphocyte subset flow cytometry
  description: >-
    Flow cytometric enumeration of T, B, and NK cells — with naive/memory CD4
    subsetting — is the confirmatory test after an abnormal newborn screen and
    the routine route to diagnosis outside screening programmes. The T/B/NK
    pattern also assigns the likely mechanism class before sequencing returns.
  diagnosis_term:
    preferred_term: flow cytometry procedure
    term:
      id: NCIT:C16585
      label: Flow Cytometry
  evidence:
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Though the diagnosis of SCID is usually established by flow cytometry-based tests, genetic diagnosis is often needed for genetic counselling, prognostication, and modification of pre-transplant chemotherapeutic agents."
    explanation: Establishes flow cytometry as the usual diagnostic modality and states why genetic testing is still required.
- name: TREC newborn screening
  description: >-
    Quantification of T-cell receptor excision circles by PCR on Guthrie-card
    dried blood spots detects failed thymic T-cell output before infection
    begins. It is the first immune disorder accepted for population-based
    screening and is now universal across US states. The result is a TREC
    copy number per microlitre of blood, read against a beta-actin
    amplification control for sample quality, and the abnormal direction is
    low: undetectable or very low TRECs are the positive result. Cut-offs
    and retest rules differ by programme and assay, and several programmes
    set a lower first-sample threshold for preterm infants, whose TREC values
    are lower at birth and rise with maturation.
  diagnosis_term:
    preferred_term: newborn screening
    term:
      id: NCIT:C81178
      label: Newborn Screening
  measurements:
  - preferred_term: SCID newborn screening panel
    term:
      id: LOINC:62333-0
      label: Severe combined immunodeficiency (SCID) newborn screening panel
  - preferred_term: T-cell receptor excision circles (TREC), DBS
    term:
      id: LOINC:62320-7
      label: T-cell receptor excision circle [#/volume] in DBS by NAA with probe detection
  - preferred_term: SCID newborn screen interpretation
    term:
      id: LOINC:62321-5
      label: Severe combined immunodeficiency newborn screen interpretation
  reference_ranges:
  - loinc_term:
      id: LOINC:62320-7
      label: T-cell receptor excision circle [#/volume] in DBS by NAA with probe detection
    unit: '{copies}/uL'
    population: >-
      term newborns, Catalonia (Spain) universal SCID newborn-screening
      programme, EnLite Neonatal TREC assay, 2017-2023 (retest threshold as
      set in 2018)
    notes: >-
      The programme's detection cut-off is 20 copies/µL throughout 2017-2023.
      Its decision algorithm, as published for 2017-2018, is tiered: a first
      sample at or below 10 copies/µL in a term newborn (with beta-actin at or
      above 50 copies/µL as the quality criterion) is a positive detection
      outright; a first sample at or below the retest threshold (34
      copies/µL in 2017, 24 from 2018) is retested in duplicate, and if two of
      the three values are at or below 20 copies/µL a second sample is
      requested, which is positive at or below 20 copies/µL. The source's
      thresholds are inclusive ("at or below"), so a value of exactly 10, 20 or
      24 falls one band lower in the source than in the half-open bands here;
      the boundaries are kept as stated rather than shifted. Preterm infants
      have their own first-sample threshold, recorded as a separate range.
      The TREC code is method-specific (nucleic acid amplification with probe
      detection) because LOINC's only DBS copy-number code for TRECs names the
      method, and quantitative PCR is the method the measurement is defined
      by; the Monarch KG search "T-cell receptor excision circle DBS" returned
      no method-less copy-number code.
    evidence:
    - reference: PMID:42079620
      reference_title: "SCID newborn screening: seven-year performance and outcomes including T-cell lymphopenia in Catalonia (Spain)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Newborns were screened for SCID using the EnLite Neonatal TREC assay (cut-off: 20 copies/μL), with confirmatory immunological and genetic testing performed in screen-positive cases."
      explanation: States the programme's assay and its 20 copies/µL detection cut-off over the seven-year period.
    - reference: PMID:42079620
      reference_title: "SCID newborn screening: seven-year performance and outcomes including T-cell lymphopenia in Catalonia (Spain)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This study summarizes the results of the consolidated SCID newborn screening (NBS) program in Catalonia (Spain) during the first seven years of program implementation (2017-2023)."
      explanation: Names the programme and the period the cut-off applies to.
    - reference: PMID:31695692
      reference_title: "First Universal Newborn Screening Program for Severe Combined Immunodeficiency in Europe. Two-Years' Experience in Catalonia (Spain)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Samples with TRECs ≤ 5 copies/μL (preterm infants) or ≤ 10 copies/μL (term newborns) in the first sample (both with beta-actin gene ≥50 copies/μL), as well as analyses with TRECs ≤ 20 copies/μL in the second sample, were considered as positive detection (retest cutoff changed from 34 to 24 copies/μL in 2018)."
      explanation: States the tiered first-sample and second-sample positive thresholds, the beta-actin quality criterion and the 2018 retest threshold that the bands encode.
    - reference: PMID:31695692
      reference_title: "First Universal Newborn Screening Program for Severe Combined Immunodeficiency in Europe. Two-Years' Experience in Catalonia (Spain)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Samples whose TREC value was ≤ 34 copies/μL were retested in duplicate. If two of the three values were ≤ 20 copies/μL, a second sample was requested."
      explanation: States the retest-in-duplicate step and the rule for requesting a second sample.
    - reference: PMID:31695692
      reference_title: "First Universal Newborn Screening Program for Severe Combined Immunodeficiency in Europe. Two-Years' Experience in Catalonia (Spain)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The detection cutoff of 20 copies/μL remained the same (0.7th percentile)"
      explanation: Confirms that lowering the retest threshold in 2018 left the 20 copies/µL detection cut-off unchanged, and gives its population percentile.
    interpretation_bands:
    - name: Positive on first sample
      upper_bound: 10
      unit: '{copies}/uL'
      abnormal_flag: CRITICAL_LOW
      interpretation: >-
        Notified to the clinical reference unit for lymphocyte phenotyping
        without waiting for a second sample.
    - name: Second sample requested
      lower_bound: 10
      upper_bound: 20
      unit: '{copies}/uL'
      abnormal_flag: LOW
      interpretation: >-
        Retested in duplicate; if two of three values are at or below 20
        copies/µL a second dried blood spot is requested, and a second sample
        at or below 20 copies/µL is a positive detection.
    - name: Retest in duplicate
      lower_bound: 20
      upper_bound: 24
      unit: '{copies}/uL'
      interpretation: >-
        Below the 2018 retest threshold but above the detection cut-off; the
        sample is re-run in duplicate and proceeds only if the repeat values
        fall to 20 copies/µL or below.
    - name: Screen negative
      lower_bound: 24
      unit: '{copies}/uL'
      abnormal_flag: NORMAL
  - loinc_term:
      id: LOINC:62320-7
      label: T-cell receptor excision circle [#/volume] in DBS by NAA with probe detection
    unit: '{copies}/uL'
    population: >-
      preterm infants, Catalonia (Spain) universal SCID newborn-screening
      programme, EnLite Neonatal TREC assay, 2017-2023 (retest threshold as
      set in 2018)
    notes: >-
      Same programme, assay, retest threshold and second-sample rule as the
      term-newborn range; only the first-sample positive threshold differs,
      at or below 5 copies/µL for preterm infants against 10 for term
      newborns. The source does not define "preterm" by gestational age in
      the sentence quoted. Inclusive thresholds in the source versus half-open
      bands here, as for the term range.
    evidence:
    - reference: PMID:31695692
      reference_title: "First Universal Newborn Screening Program for Severe Combined Immunodeficiency in Europe. Two-Years' Experience in Catalonia (Spain)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Samples with TRECs ≤ 5 copies/μL (preterm infants) or ≤ 10 copies/μL (term newborns) in the first sample (both with beta-actin gene ≥50 copies/μL), as well as analyses with TRECs ≤ 20 copies/μL in the second sample, were considered as positive detection (retest cutoff changed from 34 to 24 copies/μL in 2018)."
      explanation: States the preterm first-sample threshold of 5 copies/µL beside the term threshold.
    - reference: PMID:42079620
      reference_title: "SCID newborn screening: seven-year performance and outcomes including T-cell lymphopenia in Catalonia (Spain)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Newborns were screened for SCID using the EnLite Neonatal TREC assay (cut-off: 20 copies/μL), with confirmatory immunological and genetic testing performed in screen-positive cases."
      explanation: States the assay and the 20 copies/µL detection cut-off shared by both strata.
    interpretation_bands:
    - name: Positive on first sample
      upper_bound: 5
      unit: '{copies}/uL'
      abnormal_flag: CRITICAL_LOW
      interpretation: >-
        Notified to the clinical reference unit for lymphocyte phenotyping
        without waiting for a second sample.
    - name: Second sample requested
      lower_bound: 5
      upper_bound: 20
      unit: '{copies}/uL'
      abnormal_flag: LOW
      interpretation: >-
        Retested in duplicate; if two of three values are at or below 20
        copies/µL a second dried blood spot is requested, which in a preterm
        infant is often taken at term or once birth weight exceeds 2,500 g.
    - name: Retest in duplicate
      lower_bound: 20
      upper_bound: 24
      unit: '{copies}/uL'
      interpretation: >-
        Below the 2018 retest threshold but above the detection cut-off; re-run
        in duplicate.
    - name: Screen negative
      lower_bound: 24
      unit: '{copies}/uL'
      abnormal_flag: NORMAL
  notes: >-
    The assay measures a by-product of T-cell receptor recombination, so it is
    blind to defects acting *after* that step. MHC class II deficiency, ZAP70
    deficiency, and late-onset ADA deficiency can all screen normal — a real
    false-negative class rather than an assay-quality problem. The panel code
    identifies the test and the TREC copy-number code carries the cut-offs;
    the interpretation code is the programme's reported call. Kappa-deleting
    recombination excision circles (KREC), which some programmes run with
    TREC, are not bound: the Monarch KG search "Kappa-deleting recombination
    excision circle" returned nothing, and the entry's screening row describes
    TREC alone.
  evidence:
  - reference: PMID:31695692
    reference_title: "First Universal Newborn Screening Program for Severe Combined Immunodeficiency in Europe. Two-Years' Experience in Catalonia (Spain)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TREC quantification in DBS (1.5 mm diameter) was performed with the Enlite Neonatal TREC kit from PerkinElmer (Turku, Finland)."
    explanation: Names the assay and punch size behind the Catalonian cut-offs.
  - reference: PMID:31695692
    reference_title: "First Universal Newborn Screening Program for Severe Combined Immunodeficiency in Europe. Two-Years' Experience in Catalonia (Spain)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In relation to gestational age, the median TREC value demonstrated a progressive increase: 70 (43–127), 96 (62–155), and 105 (68–162) copies/μL in extremely preterm, preterm, and term newborns, respectively"
    explanation: Supports the statement that preterm infants have lower TREC values at birth that rise with maturation, which is why the programme stratifies its first-sample threshold.
  - reference: PMID:31695692
    reference_title: "First Universal Newborn Screening Program for Severe Combined Immunodeficiency in Europe. Two-Years' Experience in Catalonia (Spain)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cautious evaluation and a request for a second sample are needed at term and when birth weight reaches >2,500 g, respectively"
    explanation: Supports the timing of the second sample in preterm and low-birth-weight infants given in the preterm band.
  - reference: PMID:33551023
    reference_title: "SCID newborn screening: What we've learned."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The T-cell receptor excision circle test, developed in 2005, proved to be successful in pilot studies starting in the period 2008 to 2010, and by 2019 all states in the United States had adopted versions of it in their public health programs."
    explanation: Documents the TREC test and its adoption as universal US newborn screening.
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Assessment of T cell receptor excision circles (TRECs) in the dried blood spots is an effective screening method developed in the United States for the identification of infants with SCID patients and other forms of T-cell lymphopenia."
    explanation: Describes the assay substrate and its target condition.
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "normal TREC levels can be seen in defects of lymphocyte maturation beyond VDJ recombination steps such as ZAP70 defect and MHC class II deficiency"
    explanation: Records the systematic blind spot of TREC screening noted for this test.
  - reference: PMID:25138334
    reference_title: "Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "more than 80% lack a positive family history"
    explanation: >-
      Explains why population-wide screening rather than targeted family testing
      is required: most affected infants have no family history to prompt it.
- name: Molecular genetic testing
  description: >-
    Sanger or next-generation sequencing identifies the causative gene. Beyond
    confirming the diagnosis, the genotype changes management: it determines
    genetic counselling, prognosis, and whether alkylator-based pre-transplant
    conditioning is safe.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic diagnosis can be established by Sanger or Next-Generation sequencing (NGS)."
    explanation: Names the sequencing modalities used for molecular diagnosis of SCID.
  - reference: PMID:32181275
    reference_title: "Genetics of severe combined immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Though the diagnosis of SCID is usually established by flow cytometry-based tests, genetic diagnosis is often needed for genetic counselling, prognostication, and modification of pre-transplant chemotherapeutic agents."
    explanation: Supports the three management consequences of the genotype asserted in this description.
- name: ADA enzyme and metabolite testing
  description: >-
    ADA deficiency has a biochemical diagnosis independent of the immune
    phenotype: red-cell ADA catalytic activity below 1%, or elevated adenosine
    and deoxyadenosine on tandem mass spectrometry. The metabolite assay also
    detects the later-onset ADA-CID cases that TREC screening misses.
  diagnosis_term:
    preferred_term: biochemical enzyme and metabolite assay
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  notes: >-
    `diagnosis_term` is bound to a generic NCIT action term because NCIT has no
    clinical-action term for red-cell enzyme activity or tandem
    mass-spectrometry metabolite quantitation specific enough to be worth
    asserting; the free-text `preferred_term` carries the actual test.
  evidence:
  - reference: PMID:20301656
    reference_title: "Adenosine Deaminase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of ADA deficiency is established in a proband with suggestive findings either by biochemical testing showing <1% of ADA catalytic activity in red blood cells or in extracts of dried blood spots (valid in untransfused individuals), or by molecular genetic testing identifying biallelic pathogenic variants in ADA."
    explanation: Gives the biochemical diagnostic threshold and its molecular alternative.
  - reference: PMID:20301656
    reference_title: "Adenosine Deaminase Deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Screening specific for ADA deficiency can also be performed by detection of elevated levels of adenosine (Ado) and deoxyadenosine (dAdo) by tandem mass spectrometry (TMS)."
    explanation: Documents the tandem mass-spectrometry metabolite screen for ADA deficiency.
definitions:
- name: PIDTC 2022 typical SCID criteria
  definition_type: DIAGNOSTIC_CRITERIA
  derivation_basis: ESTABLISHED_CRITERIA
  description: >-
    Typical SCID requires fewer than 0.05 x 10^9 autologous T cells/L on
    repetitive testing, plus at least one of: a pathogenic variant in a
    SCID-associated gene; very low or undetectable TRECs or under 20% of CD4 T
    cells expressing naive markers; or transplacentally engrafted maternal T
    cells.
  evidence:
  - reference: PMID:36456361
    reference_title: "The diagnosis of severe combined immunodeficiency (SCID): The Primary Immune Deficiency Treatment Consortium (PIDTC) 2022 Definitions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with typical SCID must have less than 0.05 × 109 autologous T cells/L on repetitive testing, with either pathogenic variant(s) in a SCID-associated gene, very low/undetectable T-cell receptor excision circles or less than 20% of CD4 T cells expressing naive markers, and/or transplacental maternally engrafted T cells."
    explanation: The PIDTC 2022 consensus definition of typical SCID quoted verbatim.
- name: PIDTC 2022 leaky/atypical SCID criteria
  definition_type: DIAGNOSTIC_CRITERIA
  derivation_basis: ESTABLISHED_CRITERIA
  description: >-
    Leaky/atypical SCID covers patients with less profoundly impaired autologous
    T-cell differentiation, requiring two or more of: low T-cell numbers,
    oligoclonal T cells, low TRECs, and under 20% of CD4 T cells expressing naive
    markers, together with either a pathogenic SCID-gene variant or reduced
    T-cell proliferation to certain mitogens.
  evidence:
  - reference: PMID:36456361
    reference_title: "The diagnosis of severe combined immunodeficiency (SCID): The Primary Immune Deficiency Treatment Consortium (PIDTC) 2022 Definitions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with less profoundly impaired autologous T-cell differentiation are designated as having leaky/atypical SCID, with 2 or more of these: low T-cell numbers, oligoclonal T cells, low T-cell receptor excision circles, and less than 20% of CD4 T cells expressing naive markers."
    explanation: The PIDTC 2022 consensus definition of leaky/atypical SCID quoted verbatim.
- name: PIDTC 2022 Omenn syndrome criteria
  definition_type: DIAGNOSTIC_CRITERIA
  derivation_basis: ESTABLISHED_CRITERIA
  description: >-
    Omenn syndrome requires a generalized erythematous rash and absent
    transplacentally acquired maternal engraftment, plus two or more of
    eosinophilia, elevated IgE, lymphadenopathy, and hepatosplenomegaly.
  evidence:
  - reference: PMID:36456361
    reference_title: "The diagnosis of severe combined immunodeficiency (SCID): The Primary Immune Deficiency Treatment Consortium (PIDTC) 2022 Definitions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Omenn syndrome requires a generalized erythematous rash, absent transplacentally acquired maternal engraftment, and 2 or more of these: eosinophilia, elevated IgE, lymphadenopathy, hepatosplenomegaly."
    explanation: The PIDTC 2022 consensus definition of Omenn syndrome quoted verbatim.
- name: PIDTC 2022 scope exclusion
  definition_type: CASE_DEFINITION
  derivation_basis: ESTABLISHED_CRITERIA
  description: >-
    Thymic stromal defects and other causes of secondary T-cell deficiency are
    excluded from the definition of SCID. This is why complete DiGeorge syndrome
    and FOXN1 athymia, which also present with profound T-cell lymphopenia and an
    absent thymic shadow, are not curated as SCID subtypes here.
  evidence:
  - reference: PMID:36456361
    reference_title: "The diagnosis of severe combined immunodeficiency (SCID): The Primary Immune Deficiency Treatment Consortium (PIDTC) 2022 Definitions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Thymic stromal defects and other causes of secondary T-cell deficiency are excluded from the definition of SCID."
    explanation: States the boundary the consensus definition draws around SCID.
discussions:
- discussion_id: ada_extraimmune_mechanism
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    By what route do accumulating purine metabolites damage the brain, cochlea
    and growth plate in ADA deficiency, and is that route the same one that kills
    thymocytes?
  attaches_to:
  - pathophysiology#Non-lymphoid tissue purine metabolite toxicity
  rationale: >-
    The extra-immune features are established as features — they are more
    frequent in ADA deficiency than in other SCID subtypes receiving the same
    treatment, they occur in children transplanted without conditioning, and IQ
    correlates inversely with diagnostic dATP. What is missing is the mechanism
    connecting metabolite to organ. The review this node is built from says the
    mechanism of the neurological pathology has not been investigated, and
    proposes dATP neurotoxicity by analogy with the immune system as an untested
    possibility. The two molecular routes bound on the node — SAH hydrolase
    inactivation and ribonucleotide reductase inhibition — are characterised in
    lymphocytes and carried across on the strength of ubiquitous ADA expression,
    which is an inference rather than a measurement. This matters clinically
    because current therapies correct the immune phenotype while leaving the
    neurological one: six of twelve patients showed distinct neurological
    abnormality at a mean twelve years of follow-up despite complete immune
    reconstitution.
  evidence:
  - reference: PMID:27579027
    reference_title: "Adenosine Deaminase Deficiency - More Than Just an Immunodeficiency."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Current research has not, so far, investigated the mechanism of pathology. One possibility is that the accumulation of dATP causes neurotoxic effects by a similar mechanism elucidated in the immune system"
    explanation: >-
      States the gap directly: the mechanism of the CNS pathology is
      uninvestigated, and the immune-system analogy is offered as a hypothesis.
  - reference: PMID:27579027
    reference_title: "Adenosine Deaminase Deficiency - More Than Just an Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "neurological abnormalities are far more prevalent in ADA-SCID than other forms of immunodeficiency"
    explanation: >-
      Establishes that the gap is about a real, ADA-specific phenomenon rather
      than a general consequence of severe immunodeficiency or its treatment.
notes: >-
  SCID is curated as a CURATE_ROOT_WITH_SUBTYPES entry: the root captures the shared
  final-common-pathway mechanism (gene defect -> blocked T-lymphocyte development ->
  absent adaptive immunity -> early life-threatening infection and failure to thrive),
  while has_subtypes records the major genetic forms grouped by mechanism class
  (cytokine signaling: IL2RG/JAK3/IL7R; V(D)J recombination/DNA repair: RAG1/RAG2/
  DCLRE1C; purine metabolism: ADA; haematopoietic precursor survival: AK2/reticular
  dysgenesis). Immunophenotypes follow the classic T/B/NK framework. Newborn screening
  uses the T-cell receptor excision circle (TREC) assay.

  This entry does not enumerate every SCID gene - more than 20 are described - and it
  does not give every gene a has_subtypes row. A gene beyond the eight subtype-defining
  ones is bound to the pathophysiology node it acts at and left without a subtype row,
  which keeps the mechanism classes legible and leaves the leaf entities their own
  entries: CD3E, CD3G, CD247 and ZAP70 each already have one. On that basis PRKDC and
  LIG4 are bound to the V(D)J recombination and DNA repair node, CD3D and LAT to the
  receptor-proximal T-cell receptor signalling node, and CORO1A to the thymocyte
  egress node.

  Those last two nodes were added because receptor-proximal signalling and thymocyte
  egress are mechanism classes in their own right rather than variants of cytokine
  signalling, V(D)J recombination, purine metabolism, or precursor survival. An
  earlier version of this note grouped the CD3 subunits and CORO1A with the four
  classes then modelled, which was wrong on both counts. CD45/PTPRC and the remaining
  CD3 chains belong to the signalling class; PNP belongs with ADA in purine
  metabolism, and IL2RA with the cytokine receptors.

  Three further genes are deliberately not curated here. All three dispositions rest
  on the IUIS 2022 classification tables in PMID:35748970, the reference this entry
  already cites for its IUIS category. LCK is placed there in Table 1 section 3,
  "Combined Immunodeficiency (CID), Generally Less Profound than SCID". CD70
  deficiency is a
  disease of immune dysregulation defined by Epstein-Barr-virus susceptibility and
  Hodgkin lymphoma; IUIS files it in Table 4 section 7, "Susceptibility to EBV and
  Lymphoproliferative Conditions", rather than in either SCID table. BCL11B deficiency
  is autosomal dominant and appears in Table 2, "Combined immunodeficiencies with
  associated or syndromic features", alongside craniofacial and central-nervous-system
  anomalies. MONDO labels the first two "severe combined immunodeficiency due to LCK
  deficiency" (MONDO:0014334) and "severe combined immunodeficiency due to CD70
  deficiency" (MONDO:0034054); neither label is supported by the sources read here.

  This entry also does not assert a single per-gene case fraction: `genetic[].case_fractions`
  records IL2RG, RAG1, IL7R, and ADA shares separately per cohort, because the numbers
  differ by roughly twofold between referral-centre series and population-based newborn
  screening, and by ancestry. The 19%-versus-"nearly half" gap for IL2RG is an
  ascertainment artefact that PMID:25138334 diagnoses explicitly; presenting either
  figure alone would be wrong.
references:
- reference: PMID:20301584
  title: "X-Linked Severe Combined Immunodeficiency."
  tags:
  - GeneReviews
  findings: []
- reference: PMID:20301656
  title: "Adenosine Deaminase Deficiency."
  tags:
  - GeneReviews
  findings: []
- reference: PMID:32181275
  title: "Genetics of severe combined immunodeficiency."
  findings: []
- reference: PMID:36456361
  title: "The diagnosis of severe combined immunodeficiency (SCID): The Primary Immune Deficiency Treatment Consortium (PIDTC) 2022 Definitions."
  findings: []
- reference: PMID:33628209
  title: "Clinical, Immunological, and Molecular Features of Severe Combined Immune Deficiency: A Multi-Institutional Experience From India."
  findings: []
- reference: PMID:33551023
  title: "SCID newborn screening: What we've learned."
  findings: []
- reference: PMID:38355973
  title: "Long-term and real-world safety and efficacy of retroviral gene therapy for adenosine deaminase deficiency."
  findings: []
- reference: PMID:27579027
  title: "Adenosine Deaminase Deficiency - More Than Just an Immunodeficiency."
  findings: []

📚

References & Deep Research

References

8

PMID:20301584

X-Linked Severe Combined Immunodeficiency.

No top-level findings curated for this source.

PMID:20301656

Adenosine Deaminase Deficiency.

No top-level findings curated for this source.

PMID:32181275

Genetics of severe combined immunodeficiency.

No top-level findings curated for this source.

PMID:36456361

The diagnosis of severe combined immunodeficiency (SCID): The Primary Immune Deficiency Treatment Consortium (PIDTC) 2022 Definitions.

No top-level findings curated for this source.

PMID:33628209

Clinical, Immunological, and Molecular Features of Severe Combined Immune Deficiency: A Multi-Institutional Experience From India.

No top-level findings curated for this source.

PMID:33551023

SCID newborn screening: What we've learned.

No top-level findings curated for this source.

PMID:38355973

Long-term and real-world safety and efficacy of retroviral gene therapy for adenosine deaminase deficiency.

No top-level findings curated for this source.

PMID:27579027

Adenosine Deaminase Deficiency - More Than Just an Immunodeficiency.

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 25 citations 2026-06-22T12:16:48.706243

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: Severe Combined Immunodeficiency
MONDO ID: (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Severe Combined Immunodeficiency covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

I apologize, but I'm unable to complete the comprehensive disease characteristics research report for Severe Combined Immunodeficiency (SCID) as requested. While I successfully retrieved relevant scientific literature covering SCID's clinical features, genetics, treatment approaches, newborn screening, and outcomes, I encountered technical difficulties with the evidence gathering system that prevented me from systematically extracting and organizing the detailed information needed for a comprehensive report across all 15 sections you specified.

From the papers I was able to access, I can provide the following preliminary overview based on the retrieved documents:

Disease Overview

Severe Combined Immunodeficiency (SCID) is a rare, life-threatening inherited immunodeficiency disorder characterized by profound defects in T lymphocyte development and function, often affecting both cellular and humoral immunity (justizvaillant2023severecombinedimmunodeficiency—classification pages 1-2, dhomakonda2025areviewon pages 1-2, dvorak2023thediagnosisof pages 1-3). SCID is considered a pediatric emergency and, if left untreated, typically results in death within the first two years of life due to severe opportunistic infections (justizvaillant2023severecombinedimmunodeficiency—classification pages 1-2, vignesh2021clinicalimmunologicaland pages 1-2).

Key Identifiers and Synonyms

SCID is also known as "bubble boy disease" or "living in the bubble" syndrome, named after the historical practice of isolating affected children in sterile environments (justizvaillant2023severecombinedimmunodeficiency—classification pages 1-2).

Epidemiology and Prevalence

Recent data from newborn screening programs indicate that SCID occurs with an incidence of approximately: - 1 in 58,000 live births (with a confidence interval of 1 in 46,000 to 1 in 80,000) in the United States based on newborn screening data across 11 states (currier2021scidnewbornscreening pages 1-2) - 1 in 103,240 for SCID in the Chinese population based on large-scale screening in Zhejiang Province, China (chen2024comprehensivenewbornscreening pages 1-2) - Earlier estimates had placed incidence at about 1 in 50,000 to 100,000 live births globally, though recent assessments based on newborn screening suggest higher rates (kumrah2020geneticsofsevere pages 1-2, vignesh2021clinicalimmunologicaland pages 2-3)

In countries with high consanguinity rates, incidence may be as high as 1 in 3,000 live births (vignesh2021clinicalimmunologicaland pages 2-3).

Genetic Basis and Causal Genes

SCID is caused by mutations in more than 20 different genes involved in lymphocyte development and function (vignesh2021clinicalimmunologicaland pages 2-3, kumrah2020geneticsofsevere pages 2-4). The major causal genes identified include:

X-linked SCID (most common in Western populations): - IL2RG (encoding the common gamma chain of IL-2 receptor) - accounts for approximately 50% of SCID cases in the US, Canada, and Europe (justizvaillant2023severecombinedimmunodeficiency—classification pages 1-2, vignesh2021clinicalimmunologicaland pages 2-3)

Autosomal recessive forms (more common in populations with high consanguinity): - RAG1 and RAG2 (recombination activating genes) - most common in countries with high consanguinity rates (vignesh2021clinicalimmunologicaland pages 2-3, kumrah2020geneticsofsevere pages 2-4) - ADA (adenosine deaminase) - accounts for approximately 15% of all SCID cases (justizvaillant2023severecombinedimmunodeficiency—classification pages 1-2) - JAK3 (Janus kinase 3) - DCLRE1C (Artemis/DNA cross-link repair enzyme 1c) - IL7RA (IL-7 receptor alpha chain) - Other genes: NHEJ1, LIG4, PRKDC, CD3D, CD3E, CD3Z, PTPRC, AK2, PNP, and others (vignesh2021clinicalimmunologicaland pages 2-3, kumrah2020geneticsofsevere pages 2-4)

Clinical Manifestations and Phenotypes

Primary Symptoms:

Recurrent and severe opportunistic infections (bacterial, viral, fungal, and protozoal) beginning in early infancy (justizvaillant2023severecombinedimmunodeficiency—classification pages 1-2, vignesh2021clinicalimmunologicaland pages 1-2)
Persistent oral thrush
Disseminated BCG infection (in countries with universal BCG vaccination)
Disseminated cytomegalovirus infection
Chronic diarrhea
Failure to thrive (justizvaillant2023severecombinedimmunodeficiency—classification pages 1-2, vignesh2021clinicalimmunologicaland pages 1-2)

Age of Onset:

Symptoms typically present before 3 months of age (justizvaillant2023severecombinedimmunodeficiency—classification pages 1-2)
Median age of symptom onset: 2.5 months (interquartile range 1-5 months) based on Indian cohort (vignesh2021clinicalimmunologicaland pages 2-3)
Median age at diagnosis: 5 months (interquartile range 3.5-8 months) (vignesh2021clinicalimmunologicaland pages 2-3)

Classification:

SCID can be classified as: 1. Typical SCID: Characterized by gene mutations with severe infections, diarrhea, lack of T cells (<0.05 × 10⁹/L autologous T cells), reduction in naive T cells, and absence of proliferative responses to mitogens (dhomakonda2025areviewon pages 1-2, dvorak2023thediagnosisof pages 1-3) 2. Atypical/Leaky SCID: CD3+ > 300 cells/μL with diminished but detectable proliferative response to PHA (>10-30% of control) (justizvaillant2023severecombinedimmunodeficiency—classification pages 1-2, dhomakonda2025areviewon pages 1-2) 3. Variant SCID: No known gene defect with 300-1500 T cells/L with reduced function (justizvaillant2023severecombinedimmunodeficiency—classification pages 1-2, dhomakonda2025areviewon pages 1-2) 4. Omenn Syndrome: Characterized by generalized erythematous rash, elevated IgE, eosinophilia, hepatosplenomegaly, and lymphadenopathy (dvorak2023thediagnosisof pages 1-3, vignesh2021clinicalimmunologicaland pages 2-3)

Diagnostic Approaches

Newborn Screening:

T-cell receptor excision circle (TREC) testing from dried blood spots is now the standard newborn screening method for SCID (chen2024comprehensivenewbornscreening pages 1-2, currier2021scidnewbornscreening pages 1-2)
Universal newborn screening for SCID was added to the US Recommended Uniform Screening Panel in 2010, and by 2019 all US states had adopted TREC-based screening (currier2021scidnewbornscreening pages 1-2)
Multiplex real-time PCR can simultaneously detect TRECs, KRECs (kappa-deleting recombination excision circles for B-cell deficiencies), and other markers (chen2024comprehensivenewbornscreening pages 1-2)

Laboratory Testing:

Flow cytometry for lymphocyte subset analysis (CD3, CD4, CD8, CD19, CD56)
T-cell proliferation assays
Genetic testing via Sanger sequencing or next-generation sequencing (vignesh2021clinicalimmunologicaland pages 2-3)

Treatment Modalities

Hematopoietic Stem Cell Transplantation (HSCT):

HSCT is the definitive curative treatment for SCID (justizvaillant2023severecombinedimmunodeficiency—classification pages 1-2, slatter2023personalizedhematopoieticstem pages 1-3)
Early diagnosis and transplantation before onset of infections dramatically improves outcomes (currier2021scidnewbornscreening pages 1-2, slatter2023personalizedhematopoieticstem pages 1-3)
Survival rates exceed 90% with matched sibling donors (slatter2023personalizedhematopoieticstem pages 1-3)
In the Indian cohort, only 8.3% (23/277) of patients received HSCT, with 11 survivors; mortality was recorded in 75.8% (210/277) of children, highlighting disparities in access to curative therapy (vignesh2021clinicalimmunologicaland pages 2-3)

Gene Therapy:

Autologous hematopoietic stem cell gene therapy has emerged as an alternative to allogeneic HSCT (kohn2023successesandchallenges pages 1-2, bruin2023advancesingene pages 1-2)
Gene therapy approaches include viral vector-mediated gene addition and gene editing with programmable nucleases (bruin2023advancesingene pages 1-2)
Long-term safety and efficacy have been demonstrated for ADA-SCID gene therapy, with market authorization granted in Europe (Strimvelis) (bruin2023advancesingene pages 1-2, migliavacca2024longtermandrealworld pages 1-2)
Gene therapy for X-SCID, Artemis SCID, and other forms has shown clinical success in trials (kohn2023successesandchallenges pages 1-2)
In one long-term study of 43 patients with ADA-SCID receiving retroviral gene therapy, all patients were alive at data cutoff with median follow-up of 5.0 years, and 2-year intervention-free survival was 88% (migliavacca2024longtermandrealworld pages 1-2)

Enzyme Replacement Therapy:

PEG-ADA (pegylated adenosine deaminase) for ADA-deficiency SCID
Can stabilize patients but provides limited long-term immune reconstitution (migliavacca2024longtermandrealworld pages 1-2)

Supportive Care:

Antimicrobial prophylaxis
Immunoglobulin replacement therapy
Strict isolation to prevent infections

Prognosis and Outcomes

Without Treatment:

Most children die before age 2 without bone marrow transplantation (dhomakonda2025areviewon pages 1-2)
Mortality rate of 75.8% was observed in an Indian cohort where most patients did not receive definitive treatment (vignesh2021clinicalimmunologicaland pages 2-3)

With Early Treatment:

Patients diagnosed through newborn screening and treated early have significantly better outcomes compared to those diagnosed after developing clinical symptoms (currier2021scidnewbornscreening pages 1-2, slatter2023personalizedhematopoieticstem pages 1-3)
Overall survival >90% after matched sibling/family donor HSCT (migliavacca2024longtermandrealworld pages 1-2)
Overall survival >85% after matched unrelated donor HSCT (improved over time) (migliavacca2024longtermandrealworld pages 1-2)

Animal Models

Immunodeficient Mouse Models:

Multiple immunodeficient mouse models have been developed to study SCID and test therapies: - SCID mice (Prkdc mutation) - deficient in T and B lymphocytes but retain NK cells (chen2022thedevelopmentand pages 1-2) - NOD/SCID mice - improved NK cell defects (chen2022thedevelopmentand pages 1-2) - NOD/SCID rg^null mice - lacking T, B, and NK cells, considered the gold standard for humanized mouse models (chen2022thedevelopmentand pages 1-2) - Rag1 and Rag2 knockout mice - lack mature T and B lymphocytes without spontaneous recovery (chen2022thedevelopmentand pages 1-2)

These models are used for xenograft studies, testing gene therapies, and understanding disease pathophysiology.

Limitations of this Response:

Due to technical difficulties with the evidence gathering system, I was unable to complete the comprehensive, fully-cited report across all 15 sections as specified in your template. A complete report would require:

Systematic extraction of specific molecular pathways, cellular processes, and biochemical mechanisms
Detailed ontology term mapping (HPO, GO, CL, UBERON, CHEBI, MAXO terms)
Comprehensive coverage of environmental factors, epigenetics, and metabolic profiling
Detailed therapeutic strategies with MAXO terms
Prevention strategies at all levels
Comparative biology and veterinary relevance
Complete model organism characterization

To provide you with the comprehensive disease knowledge base entry you need, I recommend re-running this analysis or accessing the retrieved papers directly for detailed extraction of the information outlined in sections you specifically require.

References

(justizvaillant2023severecombinedimmunodeficiency—classification pages 1-2): Angel A. Justiz-Vaillant, Darren Gopaul, Patrick Eberechi Akpaka, Sachin Soodeen, and Rodolfo Arozarena Fundora. Severe combined immunodeficiency—classification, microbiology association and treatment. Microorganisms, 11:1589, Jun 2023. URL: https://doi.org/10.3390/microorganisms11061589, doi:10.3390/microorganisms11061589. This article has 36 citations.
(dhomakonda2025areviewon pages 1-2): Bhavani Dhomakonda, Vankodoth Sireesha, Boddu Shirisha, Gadila Sushma, Mekala Sai Charitha, and T. Rama Rao. A review on types and treatment strategies of severe combined immunodeficiency. Journal of Drug Delivery and Therapeutics, 15:161-167, Mar 2025. URL: https://doi.org/10.22270/jddt.v15i3.7031, doi:10.22270/jddt.v15i3.7031. This article has 0 citations.
(dvorak2023thediagnosisof pages 1-3): Christopher C. Dvorak, Elie Haddad, Jennifer Heimall, Elizabeth Dunn, Rebecca H. Buckley, Donald B. Kohn, Morton J. Cowan, Sung-Yun Pai, Linda M. Griffith, Geoffrey D.E. Cuvelier, Hesham Eissa, Ami J. Shah, Richard J. O’Reilly, Michael A. Pulsipher, Nicola A.M. Wright, Roshini S. Abraham, Lisa Forbes Satter, Luigi D. Notarangelo, and Jennifer M. Puck. The diagnosis of severe combined immunodeficiency (scid): the primary immune deficiency treatment consortium (pidtc) 2022 definitions. Journal of Allergy and Clinical Immunology, 151:539-546, Feb 2023. URL: https://doi.org/10.1016/j.jaci.2022.10.022, doi:10.1016/j.jaci.2022.10.022. This article has 157 citations and is from a highest quality peer-reviewed journal.
(vignesh2021clinicalimmunologicaland pages 1-2): Pandiarajan Vignesh, Amit Rawat, Rajni Kumrah, Ankita Singh, Anjani Gummadi, Madhubala Sharma, Anit Kaur, Johnson Nameirakpam, Ankur Jindal, Deepti Suri, Anju Gupta, Alka Khadwal, Biman Saikia, Ranjana Walker Minz, Kaushal Sharma, Mukesh Desai, Prasad Taur, Vijaya Gowri, Ambreen Pandrowala, Aparna Dalvi, Neha Jodhawat, Priyanka Kambli, Manisha Rajan Madkaikar, Sagar Bhattad, Stalin Ramprakash, Raghuram CP, Ananthvikas Jayaram, Meena Sivasankaran, Deenadayalan Munirathnam, Sarath Balaji, Aruna Rajendran, Amita Aggarwal, Komal Singh, Fouzia Na, Biju George, Ankit Mehta, Harsha Prasada Lashkari, Ramya Uppuluri, Revathi Raj, Sandip Bartakke, Kirti Gupta, Sreejesh Sreedharanunni, Yumi Ogura, Tamaki Kato, Kohsuke Imai, Koon Wing Chan, Daniel Leung, Osamu Ohara, Shigeaki Nonoyama, Michael Hershfield, Yu-Lung Lau, and Surjit Singh. Clinical, immunological, and molecular features of severe combined immune deficiency: a multi-institutional experience from india. Frontiers in Immunology, Feb 2021. URL: https://doi.org/10.3389/fimmu.2020.619146, doi:10.3389/fimmu.2020.619146. This article has 62 citations and is from a peer-reviewed journal.
(currier2021scidnewbornscreening pages 1-2): Robert Currier and Jennifer M. Puck. Scid newborn screening: what we've learned. The Journal of allergy and clinical immunology, 147 2:417-426, Feb 2021. URL: https://doi.org/10.1016/j.jaci.2020.10.020, doi:10.1016/j.jaci.2020.10.020. This article has 138 citations.
(chen2024comprehensivenewbornscreening pages 1-2): Chi Chen, Chao Zhang, Ding-Wen Wu, Bing-Yi Wang, Rui Xiao, Xiao-Lei Huang, Xin Yang, Zhi-Gang Gao, and Ru-Lai Yang. Comprehensive newborn screening for severe combined immunodeficiency, x-linked agammaglobulinemia, and spinal muscular atrophy: the chinese experience. World Journal of Pediatrics, 20:1270-1282, Nov 2024. URL: https://doi.org/10.1007/s12519-024-00846-7, doi:10.1007/s12519-024-00846-7. This article has 12 citations and is from a peer-reviewed journal.
(kumrah2020geneticsofsevere pages 1-2): Rajni Kumrah, Pandiarajan Vignesh, Pratap Patra, Ankita Singh, Gummadi Anjani, Poonam Saini, Madhubala Sharma, Anit Kaur, and Amit Rawat. Genetics of severe combined immunodeficiency. Mar 2020. URL: https://doi.org/10.1016/j.gendis.2019.07.004, doi:10.1016/j.gendis.2019.07.004. This article has 88 citations.
(vignesh2021clinicalimmunologicaland pages 2-3): Pandiarajan Vignesh, Amit Rawat, Rajni Kumrah, Ankita Singh, Anjani Gummadi, Madhubala Sharma, Anit Kaur, Johnson Nameirakpam, Ankur Jindal, Deepti Suri, Anju Gupta, Alka Khadwal, Biman Saikia, Ranjana Walker Minz, Kaushal Sharma, Mukesh Desai, Prasad Taur, Vijaya Gowri, Ambreen Pandrowala, Aparna Dalvi, Neha Jodhawat, Priyanka Kambli, Manisha Rajan Madkaikar, Sagar Bhattad, Stalin Ramprakash, Raghuram CP, Ananthvikas Jayaram, Meena Sivasankaran, Deenadayalan Munirathnam, Sarath Balaji, Aruna Rajendran, Amita Aggarwal, Komal Singh, Fouzia Na, Biju George, Ankit Mehta, Harsha Prasada Lashkari, Ramya Uppuluri, Revathi Raj, Sandip Bartakke, Kirti Gupta, Sreejesh Sreedharanunni, Yumi Ogura, Tamaki Kato, Kohsuke Imai, Koon Wing Chan, Daniel Leung, Osamu Ohara, Shigeaki Nonoyama, Michael Hershfield, Yu-Lung Lau, and Surjit Singh. Clinical, immunological, and molecular features of severe combined immune deficiency: a multi-institutional experience from india. Frontiers in Immunology, Feb 2021. URL: https://doi.org/10.3389/fimmu.2020.619146, doi:10.3389/fimmu.2020.619146. This article has 62 citations and is from a peer-reviewed journal.
(kumrah2020geneticsofsevere pages 2-4): Rajni Kumrah, Pandiarajan Vignesh, Pratap Patra, Ankita Singh, Gummadi Anjani, Poonam Saini, Madhubala Sharma, Anit Kaur, and Amit Rawat. Genetics of severe combined immunodeficiency. Mar 2020. URL: https://doi.org/10.1016/j.gendis.2019.07.004, doi:10.1016/j.gendis.2019.07.004. This article has 88 citations.
(slatter2023personalizedhematopoieticstem pages 1-3): Mary Slatter and Su Han Lum. Personalized hematopoietic stem cell transplantation for inborn errors of immunity. Frontiers in Immunology, Apr 2023. URL: https://doi.org/10.3389/fimmu.2023.1162605, doi:10.3389/fimmu.2023.1162605. This article has 32 citations and is from a peer-reviewed journal.
(kohn2023successesandchallenges pages 1-2): Donald B. Kohn, Yvonne Y. Chen, and Melissa J. Spencer. Successes and challenges in clinical gene therapy. Gene Therapy, 30:738-746, Nov 2023. URL: https://doi.org/10.1038/s41434-023-00390-5, doi:10.1038/s41434-023-00390-5. This article has 228 citations and is from a peer-reviewed journal.
(bruin2023advancesingene pages 1-2): Lisa M. Ott de Bruin, Arjan C. Lankester, and Frank J.T. Staal. Advances in gene therapy for inborn errors of immunity. Current Opinion in Allergy and Clinical Immunology, 23:467-477, Oct 2023. URL: https://doi.org/10.1097/aci.0000000000000952, doi:10.1097/aci.0000000000000952. This article has 32 citations and is from a peer-reviewed journal.
(migliavacca2024longtermandrealworld pages 1-2): Maddalena Migliavacca, Federica Barzaghi, Claudia Fossati, Paola M. V. Rancoita, Michela Gabaldo, Francesca Dionisio, Stefania Giannelli, Federica Andrea Salerio, Francesca Ferrua, Francesca Tucci, Valeria Calbi, Vera Gallo, Salvatore Recupero, Giulia Consiglieri, Roberta Pajno, Maria Sambuco, Alessio Priolo, Chiara Ferri, Vittoria Garella, Ilaria Monti, Paolo Silvani, Silvia Darin, Miriam Casiraghi, Ambra Corti, Stefano Zancan, Margherita Levi, Daniela Cesana, Filippo Carlucci, Anna Pituch-Noworolska, Dalia AbdElaziz, Ulrich Baumann, Andrea Finocchi, Caterina Cancrini, Saverio Ladogana, Andrea Meinhardt, Isabelle Meyts, Davide Montin, Lucia Dora Notarangelo, Fulvio Porta, Marlène Pasquet, Carsten Speckmann, Polina Stepensky, Alberto Tommasini, Marco Rabusin, Zeynep Karakas, Miguel Galicchio, Lucia Leonardi, Marzia Duse, Sukru Nail Guner, Clelia Di Serio, Fabio Ciceri, Maria Ester Bernardo, Alessandro Aiuti, and Maria Pia Cicalese. Long-term and real-world safety and efficacy of retroviral gene therapy for adenosine deaminase deficiency. Nature medicine, 30:488-497, Feb 2024. URL: https://doi.org/10.1038/s41591-023-02789-4, doi:10.1038/s41591-023-02789-4. This article has 31 citations and is from a highest quality peer-reviewed journal.
(chen2022thedevelopmentand pages 1-2): Jiaxuan Chen, Shuzhen Liao, Zengzhi Xiao, Quanren Pan, Xi Wang, Kangyuan Shen, Shuting Wang, Lawei Yang, Fengbiao Guo, Hua-feng Liu, and Qingjun Pan. The development and improvement of immunodeficient mice and humanized immune system mouse models. Frontiers in Immunology, Oct 2022. URL: https://doi.org/10.3389/fimmu.2022.1007579, doi:10.3389/fimmu.2022.1007579. This article has 224 citations and is from a peer-reviewed journal.

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1. Disease Information

2. Etiology

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Animal Models

Immunodeficient Mouse Models: