Immunodeficiency 93 and Hypertrophic Cardiomyopathy

Mendelian MONDO:0030528 Pathograph 15 Show in embeddings browser Inborn error of immunity Agammaglobulinemia

Immunodeficiency 93 and hypertrophic cardiomyopathy (IMD93; FNIP1 deficiency; OMIM 619705) is an autosomal recessive syndromic inborn error of immunity caused by biallelic loss-of-function variants in FNIP1, the gene encoding folliculin-interacting protein 1. Onset is in the first months to years of life with recurrent viral and bacterial infection — particularly sinopulmonary infection with encapsulated organisms — together with hypertrophic cardiomyopathy. Immunologic workup characteristically shows profoundly decreased or absent circulating B cells with hypo- or agammaglobulinemia, reflecting an early arrest of B-cell development at the pre-B stage; severe or intermittent neutropenia and a mild T-cell lymphocytosis are seen in some but not all patients, and laboratory findings vary between individuals. Immunoglobulin replacement therapy is beneficial. Cardiac involvement extends beyond hypertrophic cardiomyopathy to atrial septal defect, valvular insufficiency, tachyarrhythmia, and ventricular pre-excitation (Wolff-Parkinson-White syndrome). Mechanistically, FNIP1 partners with folliculin (FLCN) to couple nutrient and energy sensing to the AMPK and mTORC1 pathways; its loss produces an AMPK gain-of-function state that both blocks the pre-B-cell metabolic checkpoint and drives glycogen accumulation in cardiomyocytes, phenocopying PRKAG2 (AMPK gamma-2) gain-of-function cardiomyopathy with pre-excitation.

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1
Inheritance
9
Pathophys.
14
Phenotypes
2
Gaps
15
Pathograph
1
Genes
2
Variants
6
Medical Actions
5
Differentials
1
Models
10
References
1
Deep Research
🏷

Classifications

Harrison's Part
IMMUNE RHEUMATOLOGIC CARDIOVASCULAR GENETICS ENVIRONMENT DISEASE
IUIS Category
predominantly antibody deficiency
👪

Inheritance

1
Autosomal recessive HP:0000007
IMD93 is inherited in an autosomal recessive manner. Reported patients carry homozygous FNIP1 loss-of-function variants (often in consanguineous families), compound-heterozygous variants, or a single variant unmasked by uniparental disomy or a copy-number deletion of the second allele.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:32181500 SUPPORT Human Clinical
"Mutations of the gene FNIP1 associated with a syndromic autosomal recessive immunodeficiency with cardiomyopathy and pre-excitation syndrome."
Establishes autosomal recessive inheritance for FNIP1-related immunodeficiency with cardiomyopathy.
PMID:35748970 SUPPORT Other
"FNIP1 deficiency (6 patients) FNIP1 AR"
IUIS table records the inheritance mode of FNIP1 deficiency as AR (autosomal recessive).
?

Discussions and Knowledge Gaps

2
Are the neurologic and myopathic features reported in some FNIP1-deficient patients (microcephaly, developmental delay, muscular hypotonia, cerebellar hypoplasia, metabolic myopathy) genuinely part of IMD93, or do they reflect additional, as-yet-unidentified genetic factors segregating in the consanguineous pedigrees in which they were observed?
KNOWLEDGE GAP imd93_neuro_myopathic_features_attribution
Attached to
pathophysiology#Dysregulated AMPK and mTORC1 Nutrient Sensing
OMIM 619705 and MONDO:0030528 both flag these as inconsistent features that may be related to other genetic defects, and the primary literature supplies the reason: CNS involvement was reported in 4 of 6 early patients but only in consanguineous pedigrees, where recessive homozygosity at unrelated loci is expected to be enriched. FNIP1 is nonetheless plausibly relevant to muscle — Fnip1 regulates skeletal muscle fiber-type specification in mice — so the question is genuinely open rather than settled in either direction. Curating these as core phenotypes on the current evidence would overstate the phenotypic definition; this entry therefore omits them.
Proposed experiments
Exome/genome reanalysis for a second recessive diagnosis
imd93_exp_reanalysis_second_diagnosis
Systematic reanalysis of exome/genome data from FNIP1-deficient patients with neurologic features, searching for a second, unrelated recessive diagnosis that could independently explain the CNS phenotype.
Supporting outcome
  • Finding no second candidate diagnosis in multiple such patients would support the neurologic features being genuinely FNIP1-attributable.
Refuting outcome
  • Identifying independent pathogenic biallelic variants at other loci would refute FNIP1 attribution for those features.
Deep phenotyping of non-consanguineous FNIP1-deficient patients
imd93_exp_nonconsanguineous_deep_phenotyping
Neuroimaging, muscle biopsy, and creatine kinase measurement in FNIP1-deficient patients from non-consanguineous pedigrees, in whom a co-segregating second recessive disorder is far less likely.
Supporting outcome
  • Neurologic or myopathic findings in non-consanguineous patients would support these as true FNIP1 phenotypes.
Refuting outcome
  • Consistently normal neurologic and muscle findings in non-consanguineous patients would argue the association is confounded by consanguinity.
Tissue-specific conditional Fnip1 deletion
imd93_exp_conditional_fnip1_deletion
Conditional Fnip1 deletion in neural and skeletal-muscle lineages in mice to test whether neurologic and myopathic features are cell-autonomous consequences of FNIP1 loss.
Supporting outcome
  • Cell-autonomous neural or muscle phenotypes on lineage-restricted deletion would support a direct FNIP1 role.
Refuting outcome
  • Absence of phenotype on lineage-restricted deletion would argue against a direct, cell-autonomous FNIP1 contribution.
Show evidence (2 references)
PMID:37522988 SUPPORT Human Clinical
"However, these manifestations were observed only in patients with consanguineous pedigrees , raising the possibility that they may be caused by other (as yet to be discovered) genetic factors."
The primary source for the caveat: CNS manifestations were confined to consanguineous pedigrees, so an independent genetic explanation cannot be excluded.
PMID:25548157 SUPPORT Model Organism
"Fnip1 regulates skeletal muscle fiber type specification, fatigue resistance, and susceptibility to muscular dystrophy."
Provides a biologically plausible route by which FNIP1 loss could contribute to a myopathic phenotype, which is why the question is treated as open rather than resolved against involvement.
Would allogeneic haematopoietic stem cell transplantation correct the haematopoietic arm of IMD93, and how should it be weighed against the untreatable cardiac arm?
OPEN QUESTION imd93_hsct_role_versus_cardiac_arm
Attached to
pathophysiology#Pre-B Cell Metabolic Checkpoint Failure and Developmental Arrest pathophysiology#Ventricular Hypertrophy and Hypertrophic Cardiomyopathy
The B-cell and neutrophil defects are cell-intrinsic to the haematopoietic compartment and would in principle be corrected by donor haematopoiesis, whereas the hypertrophic cardiomyopathy and pre-excitation arise in cardiomyocytes and would not. Because cardiac disease is a leading cause of death, the risk-benefit calculus for transplantation differs from that in other agammaglobulinemias, where immunoglobulin replacement alone is usually sufficient. No transplanted FNIP1-deficient patient has been reported, so this remains untested.
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Pathophysiology

9
FNIP1 Loss of Function
Biallelic loss-of-function variants in FNIP1 abolish the folliculin-interacting protein 1 polypeptide. Immunoblotting of patient-derived T-cell blasts and EBV-immortalized B cells confirms absent FNIP1 protein, and the paralogue FNIP2 is not upregulated to compensate.
FNIP1 hgnc:29418 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves absent FNIP1 (hgnc:29418). hgnc:29418 is a gene from the HUGO Gene Nomenclature Committee. ∅ ABSENT
Downstream
Dysregulated AMPK and mTORC1 Nutrient Sensing
Show evidence (2 references)
PMID:32905580 SUPPORT Human Clinical
"We identified homozygous or compound-heterozygous variants in the gene for folliculin interacting protein 1 (FNIP1), leading to loss of the FNIP1 protein."
Establishes protein-level loss of FNIP1 as the proximal molecular lesion.
PMID:37522988 SUPPORT In Vitro
"Immunoblotting demonstrated the absence of FNIP1 protein in patient-derived T cell blasts"
Direct protein-level confirmation of FNIP1 absence in patient cells.
Dysregulated AMPK and mTORC1 Nutrient Sensing
FNIP1 forms a complex with folliculin (FLCN) that couples cellular energy and amino-acid status to the two master metabolic regulators: it binds and modulates AMP-activated protein kinase (AMPK), and the FLCN-FNIP1 complex acts as a GTPase-activating protein for RagC/D, controlling mTORC1 recruitment to the lysosome. FNIP1 additionally interacts with the HSP90 chaperone machinery, coupling its own stability to proteostasis. Loss of FNIP1 produces an AMPK phosphorylation (AMPK-P) gain-of-function state; in mouse B-cell progenitors both AMPK and mTORC1 are simultaneously activated, mTOR is inappropriately localized at the lysosome under nutrient-depleted conditions, and the MiT/TFE transcription factor TFE3 accumulates in the nucleus, driving lysosomal biogenesis and increased autophagic flux. The lesion is notably not reducible to a single linear "AMPK-high" or "mTOR-high" abnormality.
mTORC1 (TOR) signaling GO:0031929 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated mTORC1 (TOR) signaling, annotated with TOR signaling (GO:0031929). GO:0031929 is a biological process from the Gene Ontology. ↕ DYSREGULATED cellular response to nutrient levels GO:0031669 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal cellular response to nutrient levels (GO:0031669). GO:0031669 is a biological process from the Gene Ontology. ⚠ ABNORMAL
AMP-activated protein kinase activity GO:0004679 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves increased AMP-activated protein kinase activity (GO:0004679). GO:0004679 is a molecular function from the Gene Ontology. ↑ INCREASED RagC/D GTPase-activating activity of the FLCN-FNIP1 complex GO:0005096 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased RagC/D GTPase-activating activity of the FLCN-FNIP1 complex, annotated with GTPase activator activity (GO:0005096). GO:0005096 is a molecular function from the Gene Ontology. ↓ DECREASED
lysosome GO:0005764 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves lysosome (GO:0005764). GO:0005764 is a cellular component from the Gene Ontology.
Downstream
Pre-B Cell Metabolic Checkpoint Failure and Developmental Arrest
Cardiomyocyte Glycogen Accumulation
Impaired Neutrophil Homeostasis
Show evidence (5 references)
PMID:32181500 SUPPORT Human Clinical
"FNIP1 deficiency patients have a AMPK-P gain of function phenotype with hypertrophic cardiomyopathy, Wolff-Parkinson-White pre-excitation syndrome, myopathy of skeletal muscles and combined immunodeficiency."
Frames human FNIP1 deficiency as an AMPK-phosphorylation gain-of-function state, the unifying molecular abnormality.
PMID:40699689 SUPPORT Other
"FNIP1 forms a complex with folliculin (FLCN) to regulate the mechanistic target of rapamycin complex 1 (mTORC1), functioning as a GTPase-activating protein (GAP) for RagC/D."
Defines the FLCN-FNIP1 complex's RagC/D GAP activity toward mTORC1.
PMID:40699689 SUPPORT Other
"Additionally, FNIP1 interacts with heat shock protein 90 (HSP90) and undergoes phosphorylation, glycosylation, and ubiquitination, which dynamically regulate its stability and function."
Documents the HSP90 chaperone axis and post-translational control of FNIP1 stability.
+ 2 more references
Pre-B Cell Metabolic Checkpoint Failure and Developmental Arrest
FNIP1 enforces a metabolic checkpoint that verifies a developing pre-B cell has sufficient metabolic capacity to undergo the proliferative burst that follows successful immunoglobulin heavy-chain rearrangement. Without FNIP1, B-cell development arrests at the pre-B-cell stage: progenitors show impaired mitochondrial number and activity, blunted PI3K/AKT signalling, increased autophagic flux, and increased apoptosis on amino-acid (lysine or arginine) withdrawal. The arrest is not rescued by genetic AMPK inhibition, mTORC1 inhibition, or Bcl-xL-mediated survival support, indicating a metabolic rather than purely apoptotic block.
pre-B cell (precursor B cell) CL:0000817 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves pre-B cell (precursor B cell), annotated with precursor B cell (CL:0000817). CL:0000817 is a cell type from the Cell Ontology. large pre-B-II cell CL:0000955 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves large pre-B-II cell, annotated with pre-B-II cell (CL:0000955). CL:0000955 is a cell type from the Cell Ontology.
B cell differentiation GO:0030183 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased B cell differentiation (GO:0030183). GO:0030183 is a biological process from the Gene Ontology. ↓ DECREASED autophagy GO:0006914 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased autophagy (GO:0006914). GO:0006914 is a biological process from the Gene Ontology. ↑ INCREASED
mitochondrion GO:0005739 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves abnormal mitochondrion (GO:0005739). GO:0005739 is a cellular component from the Gene Ontology.
Downstream
Absent Circulating B Cells and Agammaglobulinemia
Show evidence (4 references)
PMID:31676673 SUPPORT Model Organism
"We previously found that constitutive disruption of Fnip1 in mice resulted in a lack of peripheral B cells because of a block in B cell development at the pre-B cell stage."
Localizes the developmental block to the pre-B-cell stage.
PMID:31676673 SUPPORT Model Organism
"Genetic inhibition of AMPK, inhibition of mTORC1, or restoration of cell viability with a Bcl-xL transgene failed to rescue B cell development in Fnip1-deficient mice."
Shows the arrest cannot be rescued by blocking AMPK/mTORC1 or by survival support alone, arguing for a metabolic-capacity checkpoint.
PMID:32905580 SUPPORT Human Clinical
"B-cell metabolism, including mitochondrial numbers and activity and phosphatidylinositol 3-kinase/AKT pathway, was impaired. These defects recapitulated the Fnip1-/- animal model."
Confirms in patient cells the mitochondrial and PI3K/AKT metabolic defects predicted by the mouse model.
+ 1 more reference
Absent Circulating B Cells and Agammaglobulinemia
The pre-B-cell arrest translates into profoundly decreased or absent circulating CD19+/CD20+ B cells and severe reduction of all serum immunoglobulin isotypes (profound hypogammaglobulinemia to agammaglobulinemia). A mild increase in circulating CD3+ T lymphocytes has been documented in some patients.
immunoglobulin production GO:0002377 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased immunoglobulin production (GO:0002377). GO:0002377 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Susceptibility to Recurrent Sinopulmonary and Gastrointestinal Infection
Show evidence (2 references)
PMID:37522988 SUPPORT Human Clinical
"Immunological abnormalities in the peripheral blood show strongly diminished (nearly absent) B cell number s and severe reduction s in all serum immunoglobulin isotypes ( profound hypogamma/agammaglobulinemia ) associated with severe or intermittent neutropenia"
Summarises the core laboratory phenotype across reported patients: near-absent B cells with pan-isotype immunoglobulin reduction.
PMID:39537849 SUPPORT Human Clinical
"Immune workup revealed agammaglobulinemia and a lack of B lymphocytes."
Independent patient-level confirmation of agammaglobulinemia with absent B lymphocytes.
Susceptibility to Recurrent Sinopulmonary and Gastrointestinal Infection
Loss of antibody-mediated humoral immunity produces early-onset recurrent viral and bacterial infection, dominated by upper and lower respiratory tract infection (including otitis media, pneumonia, and sequelae such as bronchiectasis) and gastrointestinal infection or enteropathy, with resulting failure to thrive. Encapsulated bacteria are characteristic pathogens of this antibody-deficiency pattern.
Show evidence (2 references)
PMID:37522988 SUPPORT Human Clinical
"severe and/or recurrent upper and lower respiratory tract infections"
The review states that clinical manifestations of FNIP1 deficiency occurring within the first year of life include severe and/or recurrent upper and lower respiratory tract infections.
PMID:39537849 SUPPORT Human Clinical
"she developed recurrent viral and bacterial infections, including recurrent sinopulmonary infections"
Documents the combined viral and bacterial recurrent-infection pattern in a patient.
Cardiomyocyte Glycogen Accumulation
Within the cardiomyocyte, the AMPK gain-of-function state driven by FNIP1 loss reproduces the cell-level pathology of activating mutations in the AMPK gamma-2 subunit (PRKAG2): gamma-2-specific AMPK activity is elevated in neonatal FNIP1-deficient myocardium and glycogen accumulates within the myocyte. This is the cellular lesion that underlies the tissue-level hypertrophy modelled downstream.
cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
glycogen metabolic process GO:0005977 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased glycogen metabolic process (GO:0005977). GO:0005977 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Ventricular Hypertrophy and Hypertrophic Cardiomyopathy
Show evidence (2 references)
PMID:27303042 SUPPORT Model Organism
"Concordantly, γ2-specific AMPK activity was elevated in neonatal FNIP1-deficient myocardium"
Direct measurement of elevated gamma-2 AMPK activity in FNIP1-deficient myocardium.
PMID:27303042 SUPPORT Model Organism
"FNIP1-deficient mice developed cardiomyopathy characterized by left ventricular hypertrophy and glycogen accumulation, with close parallels to mice and humans bearing gain-of-function mutations in the γ2 subunit of AMPK."
Establishes myocardial glycogen accumulation and the AMPK-gamma-2 (PRKAG2) phenocopy as the mechanism in the mouse model.
Ventricular Hypertrophy and Hypertrophic Cardiomyopathy
At tissue level the glycogen-laden myocardium becomes hypertrophic. In patients this manifests as hypertrophic — frequently obstructive — cardiomyopathy with left or biventricular hypertrophy, presenting from the neonatal period through the first years of life, and can be fatal through cardiogenic shock or heart failure.
cardiac muscle hypertrophy GO:0003300 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cardiac muscle hypertrophy (GO:0003300). GO:0003300 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Ventricular Pre-excitation and Tachyarrhythmia
Show evidence (2 references)
PMID:32905580 SUPPORT Human Clinical
"We here investigated 3 novel patients, including the first known adult, from unrelated families with agammaglobulinemia, recurrent infections, and hypertrophic cardiomyopathy (HCM)."
Confirms hypertrophic cardiomyopathy as a human phenotype of FNIP1 deficiency.
PMID:27303042 SUPPORT Model Organism
"FNIP1-deficient mice developed cardiomyopathy characterized by left ventricular hypertrophy and glycogen accumulation"
Mouse model recapitulates the ventricular hypertrophy at tissue level.
Ventricular Pre-excitation and Tachyarrhythmia
Glycogen-laden hypertrophic myocardium provides the substrate for accessory atrioventricular conduction, producing ventricular pre-excitation (Wolff-Parkinson-White syndrome) and supraventricular tachyarrhythmia — the same electrophysiological signature seen in PRKAG2 glycogen-storage cardiomyopathy.
Show evidence (3 references)
PMID:32181500 SUPPORT Human Clinical
"hypertrophic cardiomyopathy, Wolff-Parkinson-White pre-excitation syndrome"
Documents WPW pre-excitation accompanying the hypertrophic cardiomyopathy in patients.
PMID:37522988 SUPPORT Human Clinical
"hypertrophic cardiomyopathy (left ventricle) associated with Wolff-Parkinson-White"
Independent patient with left ventricular HCM and Wolff-Parkinson-White syndrome.
PMID:39537849 SUPPORT Human Clinical
"(SVT) as well as bi-ventricular hypertrophy and hypertrophic obstructive cardiomyopathy"
Documents supraventricular tachycardia alongside biventricular hypertrophy and hypertrophic obstructive cardiomyopathy, evidencing the tachyarrhythmia limb of this node. Graded PARTIAL because the affected individual was the index patient's sibling, who died at 2 months before genetic evaluation; the authors state only that he "very likely" carried the same FNIP1 variant, so the genotype was never confirmed.
Impaired Neutrophil Homeostasis
A subset of FNIP1-deficient patients develop severe or intermittent neutropenia, sometimes with recurrent gingivitis and perianal abscesses, which is responsive to granulocyte colony-stimulating factor. Other patients have entirely normal neutrophil counts, making neutropenia a variable rather than obligate feature; the observation nonetheless suggests a non-redundant role for FNIP1 in neutrophils.
Show evidence (2 references)
PMID:32905580 SUPPORT Human Clinical
"Two of them also presented with intermittent or severe chronic neutropenia."
Documents variable neutropenia in two of three patients in the defining cohort.
PMID:37522988 SUPPORT Human Clinical
"It also suggests a non-redundant function of FNIP1 in neutrophils."
Interprets the neutropenia as evidence of a non-redundant neutrophil requirement for FNIP1.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Immunodeficiency 93 and Hypertrophic Cardiomyopathy Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

14
Blood 1
Neutropenia FREQUENT Decreased total neutrophil count HP:0001875 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neutropenia, annotated with Decreased total neutrophil count (HP:0001875), qualified as temporality recurrent. HP:0001875 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Explicitly a variable feature. In the defining Blood cohort 2 of 3 patients had neutropenia; other reported patients (e.g. Spivak et al. 2024) had normal neutrophil counts.
Show evidence (2 references)
PMID:32905580 SUPPORT Human Clinical
"Two of them also presented with intermittent or severe chronic neutropenia."
Two of three patients in the defining cohort had neutropenia, a derived-count basis for the FREQUENT band.
PMID:32905580 SUPPORT Human Clinical
"agammaglobulinemia, variable neutropenia, and HCM"
Characterises the neutropenia explicitly as variable, not obligate.
Cardiovascular 4
Hypertrophic cardiomyopathy VERY_FREQUENT HP:0001639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertrophic cardiomyopathy (HP:0001639), qualified as infantile onset. HP:0001639 is a phenotype from the Human Phenotype Ontology.
Onset: INFANTILE
Show evidence (2 references)
PMID:32905580 SUPPORT Human Clinical
"FNIP1 deficiency is a novel inborn error of immunity characterized by early and severe B-cell development defect, agammaglobulinemia, variable neutropenia, and HCM."
HCM is listed among the defining (non-variable) characteristics of the disorder, supporting a VERY_FREQUENT band.
PMID:38748614 SUPPORT Human Clinical
"Deficiency in folliculin-interacting protein 1 (FNIP1) is a novel inborn error of immunity characterized by a severe defect in B-cell development, agammaglobulinemia, variable neutropenia, and hypertrophic cardiomyopathy."
Independent confirmation of HCM as a core disease characteristic.
Left ventricular hypertrophy HP:0001712 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Left ventricular hypertrophy (HP:0001712). HP:0001712 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39537849 SUPPORT Human Clinical
"HCM, and left ventricular hypertrophy (LVH) on transthoracic echocardiography"
Echocardiographic documentation of left ventricular hypertrophy in a patient.
PMID:27303042 SUPPORT Model Organism
"FNIP1-deficient mice developed cardiomyopathy characterized by left ventricular hypertrophy and glycogen accumulation"
Mouse model recapitulates the left ventricular hypertrophy.
Wolff-Parkinson-White syndrome FREQUENT HP:0001716 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Wolff-Parkinson-White pre-excitation syndrome, annotated with Wolff-Parkinson-White syndrome (HP:0001716). HP:0001716 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32181500 SUPPORT Human Clinical
"hypertrophic cardiomyopathy, Wolff-Parkinson-White pre-excitation syndrome"
WPW is named as part of the phenotype of FNIP1 deficiency patients as a group (and in the article title), supporting a FREQUENT band.
PMID:37522988 SUPPORT Human Clinical
"hypertrophic cardiomyopathy (left ventricle) associated with Wolff-Parkinson-White"
A further independent patient with WPW accompanying the HCM.
Atrial septal defect OCCASIONAL HP:0001631 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atrial septal defect (HP:0001631), qualified as congenital onset. HP:0001631 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Show evidence (1 reference)
PMID:39537849 SUPPORT Human Clinical
"was diagnosed with atrial-septal defect (ASD)"
Documents atrial septal defect in a genetically confirmed patient; reported in a minority of cases, hence the OCCASIONAL band.
Digestive 1
Chronic diarrhea OCCASIONAL HP:0002028 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic diarrhea (HP:0002028), qualified as temporality chronic. HP:0002028 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC
Show evidence (1 reference)
PMID:39537849 SUPPORT Human Clinical
"The index patient (subject II-4) presented with hypertrophic cardiomyopathy, recurrent infections, and chronic diarrhea during infancy."
Documents chronic diarrhea from infancy in a genetically confirmed patient.
Immune 2
Recurrent infections VERY_FREQUENT HP:0002719 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent infections (HP:0002719), qualified as infantile onset. HP:0002719 is a phenotype from the Human Phenotype Ontology.
Onset: INFANTILE
Show evidence (2 references)
PMID:37522988 SUPPORT Human Clinical
"Clinical manifestations of FNIP1 deficiency occurring within the first year of life"
Describes recurrent infection as a general clinical manifestation of FNIP1 deficiency occurring within the first year of life.
PMID:39537849 SUPPORT Human Clinical
"she developed recurrent viral and bacterial infections, including recurrent sinopulmonary infections"
Documents both viral and bacterial recurrent infection in a patient.
Recurrent respiratory infections VERY_FREQUENT HP:0002205 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent sinopulmonary infections, annotated with Recurrent respiratory infections (HP:0002205). HP:0002205 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37522988 SUPPORT Human Clinical
"severe and/or recurrent upper and lower respiratory tract infections"
Presented as a general clinical manifestation of the disorder within the first year of life rather than a single-patient observation, supporting a VERY_FREQUENT band.
Respiratory 1
Bronchiectasis OCCASIONAL HP:0002110 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bronchiectasis (HP:0002110). HP:0002110 is a phenotype from the Human Phenotype Ontology.
Recorded by the IUIS 2022 Expert Committee among the associated features of FNIP1 deficiency. Frequency is not quantified in the source, so a conservative band is used.
Show evidence (1 reference)
PMID:35748970 SUPPORT Other
"bronchiectasis, fibrosis, interstitial pneumoniae"
The IUIS Table 3 "associated features" column for the FNIP1 deficiency row lists bronchiectasis, fibrosis, and interstitial pneumonia alongside early-onset recurrent infections.
Growth 1
Failure to thrive OCCASIONAL HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39537849 SUPPORT Human Clinical
"Accordingly, she developed failure to thrive (FTT)."
Documents failure to thrive as a consequence of the infection and GI burden.
Other 4
Agammaglobulinemia VERY_FREQUENT HP:0004432 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Agammaglobulinemia (HP:0004432), qualified as infantile onset. HP:0004432 is a phenotype from the Human Phenotype Ontology.
Onset: INFANTILE
Show evidence (2 references)
PMID:32905580 SUPPORT Human Clinical
"FNIP1 deficiency is a novel inborn error of immunity characterized by early and severe B-cell development defect, agammaglobulinemia, variable neutropenia, and HCM."
Names agammaglobulinemia as a defining (not variable) feature of the disorder — contrasted in the same sentence with "variable" neutropenia — supporting a VERY_FREQUENT band.
PMID:39537849 SUPPORT Human Clinical
"Immune workup revealed agammaglobulinemia and a lack of B lymphocytes."
Patient-level documentation of agammaglobulinemia.
Decreased total B cell count VERY_FREQUENT HP:0010976 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Absent circulating B cells, annotated with Decreased total B cell count (HP:0010976). HP:0010976 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:39537849 SUPPORT Human Clinical
"FNIP1 loss-of-function should be considered in patients presenting in infancy with cardiac manifestations along with agammaglobulinemia (and B-cell lymphopenia)."
B-cell lymphopenia is presented as a consistent diagnostic hallmark of the disorder, supporting a VERY_FREQUENT band.
PMID:39537849 SUPPORT Human Clinical
"Due to complete absence of B lymphocytes, low levels of IgG and undetectable levels of IgA and IgM"
Patient-level flow-cytometric and immunochemical documentation of completely absent circulating B lymphocytes.
Supraventricular tachycardia OCCASIONAL HP:0004755 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Supraventricular tachycardia (HP:0004755). HP:0004755 is a phenotype from the Human Phenotype Ontology.
Reported in the index patient's sibling, who died of cardiogenic shock at 2 months before genetic confirmation; the authors infer he "very likely" carried the same FNIP1 variant. Evidence graded PARTIAL accordingly.
Show evidence (1 reference)
PMID:39537849 SUPPORT Human Clinical
"(SVT) as well as bi-ventricular hypertrophy and hypertrophic obstructive cardiomyopathy"
Documents supraventricular tachycardia with biventricular hypertrophy and HOCM in a clinically affected but genetically unconfirmed sibling of a molecularly diagnosed FNIP1 patient.
Increased total T cell count OCCASIONAL HP:0100828 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is T cell lymphocytosis, annotated with Increased total T cell count (HP:0100828). HP:0100828 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37522988 SUPPORT Human Clinical
"increase in CD3 T lymphocytes was observed at 30 years of age"
Single-patient observation of mild CD3+ T-lymphocytosis; reported as an isolated finding, hence the conservative OCCASIONAL band.
🧬

Genetic Associations

1
FNIP1
Gene: FNIP1 hgnc:29418 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is FNIP1 (hgnc:29418). hgnc:29418 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (4 references)
PMID:32905580 SUPPORT Human Clinical
"We identified homozygous or compound-heterozygous variants in the gene for folliculin interacting protein 1 (FNIP1), leading to loss of the FNIP1 protein."
Establishes biallelic FNIP1 loss-of-function as the cause of the disorder.
PMID:32905580 SUPPORT Human Clinical
"Moreover, we identified either uniparental disomy or copy-number variants (CNVs) in 2 patients, expanding the variant spectrum of this novel inborn error of immunity."
Documents uniparental disomy and CNVs as non-canonical routes to biallelic FNIP1 inactivation, motivating CNV analysis alongside exome sequencing.
PMID:39537849 SUPPORT Human Clinical
"Genetic evaluation identified a homozygous 13-bp duplication variant in FNIP1 (c.52_64dupGCGCCCGGCCGCG, p. Asp22GlyfsTer21) resulting in a frameshift in exon 1/18."
Documents a novel homozygous frameshift allele in a patient with the full IMD93 phenotype.
+ 1 more reference
Variants (2)
NM_133372.3:c.52_64dup (p.Asp22GlyfsTer21)
Homozygous 13-bp duplication in exon 1 of 18 causing a frameshift and premature stop; classified likely pathogenic (ACMG).
NM_133372.3:c.3334C>T (p.Gln1112*)
Nonsense variant in exon 17, present in a hemizygous state due to a de novo paternal copy-number deletion spanning FNIP1; immunoblotting showed complete absence of FNIP1 protein in patient cells.
💊

Medical Actions

6
Immunoglobulin Replacement Therapy
Action: intravenous immunoglobulin therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is intravenous immunoglobulin therapy (NCIT:C121331). NCIT:C121331 is a clinical intervention from the NCI Thesaurus. Ontology label: Intravenous Immunoglobulin Therapy NCIT:C121331
Regular immunoglobulin replacement (IVIg or SCIG) is the mainstay of management, supplying the antibody the patient cannot produce. Reported patients achieved normal IgG trough levels with marked reduction in sinopulmonary infections and substantial improvement in gastrointestinal symptoms.
Mechanism Target:
BYPASSES Absent Circulating B Cells and Agammaglobulinemia — Exogenous polyclonal IgG substitutes for the antibody the arrested B-cell compartment cannot make; it bypasses rather than corrects the pre-B-cell developmental block.
Show evidence (2 references)
PMID:39537849 SUPPORT Human Clinical
"She was treated with supplemental intravenous immunoglobulins (IVIg) with good control of sinopulmonary and gastrointestinal manifestations."
Clinical benefit of IVIg on the infectious and gastrointestinal burden.
PMID:39537849 SUPPORT Human Clinical
"treatment with monthly intravenous immunoglobulin (IVIg) infusion was initiated, achieving normal IgG levels and exhibiting marked improve"
Documents normalization of IgG and improvement in infection frequency on monthly IVIg.
Granulocyte Colony-Stimulating Factor
Action: granulocyte colony-stimulating factor therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is granulocyte colony-stimulating factor therapy, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: recombinant G-CSF NCIT:C1287 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses recombinant G-CSF, annotated with Recombinant Granulocyte Colony-Stimulating Factor (NCIT:C1287). NCIT:C1287 is a therapeutic agent from the NCI Thesaurus.
G-CSF is used in the subset of patients with severe or chronic neutropenia and its complications (recurrent gingivitis, perianal abscesses); the neutropenia has been documented as G-CSF-responsive. Not indicated in patients with normal neutrophil counts.
Mechanism Target:
MODULATES Impaired Neutrophil Homeostasis — Pharmacologic G-CSF drives granulopoiesis, raising neutrophil counts in the neutropenic subset of patients.
Show evidence (1 reference)
PMID:37522988 SUPPORT Human Clinical
"which was responsive to granulocyte-colony stimulating factor"
Documents G-CSF responsiveness of the neutropenia in a FNIP1-deficient patient.
Heart Failure Pharmacotherapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: captopril CHEBI:3380 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses captopril (CHEBI:3380). CHEBI:3380 is a therapeutic agent from Chemical Entities of Biological Interest. furosemide CHEBI:47426 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses furosemide (CHEBI:47426). CHEBI:47426 is a therapeutic agent from Chemical Entities of Biological Interest.
Supportive cardiac pharmacotherapy for the hypertrophic cardiomyopathy and its haemodynamic consequences. Reported regimens have included an ACE inhibitor (captopril), a loop diuretic (furosemide), antiplatelet therapy (acetylsalicylic acid), and carnitine in one patient, and digoxin in another. These are symptomatic measures; none targets the underlying AMPK gain-of-function lesion.
Show evidence (1 reference)
PMID:39537849 SUPPORT Human Clinical
"she is also treated with acetylsalicylic acid, captopril, furosemide, and carnitine achieving normal growth and no physical limitations."
Documents the supportive cardiac drug regimen used in a FNIP1-deficient patient.
Rate Control and Arrhythmia Management
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: beta-adrenergic antagonist NCIT:C29576 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses beta-adrenergic antagonist (NCIT:C29576). NCIT:C29576 is a therapeutic agent from the NCI Thesaurus. verapamil CHEBI:9948 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses verapamil (CHEBI:9948). CHEBI:9948 is a therapeutic agent from Chemical Entities of Biological Interest.
Negative-inotropic rate control — a beta-adrenergic antagonist, or a non-dihydropyridine calcium channel blocker (verapamil, diltiazem) as an alternative — is the standard first-line pharmacotherapy for symptomatic hypertrophic cardiomyopathy, improving diastolic filling and reducing any outflow tract gradient, in contrast to the vasodilators and diuretics that are relatively contraindicated when obstruction is present. Catheter ablation of the accessory pathway is the definitive treatment for symptomatic or high-risk ventricular pre-excitation.
Mechanism Target:
INHIBITS Ventricular Pre-excitation and Tachyarrhythmia — Rate control suppresses the tachyarrhythmia; catheter ablation eliminates the accessory atrioventricular pathway that carries the pre-excitation.
Genetic Counseling
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Genetic counseling for the family once biallelic FNIP1 loss of function is confirmed, covering the 25% recurrence risk of an autosomal recessive disorder, carrier testing of parents and siblings, and reproductive options. Particularly relevant here because reported families include consanguineous pedigrees and because an undiagnosed sibling died of cardiogenic shock in infancy before genetic evaluation was possible.
Show evidence (1 reference)
PMID:39537849 SUPPORT Human Clinical
"enabling genetic counseling as herein"
The authors present genetic counseling as a direct benefit of establishing the molecular diagnosis in this disorder.
Cardiac Surveillance
Action: cardiac monitoringNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is cardiac monitoring, annotated with Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Because cardiac involvement can be the presenting and life-limiting feature — including fatal cardiogenic shock in infancy — echocardiographic and electrocardiographic surveillance for hypertrophic cardiomyopathy, valvular disease, and pre-excitation is a core component of management for any patient with confirmed FNIP1 deficiency.
Show evidence (1 reference)
PMID:39537849 SUPPORT Human Clinical
"Her sibling (subject II-1) had similar clinical features, along with dysmorphic facial features and hypotony, and succumbed to cardiogenic shock at the age of 2 months, prior to genetic evaluation."
Illustrates the lethal potential of unrecognised cardiac involvement, motivating systematic cardiac surveillance.
🔬

Diagnosis

2
Molecular genetic testing with copy-number analysis
Definitive diagnosis rests on demonstrating biallelic FNIP1 loss-of-function. Exome sequencing alone can be insufficient: reported patients have required copy-number variant analysis or detection of uniparental disomy to establish biallelic inactivation, so CNV analysis should accompany sequencing when a single heterozygous FNIP1 variant is found in a compatible phenotype.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:32905580 SUPPORT Human Clinical
"The results indicate that FNIP1 deficiency can be caused by complex genetic mechanisms and support the clinical utility of exome sequencing and CNV analysis in patients with broad phenotypes, including agammaglobulinemia and HCM."
Directly recommends combined exome plus CNV analysis for this diagnostic scenario.
Lymphocyte immunophenotyping and immunoglobulin quantification
Flow-cytometric enumeration of B (CD19+/CD20+) and T (CD3+) lymphocytes together with quantitative serum IgG, IgA, and IgM establishes the characteristic pattern of absent B cells with pan-isotype hypogammaglobulinemia and preserved or mildly increased T cells.
lymphocyte immunophenotyping NCIT:C16585 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:37522988 SUPPORT Human Clinical
"Immunological abnormalities in the peripheral blood show strongly diminished (nearly absent) B cell number s and severe reduction s in all serum immunoglobulin isotypes"
Defines the immunophenotypic and immunochemical pattern that raises suspicion of FNIP1 deficiency.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Ultra-rare. Only a handful of patients have been reported since the first descriptions in 2020; a 2023 case report placed the cumulative published total at seven, with further isolated cases reported subsequently. No population prevalence or incidence estimate has been established. Orphanet epidemiology was not consulted because the repository's Orphadata refresh currently fails a manifest checksum, so a qualitative prevalence band is used instead of an Orphanet numeric class.
Show evidence (2 references)
PMID:37522988 SUPPORT Human Clinical
"we identified a new FNIP1 -deficient male patient, bringing the total number of reported FNIP1-deficient patients to 7"
Establishes the ultra-rare, cases-in-literature occurrence (7 published patients as of 2023).
PMID:39537849 SUPPORT Human Clinical
"Genetic variants in Folliculin interacting protein 1 (FNIP1) were recently discovered as monogenic causes for immunodeficiency and cardiomyopathy, with only a few patients diagnosed thus far."
Independently confirms that only a few patients have been diagnosed to date.
🔀

Differential Diagnoses

5

Conditions with similar clinical presentations that must be differentiated from Immunodeficiency 93 and Hypertrophic Cardiomyopathy:

X-linked agammaglobulinemia (BTK deficiency)
Overlapping Features The prototypical agammaglobulinemia with absent B cells and recurrent sinopulmonary infection with encapsulated organisms. Distinguished from IMD93 by X-linked (not autosomal recessive) inheritance, absence of cardiac involvement, and a block earlier in B-cell development with normal numbers of pro-B cells.
Show evidence (1 reference)
PMID:35748970 SUPPORT Other
"Severe bacterial infections, normal numbers of pro-B cells"
The IUIS table records the classical agammaglobulinemias as having normal pro-B cell numbers and severe bacterial infection without a cardiac axis.
Autosomal recessive agammaglobulinemia (IGHM, IGLL1, CD79A/B, BLNK, PIK3R1)
Overlapping Features The autosomal recessive agammaglobulinemias share absent B cells and agammaglobulinemia with IMD93 and sit in the same IUIS category, but lack hypertrophic cardiomyopathy and pre-excitation. The presence of infantile hypertrophic cardiomyopathy in an agammaglobulinemic child should prompt FNIP1 testing specifically.
Show evidence (1 reference)
PMID:39537849 SUPPORT Human Clinical
"FNIP1 loss-of-function should be considered in patients presenting in infancy with cardiac manifestations along with agammaglobulinemia (and B-cell lymphopenia)."
States the discriminating clinical rule — cardiac involvement plus agammaglobulinemia points to FNIP1 rather than the other agammaglobulinemias.
PRKAG2 glycogen-storage cardiomyopathy
Overlapping Features Gain-of-function mutations in the AMPK gamma-2 subunit (PRKAG2) cause hypertrophic cardiomyopathy with myocardial glycogen accumulation and ventricular pre-excitation — the closest cardiac mimic of IMD93, and mechanistically the same AMPK gain-of-function endpoint. PRKAG2 disease is autosomal dominant and has no immunologic phenotype.
Show evidence (1 reference)
PMID:27303042 SUPPORT Model Organism
"with close parallels to mice and humans bearing gain-of-function mutations in the γ2 subunit of AMPK"
Explicitly draws the parallel between FNIP1-deficient cardiomyopathy and AMPK gamma-2 (PRKAG2) gain-of-function disease.
Danon disease MONDO:0010281
Overlapping Features An X-linked LAMP2 deficiency causing a cardiac glycogen-storage cardiomyopathy with massive ventricular hypertrophy and ventricular pre-excitation — the same cardiac triad as IMD93 — but accompanied by skeletal myopathy and intellectual disability rather than agammaglobulinemia, and with no B-cell or immunoglobulin defect. Curated separately in dismech as `Danon_disease`.
Distinguishing Features
  • X-linked LAMP2 inheritance rather than autosomal recessive FNIP1
  • Normal B-cell counts and normal serum immunoglobulins
  • Skeletal myopathy and intellectual disability
  • Autophagic vacuoles with sarcolemmal features on muscle biopsy
Pompe disease (glycogen storage disease type II) MONDO:0009290
Overlapping Features Acid alpha-glucosidase (GAA) deficiency causing infantile-onset hypertrophic cardiomyopathy with lysosomal glycogen storage and a short PR interval, closely mimicking the IMD93 cardiac presentation in the first months of life. Distinguished by profound hypotonia and skeletal myopathy, a deficient GAA enzyme assay, and an intact humoral immune system.
Distinguishing Features
  • Deficient GAA enzyme activity on dried blood spot or fibroblast assay
  • Profound hypotonia with skeletal muscle involvement
  • Normal B cells and serum immunoglobulins
  • Treatable with enzyme replacement therapy
🐁

Animal Models

1
Fnip1 homozygous loss-of-function (ENU-derived recessive variant and constitutive knockout) Mouse (Mus musculus) Knockout
Fnip1-deficient mice are the defining model of IMD93 and reproduce both arms of the human disorder: profound B-cell deficiency arising from a developmental block at the pre-B-cell stage, and cardiomyopathy with left ventricular hypertrophy and myocardial glycogen accumulation accompanied by elevated AMPK gamma-2 activity. Heterozygous animals lose marginal zone B cells. The metabolic defects seen in patient B cells recapitulate this model.
Profound B-cell deficiency with pre-B-cell developmental arrest Left ventricular hypertrophy with myocardial glycogen accumulation Elevated AMPK gamma-2 activity in neonatal myocardium
Species
Mouse (Mus musculus)
Genotype
Fnip1 homozygous loss-of-function (ENU-derived recessive variant and constitutive knockout)
Genes
Fnip1 hgnc:29418 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns Fnip1 (hgnc:29418). hgnc:29418 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (2 references)
PMID:27303042 SUPPORT Model Organism
"Homozygous FNIP1 deficiency resulted in profound B-cell deficiency, partially restored by overexpression of the antiapoptotic protein BCL2, whereas heterozygous deficiency caused a loss of marginal zone B cells."
Establishes the B-cell phenotype and its gene-dosage sensitivity in the mouse model.
PMID:32905580 SUPPORT Human Clinical
"These defects recapitulated the Fnip1-/- animal model."
Confirms translational fidelity: patient B-cell metabolic defects match those of the Fnip1-null mouse.
{ }

Source YAML

click to show 
name: Immunodeficiency 93 and Hypertrophic Cardiomyopathy
creation_date: "2026-08-01T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: immunodeficiency 93 and hypertrophic cardiomyopathy
  term:
    id: MONDO:0030528
    label: immunodeficiency 93 and hypertrophic cardiomyopathy
description: >
  Immunodeficiency 93 and hypertrophic cardiomyopathy (IMD93; FNIP1 deficiency;
  OMIM 619705) is an autosomal recessive syndromic inborn error of immunity
  caused by biallelic loss-of-function variants in FNIP1, the gene encoding
  folliculin-interacting protein 1. Onset is in the first months to years of
  life with recurrent viral and bacterial infection — particularly
  sinopulmonary infection with encapsulated organisms — together with
  hypertrophic cardiomyopathy. Immunologic workup characteristically shows
  profoundly decreased or absent circulating B cells with hypo- or
  agammaglobulinemia, reflecting an early arrest of B-cell development at the
  pre-B stage; severe or intermittent neutropenia and a mild T-cell
  lymphocytosis are seen in some but not all patients, and laboratory findings
  vary between individuals. Immunoglobulin replacement therapy is beneficial.
  Cardiac involvement extends beyond hypertrophic cardiomyopathy to atrial
  septal defect, valvular insufficiency, tachyarrhythmia, and ventricular
  pre-excitation (Wolff-Parkinson-White syndrome). Mechanistically, FNIP1
  partners with folliculin (FLCN) to couple nutrient and energy sensing to the
  AMPK and mTORC1 pathways; its loss produces an AMPK gain-of-function state
  that both blocks the pre-B-cell metabolic checkpoint and drives glycogen
  accumulation in cardiomyocytes, phenocopying PRKAG2 (AMPK gamma-2)
  gain-of-function cardiomyopathy with pre-excitation.

synonyms:
  - IMD93
  - FNIP1 deficiency
  - Folliculin-interacting protein 1 deficiency
  - Immunodeficiency and hypertrophic cardiomyopathy

parents:
  - Inborn error of immunity
  - Agammaglobulinemia

notes: >
  Scope caveat carried over from the OMIM 619705 / MONDO:0030528 definition:
  rare myopathic and neurologic features (metabolic myopathy, muscular
  hypotonia, microcephaly, developmental delay, cerebellar hypoplasia) have
  been reported in individual FNIP1-deficient patients but are NOT consistently
  part of the disorder and may reflect additional genetic factors in the
  consanguineous pedigrees in which they were observed. They are therefore not
  curated here as core phenotypes; the open question is recorded under
  `discussions`.

classifications:
  harrisons_chapter:
    - classification_value: IMMUNE_RHEUMATOLOGIC
      evidence:
        - reference: PMID:32905580
          reference_title: "Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency."
          supports: SUPPORT
          evidence_source: HUMAN_CLINICAL
          snippet: "FNIP1 deficiency is a novel inborn error of immunity characterized by early and severe B-cell development defect, agammaglobulinemia, variable neutropenia, and HCM."
          explanation: >
            IMD93 is a primary immunodeficiency (inborn error of immunity),
            placing it in Harrison's immune/rheumatologic Part.
    - classification_value: CARDIOVASCULAR
      evidence:
        - reference: PMID:32181500
          reference_title: "Mutations of the gene FNIP1 associated with a syndromic autosomal recessive immunodeficiency with cardiomyopathy and pre-excitation syndrome."
          supports: SUPPORT
          evidence_source: HUMAN_CLINICAL
          snippet: "FNIP1 deficiency patients have a AMPK-P gain of function phenotype with hypertrophic cardiomyopathy, Wolff-Parkinson-White pre-excitation syndrome, myopathy of skeletal muscles and combined immunodeficiency."
          explanation: >
            Hypertrophic cardiomyopathy with pre-excitation is a defining,
            frequently life-limiting axis of the disorder, warranting a
            cardiovascular Part assignment alongside the immunologic one.
    - classification_value: GENETICS_ENVIRONMENT_DISEASE
      evidence:
        - reference: PMID:32905580
          reference_title: "Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency."
          supports: SUPPORT
          evidence_source: HUMAN_CLINICAL
          snippet: "We identified homozygous or compound-heterozygous variants in the gene for folliculin interacting protein 1 (FNIP1), leading to loss of the FNIP1 protein."
          explanation: >
            IMD93 is a Mendelian single-gene (FNIP1) recessive disorder,
            supporting placement in Harrison's genetics Part.
  iuis_category:
    classification_value: predominantly antibody deficiency
    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: "FNIP1 deficiency (6 patients) FNIP1 AR"
        explanation: >
          The IUIS 2022 Expert Committee update lists FNIP1 deficiency in
          Table 3 (predominantly antibody deficiencies), in the subsection
          "severe reduction in all serum immunoglobulin isotypes with
          profoundly decreased or absent B cells" — the same category as XLA.
      - 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: "B cell deficiencies, agammaglobulinemia, or hypogamma"
        explanation: >
          Confirms that FNIP1 was added to the IUIS "B cell deficiencies,
          agammaglobulinemia, or hypogammaglobulinemia" table (Table 3) rather
          than to the combined-immunodeficiency tables.

inheritance:
  - name: Autosomal recessive
    description: >
      IMD93 is inherited in an autosomal recessive manner. Reported patients
      carry homozygous FNIP1 loss-of-function variants (often in consanguineous
      families), compound-heterozygous variants, or a single variant unmasked
      by uniparental disomy or a copy-number deletion of the second allele.
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
      - reference: PMID:32181500
        reference_title: "Mutations of the gene FNIP1 associated with a syndromic autosomal recessive immunodeficiency with cardiomyopathy and pre-excitation syndrome."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Mutations of the gene FNIP1 associated with a syndromic autosomal recessive immunodeficiency with cardiomyopathy and pre-excitation syndrome."
        explanation: Establishes autosomal recessive inheritance for FNIP1-related immunodeficiency with cardiomyopathy.
      - 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: "FNIP1 deficiency (6 patients) FNIP1 AR"
        explanation: IUIS table records the inheritance mode of FNIP1 deficiency as AR (autosomal recessive).

prevalence:
  - population: Worldwide
    measure_type: CASES_IN_LITERATURE
    prevalence_class: ULTRA_RARE
    notes: >
      Ultra-rare. Only a handful of patients have been reported since the first
      descriptions in 2020; a 2023 case report placed the cumulative published
      total at seven, with further isolated cases reported subsequently. No
      population prevalence or incidence estimate has been established.
      Orphanet epidemiology was not consulted because the repository's
      Orphadata refresh currently fails a manifest checksum, so a qualitative
      prevalence band is used instead of an Orphanet numeric class.
    evidence:
      - reference: PMID:37522988
        reference_title: "A Case Report of Folliculin-Interacting Protein 1 Deficiency."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "we identified a new FNIP1 -deficient male patient, bringing the total number of reported FNIP1-deficient patients to 7"
        explanation: >
          Establishes the ultra-rare, cases-in-literature occurrence (7
          published patients as of 2023).
      - reference: PMID:39537849
        reference_title: "A novel mutation in FNIP1 associated with a syndromic immunodeficiency and cardiomyopathy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Genetic variants in Folliculin interacting protein 1 (FNIP1) were recently discovered as monogenic causes for immunodeficiency and cardiomyopathy, with only a few patients diagnosed thus far."
        explanation: Independently confirms that only a few patients have been diagnosed to date.

genetic:
  - name: FNIP1
    gene_term:
      preferred_term: FNIP1
      term:
        id: hgnc:29418
        label: FNIP1
    relationship_type: CAUSATIVE
    notes: >
      Biallelic loss-of-function variants in FNIP1 (chromosome 5q31.1) abolish
      the FNIP1 protein. Reported alleles span nonsense (c.868C>T; c.3334C>T,
      p.Gln1112*), splice-site (c.3306+1G>A), frameshift
      (c.52_64dup, p.Asp22GlyfsTer21; c.3218delT, p.Leu1073Trpfs*32) and
      multi-exon deletion variants. Two mechanistically instructive
      "second-hit" configurations have been documented: unmasking of a
      heterozygous variant by uniparental disomy, and hemizygosity created by a
      de novo copy-number deletion spanning FNIP1 on the other allele. FNIP2,
      the close paralogue, is not upregulated to compensate — FNIP2 protein
      abundance was unchanged in patient cells.
    variants:
      - name: "NM_133372.3:c.52_64dup (p.Asp22GlyfsTer21)"
        description: >
          Homozygous 13-bp duplication in exon 1 of 18 causing a frameshift and
          premature stop; classified likely pathogenic (ACMG).
      - name: "NM_133372.3:c.3334C>T (p.Gln1112*)"
        description: >
          Nonsense variant in exon 17, present in a hemizygous state due to a
          de novo paternal copy-number deletion spanning FNIP1; immunoblotting
          showed complete absence of FNIP1 protein in patient cells.
    evidence:
      - reference: PMID:32905580
        reference_title: "Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "We identified homozygous or compound-heterozygous variants in the gene for folliculin interacting protein 1 (FNIP1), leading to loss of the FNIP1 protein."
        explanation: Establishes biallelic FNIP1 loss-of-function as the cause of the disorder.
      - reference: PMID:32905580
        reference_title: "Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Moreover, we identified either uniparental disomy or copy-number variants (CNVs) in 2 patients, expanding the variant spectrum of this novel inborn error of immunity."
        explanation: >
          Documents uniparental disomy and CNVs as non-canonical routes to
          biallelic FNIP1 inactivation, motivating CNV analysis alongside
          exome sequencing.
      - reference: PMID:39537849
        reference_title: "A novel mutation in FNIP1 associated with a syndromic immunodeficiency and cardiomyopathy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Genetic evaluation identified a homozygous 13-bp duplication variant in FNIP1 (c.52_64dupGCGCCCGGCCGCG, p. Asp22GlyfsTer21) resulting in a frameshift in exon 1/18."
        explanation: Documents a novel homozygous frameshift allele in a patient with the full IMD93 phenotype.
      - reference: PMID:37522988
        reference_title: "A Case Report of Folliculin-Interacting Protein 1 Deficiency."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Of note, the absence of the FNIP1 protein did not appear to affect FNIP2 protein abundance in these cells"
        explanation: >
          Shows that the paralogue FNIP2 does not compensate at the protein
          level, consistent with a non-redundant FNIP1 requirement.

pathophysiology:
  - name: FNIP1 Loss of Function
    biological_scale: MOLECULAR
    description: >
      Biallelic loss-of-function variants in FNIP1 abolish the
      folliculin-interacting protein 1 polypeptide. Immunoblotting of
      patient-derived T-cell blasts and EBV-immortalized B cells confirms
      absent FNIP1 protein, and the paralogue FNIP2 is not upregulated to
      compensate.
    gene:
      preferred_term: FNIP1
      term:
        id: hgnc:29418
        label: FNIP1
      modifier: ABSENT
    downstream:
      - target: Dysregulated AMPK and mTORC1 Nutrient Sensing
    evidence:
      - reference: PMID:32905580
        reference_title: "Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "We identified homozygous or compound-heterozygous variants in the gene for folliculin interacting protein 1 (FNIP1), leading to loss of the FNIP1 protein."
        explanation: Establishes protein-level loss of FNIP1 as the proximal molecular lesion.
      - reference: PMID:37522988
        reference_title: "A Case Report of Folliculin-Interacting Protein 1 Deficiency."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Immunoblotting demonstrated the absence of FNIP1 protein in patient-derived T cell blasts"
        explanation: Direct protein-level confirmation of FNIP1 absence in patient cells.

  - name: Dysregulated AMPK and mTORC1 Nutrient Sensing
    biological_scale: MOLECULAR
    description: >
      FNIP1 forms a complex with folliculin (FLCN) that couples cellular energy
      and amino-acid status to the two master metabolic regulators: it binds
      and modulates AMP-activated protein kinase (AMPK), and the FLCN-FNIP1
      complex acts as a GTPase-activating protein for RagC/D, controlling
      mTORC1 recruitment to the lysosome. FNIP1 additionally interacts with the
      HSP90 chaperone machinery, coupling its own stability to proteostasis.
      Loss of FNIP1 produces an AMPK phosphorylation (AMPK-P) gain-of-function
      state; in mouse B-cell progenitors both AMPK and mTORC1 are
      simultaneously activated, mTOR is inappropriately localized at the
      lysosome under nutrient-depleted conditions, and the MiT/TFE
      transcription factor TFE3 accumulates in the nucleus, driving lysosomal
      biogenesis and increased autophagic flux. The lesion is notably not
      reducible to a single linear "AMPK-high" or "mTOR-high" abnormality.
    molecular_functions:
      - preferred_term: AMP-activated protein kinase activity
        term:
          id: GO:0004679
          label: AMP-activated protein kinase activity
        modifier: INCREASED
      - preferred_term: RagC/D GTPase-activating activity of the FLCN-FNIP1 complex
        term:
          id: GO:0005096
          label: GTPase activator activity
        modifier: DECREASED
    biological_processes:
      - preferred_term: mTORC1 (TOR) signaling
        term:
          id: GO:0031929
          label: TOR signaling
        modifier: DYSREGULATED
      - preferred_term: cellular response to nutrient levels
        term:
          id: GO:0031669
          label: cellular response to nutrient levels
        modifier: ABNORMAL
    cellular_components:
      - preferred_term: lysosome
        term:
          id: GO:0005764
          label: lysosome
    downstream:
      - target: Pre-B Cell Metabolic Checkpoint Failure and Developmental Arrest
      - target: Cardiomyocyte Glycogen Accumulation
      - target: Impaired Neutrophil Homeostasis
    evidence:
      - reference: PMID:32181500
        reference_title: "Mutations of the gene FNIP1 associated with a syndromic autosomal recessive immunodeficiency with cardiomyopathy and pre-excitation syndrome."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "FNIP1 deficiency patients have a AMPK-P gain of function phenotype with hypertrophic cardiomyopathy, Wolff-Parkinson-White pre-excitation syndrome, myopathy of skeletal muscles and combined immunodeficiency."
        explanation: >
          Frames human FNIP1 deficiency as an AMPK-phosphorylation
          gain-of-function state, the unifying molecular abnormality.
      - reference: PMID:40699689
        reference_title: "FNIP1 Deficiency: Pathophysiology and Clinical Manifestations of a Rare Syndromic Primary Immunodeficiency."
        supports: SUPPORT
        evidence_source: OTHER
        snippet: "FNIP1 forms a complex with folliculin (FLCN) to regulate the mechanistic target of rapamycin complex 1 (mTORC1), functioning as a GTPase-activating protein (GAP) for RagC/D."
        explanation: Defines the FLCN-FNIP1 complex's RagC/D GAP activity toward mTORC1.
      - reference: PMID:40699689
        reference_title: "FNIP1 Deficiency: Pathophysiology and Clinical Manifestations of a Rare Syndromic Primary Immunodeficiency."
        supports: SUPPORT
        evidence_source: OTHER
        snippet: "Additionally, FNIP1 interacts with heat shock protein 90 (HSP90) and undergoes phosphorylation, glycosylation, and ubiquitination, which dynamically regulate its stability and function."
        explanation: Documents the HSP90 chaperone axis and post-translational control of FNIP1 stability.
      - reference: PMID:31676673
        reference_title: "Folliculin Interacting Protein 1 Maintains Metabolic Homeostasis during B Cell Development by Modulating AMPK, mTORC1, and TFE3."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Both AMPK and mTORC1 were activated in Fnip1-deficient B cell progenitors. In this study, we found inappropriate mTOR localization at the lysosome under nutrient-depleted conditions."
        explanation: >
          Mouse data establishing simultaneous AMPK/mTORC1 activation and
          mislocalized lysosomal mTOR on FNIP1 loss.
      - reference: PMID:31676673
        reference_title: "Folliculin Interacting Protein 1 Maintains Metabolic Homeostasis during B Cell Development by Modulating AMPK, mTORC1, and TFE3."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Fnip1-deficient B cell progenitors exhibited increased nuclear localization of transcription factor binding to IgHM enhancer 3 (TFE3) in developing B cells, which correlated with an increased expression of TFE3-target genes, increased lysosome numbers and function, and increased autophagic flux."
        explanation: >
          Identifies TFE3 nuclear accumulation with increased lysosomal
          biogenesis and autophagic flux downstream of FNIP1 loss.

  - name: Pre-B Cell Metabolic Checkpoint Failure and Developmental Arrest
    biological_scale: CELLULAR
    description: >
      FNIP1 enforces a metabolic checkpoint that verifies a developing pre-B
      cell has sufficient metabolic capacity to undergo the proliferative burst
      that follows successful immunoglobulin heavy-chain rearrangement. Without
      FNIP1, B-cell development arrests at the pre-B-cell stage: progenitors
      show impaired mitochondrial number and activity, blunted PI3K/AKT
      signalling, increased autophagic flux, and increased apoptosis on
      amino-acid (lysine or arginine) withdrawal. The arrest is not rescued by
      genetic AMPK inhibition, mTORC1 inhibition, or Bcl-xL-mediated survival
      support, indicating a metabolic rather than purely apoptotic block.
    cell_types:
      - preferred_term: pre-B cell (precursor B cell)
        term:
          id: CL:0000817
          label: precursor B cell
      - preferred_term: large pre-B-II cell
        term:
          id: CL:0000955
          label: pre-B-II cell
    biological_processes:
      - preferred_term: B cell differentiation
        term:
          id: GO:0030183
          label: B cell differentiation
        modifier: DECREASED
      - preferred_term: autophagy
        term:
          id: GO:0006914
          label: autophagy
        modifier: INCREASED
    cellular_components:
      - preferred_term: mitochondrion
        term:
          id: GO:0005739
          label: mitochondrion
        modifier: ABNORMAL
    downstream:
      - target: Absent Circulating B Cells and Agammaglobulinemia
    evidence:
      - reference: PMID:31676673
        reference_title: "Folliculin Interacting Protein 1 Maintains Metabolic Homeostasis during B Cell Development by Modulating AMPK, mTORC1, and TFE3."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "We previously found that constitutive disruption of Fnip1 in mice resulted in a lack of peripheral B cells because of a block in B cell development at the pre-B cell stage."
        explanation: Localizes the developmental block to the pre-B-cell stage.
      - reference: PMID:31676673
        reference_title: "Folliculin Interacting Protein 1 Maintains Metabolic Homeostasis during B Cell Development by Modulating AMPK, mTORC1, and TFE3."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Genetic inhibition of AMPK, inhibition of mTORC1, or restoration of cell viability with a Bcl-xL transgene failed to rescue B cell development in Fnip1-deficient mice."
        explanation: >
          Shows the arrest cannot be rescued by blocking AMPK/mTORC1 or by
          survival support alone, arguing for a metabolic-capacity checkpoint.
      - reference: PMID:32905580
        reference_title: "Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "B-cell metabolism, including mitochondrial numbers and activity and phosphatidylinositol 3-kinase/AKT pathway, was impaired. These defects recapitulated the Fnip1-/- animal model."
        explanation: >
          Confirms in patient cells the mitochondrial and PI3K/AKT metabolic
          defects predicted by the mouse model.
      - reference: PMID:38748614
        reference_title: "Clinical and Immunologic Features of a Patient With Homozygous FNIP1 Variant."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "FNIP1 plays a critical role in B-cell development and metabolic homeostasis, establishing a metabolic checkpoint that ensures pre-B cells possess sufficient metabolic capacity to undergo division while concurrently limiting lymphogenesis due to abnormal growth."
        explanation: States the pre-B-cell metabolic checkpoint role explicitly.

  - name: Absent Circulating B Cells and Agammaglobulinemia
    biological_scale: ORGANISM
    description: >
      The pre-B-cell arrest translates into profoundly decreased or absent
      circulating CD19+/CD20+ B cells and severe reduction of all serum
      immunoglobulin isotypes (profound hypogammaglobulinemia to
      agammaglobulinemia). A mild increase in circulating CD3+ T lymphocytes
      has been documented in some patients.
    biological_processes:
      - preferred_term: immunoglobulin production
        term:
          id: GO:0002377
          label: immunoglobulin production
        modifier: DECREASED
    downstream:
      - target: Susceptibility to Recurrent Sinopulmonary and Gastrointestinal Infection
    evidence:
      - reference: PMID:37522988
        reference_title: "A Case Report of Folliculin-Interacting Protein 1 Deficiency."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Immunological abnormalities in the peripheral blood show strongly diminished (nearly absent)  B cell number s and severe reduction s in all serum immunoglobulin isotypes ( profound hypogamma/agammaglobulinemia ) associated with severe or intermittent neutropenia"
        explanation: >
          Summarises the core laboratory phenotype across reported patients:
          near-absent B cells with pan-isotype immunoglobulin reduction.
      - reference: PMID:39537849
        reference_title: "A novel mutation in FNIP1 associated with a syndromic immunodeficiency and cardiomyopathy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Immune workup revealed agammaglobulinemia and a lack of B lymphocytes."
        explanation: Independent patient-level confirmation of agammaglobulinemia with absent B lymphocytes.

  - name: Susceptibility to Recurrent Sinopulmonary and Gastrointestinal Infection
    biological_scale: ORGANISM
    description: >
      Loss of antibody-mediated humoral immunity produces early-onset recurrent
      viral and bacterial infection, dominated by upper and lower respiratory
      tract infection (including otitis media, pneumonia, and sequelae such as
      bronchiectasis) and gastrointestinal infection or enteropathy, with
      resulting failure to thrive. Encapsulated bacteria are characteristic
      pathogens of this antibody-deficiency pattern.
    evidence:
      - reference: PMID:37522988
        reference_title: "A Case Report of Folliculin-Interacting Protein 1 Deficiency."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "severe and/or recurrent upper and lower respiratory tract infections"
        explanation: >
          The review states that clinical manifestations of FNIP1 deficiency
          occurring within the first year of life include severe and/or
          recurrent upper and lower respiratory tract infections.
      - reference: PMID:39537849
        reference_title: "A novel mutation in FNIP1 associated with a syndromic immunodeficiency and cardiomyopathy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "she developed recurrent viral and bacterial infections, including recurrent sinopulmonary infections"
        explanation: Documents the combined viral and bacterial recurrent-infection pattern in a patient.

  - name: Cardiomyocyte Glycogen Accumulation
    biological_scale: CELLULAR
    description: >
      Within the cardiomyocyte, the AMPK gain-of-function state driven by FNIP1
      loss reproduces the cell-level pathology of activating mutations in the
      AMPK gamma-2 subunit (PRKAG2): gamma-2-specific AMPK activity is elevated
      in neonatal FNIP1-deficient myocardium and glycogen accumulates within
      the myocyte. This is the cellular lesion that underlies the tissue-level
      hypertrophy modelled downstream.
    cell_types:
      - preferred_term: cardiomyocyte
        term:
          id: CL:0000746
          label: cardiac muscle cell
    biological_processes:
      - preferred_term: glycogen metabolic process
        term:
          id: GO:0005977
          label: glycogen metabolic process
        modifier: INCREASED
    downstream:
      - target: Ventricular Hypertrophy and Hypertrophic Cardiomyopathy
    evidence:
      - reference: PMID:27303042
        reference_title: "Mutation of Fnip1 is associated with B-cell deficiency, cardiomyopathy, and elevated AMPK activity."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Concordantly, γ2-specific AMPK activity was elevated in neonatal FNIP1-deficient myocardium"
        explanation: Direct measurement of elevated gamma-2 AMPK activity in FNIP1-deficient myocardium.
      - reference: PMID:27303042
        reference_title: "Mutation of Fnip1 is associated with B-cell deficiency, cardiomyopathy, and elevated AMPK activity."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "FNIP1-deficient mice developed cardiomyopathy characterized by left ventricular hypertrophy and glycogen accumulation, with close parallels to mice and humans bearing gain-of-function mutations in the γ2 subunit of AMPK."
        explanation: >
          Establishes myocardial glycogen accumulation and the AMPK-gamma-2
          (PRKAG2) phenocopy as the mechanism in the mouse model.

  - name: Ventricular Hypertrophy and Hypertrophic Cardiomyopathy
    biological_scale: TISSUE
    description: >
      At tissue level the glycogen-laden myocardium becomes hypertrophic. In
      patients this manifests as hypertrophic — frequently obstructive —
      cardiomyopathy with left or biventricular hypertrophy, presenting from
      the neonatal period through the first years of life, and can be fatal
      through cardiogenic shock or heart failure.
    biological_processes:
      - preferred_term: cardiac muscle hypertrophy
        term:
          id: GO:0003300
          label: cardiac muscle hypertrophy
        modifier: INCREASED
    downstream:
      - target: Ventricular Pre-excitation and Tachyarrhythmia
    evidence:
      - reference: PMID:32905580
        reference_title: "Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "We here investigated 3 novel patients, including the first known adult, from unrelated families with agammaglobulinemia, recurrent infections, and hypertrophic cardiomyopathy (HCM)."
        explanation: Confirms hypertrophic cardiomyopathy as a human phenotype of FNIP1 deficiency.
      - reference: PMID:27303042
        reference_title: "Mutation of Fnip1 is associated with B-cell deficiency, cardiomyopathy, and elevated AMPK activity."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "FNIP1-deficient mice developed cardiomyopathy characterized by left ventricular hypertrophy and glycogen accumulation"
        explanation: Mouse model recapitulates the ventricular hypertrophy at tissue level.

  - name: Ventricular Pre-excitation and Tachyarrhythmia
    biological_scale: ORGANISM
    description: >
      Glycogen-laden hypertrophic myocardium provides the substrate for
      accessory atrioventricular conduction, producing ventricular
      pre-excitation (Wolff-Parkinson-White syndrome) and supraventricular
      tachyarrhythmia — the same electrophysiological signature seen in PRKAG2
      glycogen-storage cardiomyopathy.
    evidence:
      - reference: PMID:32181500
        reference_title: "Mutations of the gene FNIP1 associated with a syndromic autosomal recessive immunodeficiency with cardiomyopathy and pre-excitation syndrome."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "hypertrophic cardiomyopathy, Wolff-Parkinson-White pre-excitation syndrome"
        explanation: Documents WPW pre-excitation accompanying the hypertrophic cardiomyopathy in patients.
      - reference: PMID:37522988
        reference_title: "A Case Report of Folliculin-Interacting Protein 1 Deficiency."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "hypertrophic cardiomyopathy (left ventricle) associated with Wolff-Parkinson-White"
        explanation: Independent patient with left ventricular HCM and Wolff-Parkinson-White syndrome.
      - reference: PMID:39537849
        reference_title: "A novel mutation in FNIP1 associated with a syndromic immunodeficiency and cardiomyopathy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "(SVT) as well as bi-ventricular hypertrophy and hypertrophic obstructive cardiomyopathy"
        explanation: >
          Documents supraventricular tachycardia alongside biventricular
          hypertrophy and hypertrophic obstructive cardiomyopathy, evidencing
          the tachyarrhythmia limb of this node. Graded PARTIAL because the
          affected individual was the index patient's sibling, who died at 2
          months before genetic evaluation; the authors state only that he
          "very likely" carried the same FNIP1 variant, so the genotype was
          never confirmed.

  - name: Impaired Neutrophil Homeostasis
    biological_scale: ORGANISM
    description: >
      A subset of FNIP1-deficient patients develop severe or intermittent
      neutropenia, sometimes with recurrent gingivitis and perianal abscesses,
      which is responsive to granulocyte colony-stimulating factor. Other
      patients have entirely normal neutrophil counts, making neutropenia a
      variable rather than obligate feature; the observation nonetheless
      suggests a non-redundant role for FNIP1 in neutrophils.
    evidence:
      - reference: PMID:32905580
        reference_title: "Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Two of them also presented with intermittent or severe chronic neutropenia."
        explanation: Documents variable neutropenia in two of three patients in the defining cohort.
      - reference: PMID:37522988
        reference_title: "A Case Report of Folliculin-Interacting Protein 1 Deficiency."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "It also  suggests a non-redundant function of FNIP1 in neutrophils."
        explanation: Interprets the neutropenia as evidence of a non-redundant neutrophil requirement for FNIP1.

phenotypes:
  - category: Immunologic
    name: Agammaglobulinemia
    description: >
      Severe reduction of all serum immunoglobulin isotypes, ranging from
      profound hypogammaglobulinemia to complete agammaglobulinemia, secondary
      to the early block in B-cell development.
    phenotype_term:
      preferred_term: Agammaglobulinemia
      term:
        id: HP:0004432
        label: Agammaglobulinemia
      onset:
        onset_category: INFANTILE
        notes: Detected in the first months to years of life.
    frequency: VERY_FREQUENT
    evidence:
      - reference: PMID:32905580
        reference_title: "Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "FNIP1 deficiency is a novel inborn error of immunity characterized by early and severe B-cell development defect, agammaglobulinemia, variable neutropenia, and HCM."
        explanation: >
          Names agammaglobulinemia as a defining (not variable) feature of the
          disorder — contrasted in the same sentence with "variable"
          neutropenia — supporting a VERY_FREQUENT band.
      - reference: PMID:39537849
        reference_title: "A novel mutation in FNIP1 associated with a syndromic immunodeficiency and cardiomyopathy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Immune workup revealed agammaglobulinemia and a lack of B lymphocytes."
        explanation: Patient-level documentation of agammaglobulinemia.

  - category: Immunologic
    name: Decreased total B cell count
    description: >
      Profoundly decreased to absent circulating CD19+/CD20+ B lymphocytes, the
      cellular counterpart of the agammaglobulinemia.
    phenotype_term:
      preferred_term: Absent circulating B cells
      term:
        id: HP:0010976
        label: Decreased total B cell count
    frequency: VERY_FREQUENT
    evidence:
      - reference: PMID:39537849
        reference_title: "A novel mutation in FNIP1 associated with a syndromic immunodeficiency and cardiomyopathy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "FNIP1 loss-of-function should be considered in patients presenting in infancy with cardiac manifestations along with agammaglobulinemia (and B-cell lymphopenia)."
        explanation: >
          B-cell lymphopenia is presented as a consistent diagnostic hallmark
          of the disorder, supporting a VERY_FREQUENT band.
      - reference: PMID:39537849
        reference_title: "A novel mutation in FNIP1 associated with a syndromic immunodeficiency and cardiomyopathy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Due to complete absence of B lymphocytes, low levels of IgG and undetectable levels of IgA and IgM"
        explanation: >
          Patient-level flow-cytometric and immunochemical documentation of
          completely absent circulating B lymphocytes.

  - category: Immunologic
    name: Recurrent infections
    description: >
      Early-onset recurrent viral and bacterial infections, characteristically
      with encapsulated organisms, beginning in the first months of life.
    phenotype_term:
      preferred_term: Recurrent infections
      term:
        id: HP:0002719
        label: Recurrent infections
      onset:
        onset_category: INFANTILE
        notes: Manifests within the first year of life.
    frequency: VERY_FREQUENT
    evidence:
      - reference: PMID:37522988
        reference_title: "A Case Report of Folliculin-Interacting Protein 1 Deficiency."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Clinical manifestations of FNIP1 deficiency occurring within the first year of life"
        explanation: >
          Describes recurrent infection as a general clinical manifestation of
          FNIP1 deficiency occurring within the first year of life.
      - reference: PMID:39537849
        reference_title: "A novel mutation in FNIP1 associated with a syndromic immunodeficiency and cardiomyopathy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "she developed recurrent viral and bacterial infections, including recurrent sinopulmonary infections"
        explanation: Documents both viral and bacterial recurrent infection in a patient.

  - category: Immunologic
    name: Recurrent respiratory infections
    description: >
      Severe and/or recurrent upper and lower respiratory tract infections
      (otitis media, sinusitis, pneumonia), with bronchiectasis, fibrosis, and
      interstitial pneumonia reported as sequelae.
    phenotype_term:
      preferred_term: Recurrent sinopulmonary infections
      term:
        id: HP:0002205
        label: Recurrent respiratory infections
    frequency: VERY_FREQUENT
    evidence:
      - reference: PMID:37522988
        reference_title: "A Case Report of Folliculin-Interacting Protein 1 Deficiency."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "severe and/or recurrent upper and lower respiratory tract infections"
        explanation: >
          Presented as a general clinical manifestation of the disorder within
          the first year of life rather than a single-patient observation,
          supporting a VERY_FREQUENT band.

  - category: Respiratory
    name: Bronchiectasis
    description: >
      Bronchiectasis, with pulmonary fibrosis and interstitial pneumonia, as a
      structural sequela of the recurrent lower respiratory tract infection
      that follows the antibody deficiency.
    phenotype_term:
      preferred_term: Bronchiectasis
      term:
        id: HP:0002110
        label: Bronchiectasis
    frequency: OCCASIONAL
    notes: >
      Recorded by the IUIS 2022 Expert Committee among the associated features
      of FNIP1 deficiency. Frequency is not quantified in the source, so a
      conservative band is used.
    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: "bronchiectasis, fibrosis, interstitial pneumoniae"
        explanation: >
          The IUIS Table 3 "associated features" column for the FNIP1
          deficiency row lists bronchiectasis, fibrosis, and interstitial
          pneumonia alongside early-onset recurrent infections.

  - category: Cardiovascular
    name: Supraventricular tachycardia
    description: >
      Supraventricular tachyarrhythmia, reported in an affected infant
      alongside biventricular hypertrophy and hypertrophic obstructive
      cardiomyopathy, consistent with the accessory-pathway substrate that also
      produces the pre-excitation.
    phenotype_term:
      preferred_term: Supraventricular tachycardia
      term:
        id: HP:0004755
        label: Supraventricular tachycardia
    frequency: OCCASIONAL
    notes: >
      Reported in the index patient's sibling, who died of cardiogenic shock at
      2 months before genetic confirmation; the authors infer he "very likely"
      carried the same FNIP1 variant. Evidence graded PARTIAL accordingly.
    evidence:
      - reference: PMID:39537849
        reference_title: "A novel mutation in FNIP1 associated with a syndromic immunodeficiency and cardiomyopathy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "(SVT) as well as bi-ventricular hypertrophy and hypertrophic obstructive cardiomyopathy"
        explanation: >
          Documents supraventricular tachycardia with biventricular hypertrophy
          and HOCM in a clinically affected but genetically unconfirmed sibling
          of a molecularly diagnosed FNIP1 patient.

  - category: Hematologic
    name: Neutropenia
    description: >
      Severe or intermittent neutropenia, present in some but not all patients,
      responsive to granulocyte colony-stimulating factor. Other patients have
      normal neutrophil counts and function.
    phenotype_term:
      preferred_term: Neutropenia
      term:
        id: HP:0001875
        label: Decreased total neutrophil count
      temporality: RECURRENT
    frequency: FREQUENT
    notes: >
      Explicitly a variable feature. In the defining Blood cohort 2 of 3
      patients had neutropenia; other reported patients (e.g. Spivak et al.
      2024) had normal neutrophil counts.
    evidence:
      - reference: PMID:32905580
        reference_title: "Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Two of them also presented with intermittent or severe chronic neutropenia."
        explanation: >
          Two of three patients in the defining cohort had neutropenia,
          a derived-count basis for the FREQUENT band.
      - reference: PMID:32905580
        reference_title: "Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "agammaglobulinemia, variable neutropenia, and HCM"
        explanation: Characterises the neutropenia explicitly as variable, not obligate.

  - category: Immunologic
    name: Increased total T cell count
    description: >
      A mild T-cell lymphocytosis (increased circulating CD3+ T lymphocytes)
      has been observed in some patients, in the context of otherwise normal
      T-cell function (polyclonal TCR-Vbeta repertoire, normal TRECs).
    phenotype_term:
      preferred_term: T cell lymphocytosis
      term:
        id: HP:0100828
        label: Increased total T cell count
    frequency: OCCASIONAL
    evidence:
      - reference: PMID:37522988
        reference_title: "A Case Report of Folliculin-Interacting Protein 1 Deficiency."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "increase in CD3 T lymphocytes was observed at 30 years of age"
        explanation: >
          Single-patient observation of mild CD3+ T-lymphocytosis; reported as
          an isolated finding, hence the conservative OCCASIONAL band.

  - category: Cardiovascular
    name: Hypertrophic cardiomyopathy
    description: >
      Hypertrophic — frequently obstructive — cardiomyopathy, presenting from
      the neonatal period through the first years of life and capable of
      causing cardiogenic shock or fatal heart failure.
    phenotype_term:
      preferred_term: Hypertrophic cardiomyopathy
      term:
        id: HP:0001639
        label: Hypertrophic cardiomyopathy
      onset:
        onset_category: INFANTILE
        notes: Diagnosed from the neonatal period to the first years of life.
    frequency: VERY_FREQUENT
    evidence:
      - reference: PMID:32905580
        reference_title: "Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "FNIP1 deficiency is a novel inborn error of immunity characterized by early and severe B-cell development defect, agammaglobulinemia, variable neutropenia, and HCM."
        explanation: >
          HCM is listed among the defining (non-variable) characteristics of
          the disorder, supporting a VERY_FREQUENT band.
      - reference: PMID:38748614
        reference_title: "Clinical and Immunologic Features of a Patient With Homozygous FNIP1 Variant."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Deficiency in folliculin-interacting protein 1 (FNIP1) is a novel inborn error of immunity characterized by a severe defect in B-cell development, agammaglobulinemia, variable neutropenia, and hypertrophic cardiomyopathy."
        explanation: Independent confirmation of HCM as a core disease characteristic.

  - category: Cardiovascular
    name: Left ventricular hypertrophy
    description: >
      Left ventricular hypertrophy demonstrable on transthoracic
      echocardiography and cardiac CT; bi-ventricular hypertrophy has also been
      reported.
    phenotype_term:
      preferred_term: Left ventricular hypertrophy
      term:
        id: HP:0001712
        label: Left ventricular hypertrophy
    evidence:
      - reference: PMID:39537849
        reference_title: "A novel mutation in FNIP1 associated with a syndromic immunodeficiency and cardiomyopathy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "HCM, and left ventricular hypertrophy (LVH) on transthoracic echocardiography"
        explanation: Echocardiographic documentation of left ventricular hypertrophy in a patient.
      - reference: PMID:27303042
        reference_title: "Mutation of Fnip1 is associated with B-cell deficiency, cardiomyopathy, and elevated AMPK activity."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "FNIP1-deficient mice developed cardiomyopathy characterized by left ventricular hypertrophy and glycogen accumulation"
        explanation: Mouse model recapitulates the left ventricular hypertrophy.

  - category: Cardiovascular
    name: Wolff-Parkinson-White syndrome
    description: >
      Ventricular pre-excitation via an accessory atrioventricular pathway,
      reported in multiple FNIP1-deficient patients and mirroring the
      pre-excitation of PRKAG2 glycogen-storage cardiomyopathy.
    phenotype_term:
      preferred_term: Wolff-Parkinson-White pre-excitation syndrome
      term:
        id: HP:0001716
        label: Wolff-Parkinson-White syndrome
    frequency: FREQUENT
    evidence:
      - reference: PMID:32181500
        reference_title: "Mutations of the gene FNIP1 associated with a syndromic autosomal recessive immunodeficiency with cardiomyopathy and pre-excitation syndrome."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "hypertrophic cardiomyopathy, Wolff-Parkinson-White pre-excitation syndrome"
        explanation: >
          WPW is named as part of the phenotype of FNIP1 deficiency patients
          as a group (and in the article title), supporting a FREQUENT band.
      - reference: PMID:37522988
        reference_title: "A Case Report of Folliculin-Interacting Protein 1 Deficiency."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "hypertrophic cardiomyopathy (left ventricle) associated with Wolff-Parkinson-White"
        explanation: A further independent patient with WPW accompanying the HCM.

  - category: Cardiovascular
    name: Atrial septal defect
    description: >
      Atrial septal defect diagnosed shortly after birth alongside the
      hypertrophic cardiomyopathy, part of the broader spectrum of congenital
      heart defects reported in FNIP1 deficiency.
    phenotype_term:
      preferred_term: Atrial septal defect
      term:
        id: HP:0001631
        label: Atrial septal defect
      onset:
        onset_category: CONGENITAL
        notes: Diagnosed shortly after birth.
    frequency: OCCASIONAL
    evidence:
      - reference: PMID:39537849
        reference_title: "A novel mutation in FNIP1 associated with a syndromic immunodeficiency and cardiomyopathy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "was diagnosed with atrial-septal defect (ASD)"
        explanation: >
          Documents atrial septal defect in a genetically confirmed patient;
          reported in a minority of cases, hence the OCCASIONAL band.

  - category: Gastrointestinal
    name: Chronic diarrhea
    description: >
      Chronic or prolonged diarrhea, with enteropathy also reported;
      gastrointestinal manifestations improve substantially with immunoglobulin
      replacement.
    phenotype_term:
      preferred_term: Chronic diarrhea
      term:
        id: HP:0002028
        label: Chronic diarrhea
      temporality: CHRONIC
    frequency: OCCASIONAL
    evidence:
      - reference: PMID:39537849
        reference_title: "A novel mutation in FNIP1 associated with a syndromic immunodeficiency and cardiomyopathy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "The index patient (subject II-4) presented with hypertrophic cardiomyopathy, recurrent infections, and chronic diarrhea during infancy."
        explanation: Documents chronic diarrhea from infancy in a genetically confirmed patient.

  - category: Growth
    name: Failure to thrive
    description: >
      Failure to thrive secondary to the burden of recurrent infection and
      gastrointestinal disease.
    phenotype_term:
      preferred_term: Failure to thrive
      term:
        id: HP:0001508
        label: Failure to thrive
    frequency: OCCASIONAL
    evidence:
      - reference: PMID:39537849
        reference_title: "A novel mutation in FNIP1 associated with a syndromic immunodeficiency and cardiomyopathy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Accordingly, she developed failure to thrive (FTT)."
        explanation: Documents failure to thrive as a consequence of the infection and GI burden.

animal_models:
  - species: Mouse (Mus musculus)
    genotype: Fnip1 homozygous loss-of-function (ENU-derived recessive variant and constitutive knockout)
    category: Knockout
    description: >
      Fnip1-deficient mice are the defining model of IMD93 and reproduce both
      arms of the human disorder: profound B-cell deficiency arising from a
      developmental block at the pre-B-cell stage, and cardiomyopathy with left
      ventricular hypertrophy and myocardial glycogen accumulation accompanied
      by elevated AMPK gamma-2 activity. Heterozygous animals lose marginal
      zone B cells. The metabolic defects seen in patient B cells recapitulate
      this model.
    genes:
      - preferred_term: Fnip1
        term:
          id: hgnc:29418
          label: FNIP1
    associated_phenotypes:
      - Profound B-cell deficiency with pre-B-cell developmental arrest
      - Left ventricular hypertrophy with myocardial glycogen accumulation
      - Elevated AMPK gamma-2 activity in neonatal myocardium
    evidence:
      - reference: PMID:27303042
        reference_title: "Mutation of Fnip1 is associated with B-cell deficiency, cardiomyopathy, and elevated AMPK activity."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Homozygous FNIP1 deficiency resulted in profound B-cell deficiency, partially restored by overexpression of the antiapoptotic protein BCL2, whereas heterozygous deficiency caused a loss of marginal zone B cells."
        explanation: Establishes the B-cell phenotype and its gene-dosage sensitivity in the mouse model.
      - reference: PMID:32905580
        reference_title: "Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "These defects recapitulated the Fnip1-/- animal model."
        explanation: >
          Confirms translational fidelity: patient B-cell metabolic defects
          match those of the Fnip1-null mouse.

treatments:
  - name: Immunoglobulin Replacement Therapy
    description: >
      Regular immunoglobulin replacement (IVIg or SCIG) is the mainstay of
      management, supplying the antibody the patient cannot produce. Reported
      patients achieved normal IgG trough levels with marked reduction in
      sinopulmonary infections and substantial improvement in gastrointestinal
      symptoms.
    therapeutic_modality: PROTEIN_REPLACEMENT
    treatment_term:
      preferred_term: intravenous immunoglobulin therapy
      term:
        id: NCIT:C121331
        label: Intravenous Immunoglobulin Therapy
    target_mechanisms:
      - target: Absent Circulating B Cells and Agammaglobulinemia
        treatment_effect: BYPASSES
        description: >
          Exogenous polyclonal IgG substitutes for the antibody the arrested
          B-cell compartment cannot make; it bypasses rather than corrects the
          pre-B-cell developmental block.
    evidence:
      - reference: PMID:39537849
        reference_title: "A novel mutation in FNIP1 associated with a syndromic immunodeficiency and cardiomyopathy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "She was treated with supplemental intravenous immunoglobulins (IVIg) with good control of sinopulmonary and gastrointestinal manifestations."
        explanation: Clinical benefit of IVIg on the infectious and gastrointestinal burden.
      - reference: PMID:39537849
        reference_title: "A novel mutation in FNIP1 associated with a syndromic immunodeficiency and cardiomyopathy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "treatment with monthly intravenous immunoglobulin (IVIg) infusion was initiated, achieving normal IgG levels and exhibiting marked improve"
        explanation: Documents normalization of IgG and improvement in infection frequency on monthly IVIg.

  - name: Granulocyte Colony-Stimulating Factor
    description: >
      G-CSF is used in the subset of patients with severe or chronic
      neutropenia and its complications (recurrent gingivitis, perianal
      abscesses); the neutropenia has been documented as G-CSF-responsive.
      Not indicated in patients with normal neutrophil counts.
    therapeutic_modality: PROTEIN_REPLACEMENT
    treatment_term:
      preferred_term: granulocyte colony-stimulating factor therapy
      term:
        id: NCIT:C15986
        label: Pharmacotherapy
      therapeutic_agent:
        - preferred_term: recombinant G-CSF
          term:
            id: NCIT:C1287
            label: Recombinant Granulocyte Colony-Stimulating Factor
    target_mechanisms:
      - target: Impaired Neutrophil Homeostasis
        treatment_effect: MODULATES
        description: >
          Pharmacologic G-CSF drives granulopoiesis, raising neutrophil counts
          in the neutropenic subset of patients.
    evidence:
      - reference: PMID:37522988
        reference_title: "A Case Report of Folliculin-Interacting Protein 1 Deficiency."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "which was responsive to granulocyte-colony stimulating factor"
        explanation: Documents G-CSF responsiveness of the neutropenia in a FNIP1-deficient patient.

  - name: Heart Failure Pharmacotherapy
    description: >
      Supportive cardiac pharmacotherapy for the hypertrophic cardiomyopathy
      and its haemodynamic consequences. Reported regimens have included an
      ACE inhibitor (captopril), a loop diuretic (furosemide), antiplatelet
      therapy (acetylsalicylic acid), and carnitine in one patient, and digoxin
      in another. These are symptomatic measures; none targets the underlying
      AMPK gain-of-function lesion.
    notes: >
      SAFETY CAVEAT: the afterload-reducing ACE inhibitor and the loop diuretic
      quoted below were used in a patient whose cardiomyopathy was not
      documented as obstructive. Vasodilators and aggressive diuresis are
      relatively contraindicated in obstructive HCM, where reducing preload or
      afterload worsens the left ventricular outflow tract gradient — and
      hypertrophic OBSTRUCTIVE cardiomyopathy is documented in this same
      cohort (PMID:39537849). This regimen must therefore not be generalised
      across IMD93 without echocardiographic assessment for outflow tract
      obstruction. No FNIP1-specific cardiology guideline exists; the
      contraindication is standard HCM management rather than a
      disorder-specific finding, so it is recorded here as a curator note
      rather than as an evidence-backed assertion.
    therapeutic_modality: SMALL_MOLECULE
    treatment_term:
      preferred_term: Pharmacotherapy
      term:
        id: NCIT:C15986
        label: Pharmacotherapy
      therapeutic_agent:
        - preferred_term: captopril
          term:
            id: CHEBI:3380
            label: captopril
        - preferred_term: furosemide
          term:
            id: CHEBI:47426
            label: furosemide
    evidence:
      - reference: PMID:39537849
        reference_title: "A novel mutation in FNIP1 associated with a syndromic immunodeficiency and cardiomyopathy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "she is also treated with acetylsalicylic acid, captopril, furosemide, and carnitine achieving normal growth and no physical limitations."
        explanation: Documents the supportive cardiac drug regimen used in a FNIP1-deficient patient.

  - name: Rate Control and Arrhythmia Management
    description: >
      Negative-inotropic rate control — a beta-adrenergic antagonist, or a
      non-dihydropyridine calcium channel blocker (verapamil, diltiazem) as an
      alternative — is the standard first-line pharmacotherapy for symptomatic
      hypertrophic cardiomyopathy, improving diastolic filling and reducing any
      outflow tract gradient, in contrast to the vasodilators and diuretics
      that are relatively contraindicated when obstruction is present.
      Catheter ablation of the accessory pathway is the definitive treatment
      for symptomatic or high-risk ventricular pre-excitation.
    notes: >
      Standard-of-care extrapolation from hypertrophic cardiomyopathy and
      Wolff-Parkinson-White management; NOT specifically trialled in IMD93 and
      not reported in any published FNIP1-deficient patient, so no evidence
      item is attached. Included because the disorder's documented HCM and
      pre-excitation make these the conventional interventions, and because
      the negative-inotrope-versus-vasodilator distinction is a genuine safety
      point for this phenotype.
    therapeutic_modality: SMALL_MOLECULE
    treatment_term:
      preferred_term: Pharmacotherapy
      term:
        id: NCIT:C15986
        label: Pharmacotherapy
      therapeutic_agent:
        - preferred_term: beta-adrenergic antagonist
          term:
            id: NCIT:C29576
            label: Beta-Adrenergic Antagonist
        - preferred_term: verapamil
          term:
            id: CHEBI:9948
            label: verapamil
    target_mechanisms:
      - target: Ventricular Pre-excitation and Tachyarrhythmia
        treatment_effect: INHIBITS
        description: >
          Rate control suppresses the tachyarrhythmia; catheter ablation
          eliminates the accessory atrioventricular pathway that carries the
          pre-excitation.

  - name: Genetic Counseling
    description: >
      Genetic counseling for the family once biallelic FNIP1 loss of function
      is confirmed, covering the 25% recurrence risk of an autosomal recessive
      disorder, carrier testing of parents and siblings, and reproductive
      options. Particularly relevant here because reported families include
      consanguineous pedigrees and because an undiagnosed sibling died of
      cardiogenic shock in infancy before genetic evaluation was possible.
    therapeutic_modality: BEHAVIORAL
    treatment_term:
      preferred_term: genetic counseling
      term:
        id: NCIT:C15240
        label: Genetic Counseling
    evidence:
      - reference: PMID:39537849
        reference_title: "A novel mutation in FNIP1 associated with a syndromic immunodeficiency and cardiomyopathy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "enabling genetic counseling as herein"
        explanation: >
          The authors present genetic counseling as a direct benefit of
          establishing the molecular diagnosis in this disorder.

  - name: Cardiac Surveillance
    description: >
      Because cardiac involvement can be the presenting and life-limiting
      feature — including fatal cardiogenic shock in infancy — echocardiographic
      and electrocardiographic surveillance for hypertrophic cardiomyopathy,
      valvular disease, and pre-excitation is a core component of management
      for any patient with confirmed FNIP1 deficiency.
    therapeutic_modality: OTHER
    treatment_term:
      preferred_term: cardiac monitoring
      term:
        id: NCIT:C15747
        label: Supportive Care
    evidence:
      - reference: PMID:39537849
        reference_title: "A novel mutation in FNIP1 associated with a syndromic immunodeficiency and cardiomyopathy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Her sibling (subject II-1) had similar clinical features, along with dysmorphic facial features and hypotony, and succumbed to cardiogenic shock at the age of 2 months, prior to genetic evaluation."
        explanation: >
          Illustrates the lethal potential of unrecognised cardiac involvement,
          motivating systematic cardiac surveillance.

diagnosis:
  - name: Molecular genetic testing with copy-number analysis
    description: >
      Definitive diagnosis rests on demonstrating biallelic FNIP1
      loss-of-function. Exome sequencing alone can be insufficient: reported
      patients have required copy-number variant analysis or detection of
      uniparental disomy to establish biallelic inactivation, so CNV analysis
      should accompany sequencing when a single heterozygous FNIP1 variant is
      found in a compatible phenotype.
    diagnosis_term:
      preferred_term: molecular genetic testing
      term:
        id: NCIT:C19770
        label: Molecular Analysis
    evidence:
      - reference: PMID:32905580
        reference_title: "Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "The results indicate that FNIP1 deficiency can be caused by complex genetic mechanisms and support the clinical utility of exome sequencing and CNV analysis in patients with broad phenotypes, including agammaglobulinemia and HCM."
        explanation: >
          Directly recommends combined exome plus CNV analysis for this
          diagnostic scenario.

  - name: Lymphocyte immunophenotyping and immunoglobulin quantification
    description: >
      Flow-cytometric enumeration of B (CD19+/CD20+) and T (CD3+) lymphocytes
      together with quantitative serum IgG, IgA, and IgM establishes the
      characteristic pattern of absent B cells with pan-isotype
      hypogammaglobulinemia and preserved or mildly increased T cells.
    diagnosis_term:
      preferred_term: lymphocyte immunophenotyping
      term:
        id: NCIT:C16585
        label: Flow Cytometry
    evidence:
      - reference: PMID:37522988
        reference_title: "A Case Report of Folliculin-Interacting Protein 1 Deficiency."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Immunological abnormalities in the peripheral blood show strongly diminished (nearly absent)  B cell number s and severe reduction s in all serum immunoglobulin isotypes"
        explanation: >
          Defines the immunophenotypic and immunochemical pattern that raises
          suspicion of FNIP1 deficiency.

differential_diagnoses:
  - name: X-linked agammaglobulinemia (BTK deficiency)
    description: >
      The prototypical agammaglobulinemia with absent B cells and recurrent
      sinopulmonary infection with encapsulated organisms. Distinguished from
      IMD93 by X-linked (not autosomal recessive) inheritance, absence of
      cardiac involvement, and a block earlier in B-cell development with
      normal numbers of pro-B cells.
    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: "Severe bacterial infections, normal numbers of pro-B cells"
        explanation: >
          The IUIS table records the classical agammaglobulinemias as having
          normal pro-B cell numbers and severe bacterial infection without a
          cardiac axis.

  - name: Autosomal recessive agammaglobulinemia (IGHM, IGLL1, CD79A/B, BLNK, PIK3R1)
    description: >
      The autosomal recessive agammaglobulinemias share absent B cells and
      agammaglobulinemia with IMD93 and sit in the same IUIS category, but lack
      hypertrophic cardiomyopathy and pre-excitation. The presence of infantile
      hypertrophic cardiomyopathy in an agammaglobulinemic child should prompt
      FNIP1 testing specifically.
    evidence:
      - reference: PMID:39537849
        reference_title: "A novel mutation in FNIP1 associated with a syndromic immunodeficiency and cardiomyopathy."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "FNIP1 loss-of-function should be considered in patients presenting in infancy with cardiac manifestations along with agammaglobulinemia (and B-cell lymphopenia)."
        explanation: >
          States the discriminating clinical rule — cardiac involvement plus
          agammaglobulinemia points to FNIP1 rather than the other
          agammaglobulinemias.

  - name: PRKAG2 glycogen-storage cardiomyopathy
    description: >
      Gain-of-function mutations in the AMPK gamma-2 subunit (PRKAG2) cause
      hypertrophic cardiomyopathy with myocardial glycogen accumulation and
      ventricular pre-excitation — the closest cardiac mimic of IMD93, and
      mechanistically the same AMPK gain-of-function endpoint. PRKAG2 disease
      is autosomal dominant and has no immunologic phenotype.
    evidence:
      - reference: PMID:27303042
        reference_title: "Mutation of Fnip1 is associated with B-cell deficiency, cardiomyopathy, and elevated AMPK activity."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "with close parallels to mice and humans bearing gain-of-function mutations in the γ2 subunit of AMPK"
        explanation: >
          Explicitly draws the parallel between FNIP1-deficient cardiomyopathy
          and AMPK gamma-2 (PRKAG2) gain-of-function disease.

  - name: Danon disease
    description: >
      An X-linked LAMP2 deficiency causing a cardiac glycogen-storage
      cardiomyopathy with massive ventricular hypertrophy and ventricular
      pre-excitation — the same cardiac triad as IMD93 — but accompanied by
      skeletal myopathy and intellectual disability rather than
      agammaglobulinemia, and with no B-cell or immunoglobulin defect.
      Curated separately in dismech as `Danon_disease`.
    disease_term:
      preferred_term: Danon disease
      term:
        id: MONDO:0010281
        label: Danon disease
    distinguishing_features:
      - X-linked LAMP2 inheritance rather than autosomal recessive FNIP1
      - Normal B-cell counts and normal serum immunoglobulins
      - Skeletal myopathy and intellectual disability
      - Autophagic vacuoles with sarcolemmal features on muscle biopsy

  - name: Pompe disease (glycogen storage disease type II)
    description: >
      Acid alpha-glucosidase (GAA) deficiency causing infantile-onset
      hypertrophic cardiomyopathy with lysosomal glycogen storage and a short
      PR interval, closely mimicking the IMD93 cardiac presentation in the
      first months of life. Distinguished by profound hypotonia and skeletal
      myopathy, a deficient GAA enzyme assay, and an intact humoral immune
      system.
    disease_term:
      preferred_term: glycogen storage disease II
      term:
        id: MONDO:0009290
        label: glycogen storage disease II
    distinguishing_features:
      - Deficient GAA enzyme activity on dried blood spot or fibroblast assay
      - Profound hypotonia with skeletal muscle involvement
      - Normal B cells and serum immunoglobulins
      - Treatable with enzyme replacement therapy

discussions:
  - discussion_id: imd93_neuro_myopathic_features_attribution
    kind: KNOWLEDGE_GAP
    prompt: >
      Are the neurologic and myopathic features reported in some
      FNIP1-deficient patients (microcephaly, developmental delay, muscular
      hypotonia, cerebellar hypoplasia, metabolic myopathy) genuinely part of
      IMD93, or do they reflect additional, as-yet-unidentified genetic factors
      segregating in the consanguineous pedigrees in which they were observed?
    rationale: >
      OMIM 619705 and MONDO:0030528 both flag these as inconsistent features
      that may be related to other genetic defects, and the primary literature
      supplies the reason: CNS involvement was reported in 4 of 6 early
      patients but only in consanguineous pedigrees, where recessive
      homozygosity at unrelated loci is expected to be enriched. FNIP1 is
      nonetheless plausibly relevant to muscle — Fnip1 regulates skeletal
      muscle fiber-type specification in mice — so the question is genuinely
      open rather than settled in either direction. Curating these as core
      phenotypes on the current evidence would overstate the phenotypic
      definition; this entry therefore omits them.
    attaches_to:
      - "pathophysiology#Dysregulated AMPK and mTORC1 Nutrient Sensing"
    proposed_experiments:
      - experiment_id: imd93_exp_reanalysis_second_diagnosis
        name: Exome/genome reanalysis for a second recessive diagnosis
        description: >
          Systematic reanalysis of exome/genome data from FNIP1-deficient
          patients with neurologic features, searching for a second, unrelated
          recessive diagnosis that could independently explain the CNS
          phenotype.
        supporting_outcome:
          - Finding no second candidate diagnosis in multiple such patients would support the neurologic features being genuinely FNIP1-attributable.
        refuting_outcome:
          - Identifying independent pathogenic biallelic variants at other loci would refute FNIP1 attribution for those features.
      - experiment_id: imd93_exp_nonconsanguineous_deep_phenotyping
        name: Deep phenotyping of non-consanguineous FNIP1-deficient patients
        description: >
          Neuroimaging, muscle biopsy, and creatine kinase measurement in
          FNIP1-deficient patients from non-consanguineous pedigrees, in whom a
          co-segregating second recessive disorder is far less likely.
        supporting_outcome:
          - Neurologic or myopathic findings in non-consanguineous patients would support these as true FNIP1 phenotypes.
        refuting_outcome:
          - Consistently normal neurologic and muscle findings in non-consanguineous patients would argue the association is confounded by consanguinity.
      - experiment_id: imd93_exp_conditional_fnip1_deletion
        name: Tissue-specific conditional Fnip1 deletion
        description: >
          Conditional Fnip1 deletion in neural and skeletal-muscle lineages in
          mice to test whether neurologic and myopathic features are
          cell-autonomous consequences of FNIP1 loss.
        supporting_outcome:
          - Cell-autonomous neural or muscle phenotypes on lineage-restricted deletion would support a direct FNIP1 role.
        refuting_outcome:
          - Absence of phenotype on lineage-restricted deletion would argue against a direct, cell-autonomous FNIP1 contribution.
    evidence:
      - reference: PMID:37522988
        reference_title: "A Case Report of Folliculin-Interacting Protein 1 Deficiency."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "However, these manifestations were observed only in patients with consanguineous pedigrees , raising the possibility that they may be caused by other (as yet to be discovered) genetic factors."
        explanation: >
          The primary source for the caveat: CNS manifestations were confined
          to consanguineous pedigrees, so an independent genetic explanation
          cannot be excluded.
      - reference: PMID:25548157
        reference_title: "Fnip1 regulates skeletal muscle fiber type specification, fatigue resistance, and susceptibility to muscular dystrophy."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Fnip1 regulates skeletal muscle fiber type specification, fatigue resistance, and susceptibility to muscular dystrophy."
        explanation: >
          Provides a biologically plausible route by which FNIP1 loss could
          contribute to a myopathic phenotype, which is why the question is
          treated as open rather than resolved against involvement.

  - discussion_id: imd93_hsct_role_versus_cardiac_arm
    kind: OPEN_QUESTION
    prompt: >
      Would allogeneic haematopoietic stem cell transplantation correct the
      haematopoietic arm of IMD93, and how should it be weighed against the
      untreatable cardiac arm?
    rationale: >
      The B-cell and neutrophil defects are cell-intrinsic to the
      haematopoietic compartment and would in principle be corrected by donor
      haematopoiesis, whereas the hypertrophic cardiomyopathy and
      pre-excitation arise in cardiomyocytes and would not. Because cardiac
      disease is a leading cause of death, the risk-benefit calculus for
      transplantation differs from that in other agammaglobulinemias, where
      immunoglobulin replacement alone is usually sufficient. No transplanted
      FNIP1-deficient patient has been reported, so this remains untested.
    attaches_to:
      - "pathophysiology#Pre-B Cell Metabolic Checkpoint Failure and Developmental Arrest"
      - "pathophysiology#Ventricular Hypertrophy and Hypertrophic Cardiomyopathy"

references:
  - reference: PMID:32905580
    title: "Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency."
  - reference: PMID:32181500
    title: "Mutations of the gene FNIP1 associated with a syndromic autosomal recessive immunodeficiency with cardiomyopathy and pre-excitation syndrome."
  - reference: PMID:37522988
    title: "A Case Report of Folliculin-Interacting Protein 1 Deficiency."
  - reference: PMID:39537849
    title: "A novel mutation in FNIP1 associated with a syndromic immunodeficiency and cardiomyopathy."
  - reference: PMID:38748614
    title: "Clinical and Immunologic Features of a Patient With Homozygous FNIP1 Variant."
  - reference: PMID:40699689
    title: "FNIP1 Deficiency: Pathophysiology and Clinical Manifestations of a Rare Syndromic Primary Immunodeficiency."
  - reference: PMID:27303042
    title: "Mutation of Fnip1 is associated with B-cell deficiency, cardiomyopathy, and elevated AMPK activity."
  - reference: PMID:31676673
    title: "Folliculin Interacting Protein 1 Maintains Metabolic Homeostasis during B Cell Development by Modulating AMPK, mTORC1, and TFE3."
  - reference: PMID:25548157
    title: "Fnip1 regulates skeletal muscle fiber type specification, fatigue resistance, and susceptibility to muscular dystrophy."
  - reference: PMID:35748970
    title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
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References & Deep Research

References

10
PMID:32905580
Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency.
No top-level findings curated for this source.
PMID:32181500
Mutations of the gene FNIP1 associated with a syndromic autosomal recessive immunodeficiency with cardiomyopathy and pre-excitation syndrome.
No top-level findings curated for this source.
PMID:37522988
A Case Report of Folliculin-Interacting Protein 1 Deficiency.
No top-level findings curated for this source.
PMID:39537849
A novel mutation in FNIP1 associated with a syndromic immunodeficiency and cardiomyopathy.
No top-level findings curated for this source.
PMID:38748614
Clinical and Immunologic Features of a Patient With Homozygous FNIP1 Variant.
No top-level findings curated for this source.
PMID:40699689
FNIP1 Deficiency: Pathophysiology and Clinical Manifestations of a Rare Syndromic Primary Immunodeficiency.
No top-level findings curated for this source.
PMID:27303042
Mutation of Fnip1 is associated with B-cell deficiency, cardiomyopathy, and elevated AMPK activity.
No top-level findings curated for this source.
PMID:31676673
Folliculin Interacting Protein 1 Maintains Metabolic Homeostasis during B Cell Development by Modulating AMPK, mTORC1, and TFE3.
No top-level findings curated for this source.
PMID:25548157
Fnip1 regulates skeletal muscle fiber type specification, fatigue resistance, and susceptibility to muscular dystrophy.
No top-level findings curated for this source.
PMID:35748970
Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 20 citations 2026-08-01T18:42:53.895414

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: Immunodeficiency 93 and Hypertrophic Cardiomyopathy
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Immunodeficiency 93 and Hypertrophic Cardiomyopathy 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 NCIT (NCI Thesaurus) clinical-intervention 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, NCIT, 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 (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Immunodeficiency 93 with hypertrophic cardiomyopathy: research report

Executive summary and evidence scope

Immunodeficiency 93 with hypertrophic cardiomyopathy is an ultra-rare, autosomal-recessive inborn error of immunity caused by biallelic loss-of-function variants in FNIP1 (folliculin-interacting protein 1). It is best understood as a syndromic early B-cell developmental disorder, usually producing profound B-cell lymphopenia or agammaglobulinemia, together with hypertrophic cardiomyopathy (HCM) and, in some patients, ventricular pre-excitation. Reviews available through 2023 report only six affected individuals from five unrelated families, underscoring the extremely limited natural-history evidence. The strongest mechanistic data come from Fnip1-deficient mice and B-cell progenitors rather than human tissue (siggs2016mutationoffnip1 pages 7-8, siggs2016mutationoffnip1 pages 7-7, redmond2022novelgeneticdiscoveries pages 10-11, ramirez2019folliculininteractingprotein pages 1-2).

The principal human report is Niehues et al., “Mutations of the gene FNIP1 associated with a syndromic autosomal recessive immunodeficiency with cardiomyopathy and pre-excitation syndrome,” published April 2020, DOI: 10.1002/eji.201948504. A further human case was reported by Ulaş et al. in May 2024, DOI: 10.1097/MPH.0000000000002862. Full patient-level tables and exact HGVS variants from those reports were not retrievable in the searched corpus; consequently, they are not reconstructed or guessed here.

domain established finding evidence type confidence/limitations
Inheritance / causal gene Disease is resolved as an autosomal-recessive inborn error of immunity caused by biallelic loss-of-function variants in FNIP1; authoritative reviews/classifications describe FNIP1 deficiency as a syndromic predominantly antibody/B-cell defect with cardiomyopathy/pre-excitation features (redmond2022novelgeneticdiscoveries pages 10-11, tangye2023inbornerrorsof pages 13-13) Human disease reviews/classification; mechanistic support from mouse genetics Moderate-high confidence for gene-disease relationship; exact OMIM/MONDO row and full primary human case details were not directly retrievable in available evidence
Hallmark immune phenotype Core immune phenotype is B-cell deficiency/agammaglobulinemia or severe antibody deficiency, with an early block in B-cell development inferred from human disease reviews and directly demonstrated in Fnip1-deficient mice (redmond2022novelgeneticdiscoveries pages 10-11, tangye2023inbornerrorsof pages 13-13, ramirez2019folliculininteractingprotein pages 1-2, siggs2016mutationoffnip1 pages 3-4, siggs2016mutationoffnip1 pages 1-3) Human reviews plus primary mouse/in vitro mechanistic studies High confidence for B-cell developmental defect; frequencies, infection spectrum, and exact immunoglobulin values in humans unavailable from retrieved primary human text
Cardiac phenotype Human FNIP1 deficiency is repeatedly summarized as associated with hypertrophic cardiomyopathy and sometimes pre-excitation syndrome; mouse Fnip1 loss causes left-ventricular hypertrophy/cardiomyopathy with glycogen accumulation, supporting biological plausibility (siggs2016mutationoffnip1 pages 7-8, siggs2016mutationoffnip1 pages 7-7, siggs2016mutationoffnip1 pages 1-1, siggs2016mutationoffnip1 pages 4-5) Human review summaries; primary mouse cardiovascular phenotype Moderate confidence for human HCM association; patient-level echocardiographic/ECG details were not available in accessible case reports
Mechanism / pathophysiology FNIP1 is a regulator within the FLCN–FNIP1–AMPK–mTORC1 network; in B-cell progenitors, Fnip1 deficiency causes inappropriate mTOR lysosomal localization, increased apoptosis under amino-acid deprivation, increased nuclear TFE3, increased lysosome function, and increased autophagic flux. Mouse data also support elevated AMPK activity and tissue-specific metabolic dysregulation in heart and skeletal muscle (siggs2016mutationoffnip1 pages 7-8, backe2022emerginglinkbetween pages 2-4, hasumi2015folliculininteractingproteinsfnip1 pages 1-2, ramirez2019folliculininteractingprotein pages 1-2) Primary mouse and cell-mechanistic studies; review synthesis High confidence for pathway involvement in model systems; direct human tissue validation remains limited
Diagnosis Practical diagnosis is by genetic testing identifying biallelic FNIP1 variants in a patient with severe B-cell/antibody deficiency plus syndromic features such as HCM/pre-excitation; classification papers recognize FNIP1 among novel monogenic IEIs (redmond2022novelgeneticdiscoveries pages 10-11, tangye2023inbornerrorsof pages 13-13) Human classification/review evidence Moderate confidence; no disease-specific diagnostic criteria, biomarker thresholds, or validated screening algorithm were retrieved
Management / trials No disease-specific interventional trials were found. Management in the literature base is supportive and extrapolated from phenotype: immunoglobulin replacement/infection prevention for antibody deficiency and standard cardiology surveillance/management for HCM or conduction disease (supported indirectly by disease classification and absence of trials) (redmond2022novelgeneticdiscoveries pages 10-11, tangye2023inbornerrorsof pages 13-13) Review/classification evidence plus negative clinical-trial search Low-moderate confidence for disease-specific efficacy because direct outcome studies were not retrieved
Epidemiology Condition appears ultra-rare, reported only in a very small number of families/patients in reviews; no prevalence or incidence estimates were available from the retrieved evidence (redmond2022novelgeneticdiscoveries pages 10-11, tangye2023inbornerrorsof pages 13-13) Human review summaries Low confidence for numeric epidemiology because exact counts and denominators were not available in accessible primary sources
Mouse model Fnip1 mutant/knockout mice recapitulate major disease axes: early B-cell developmental arrest, reduced/absent peripheral B cells, marginal-zone B-cell sensitivity, cardiomyopathy/LV hypertrophy, glycogen accumulation, and altered skeletal-muscle metabolism/AMPK signaling (siggs2016mutationoffnip1 pages 7-8, siggs2016mutationoffnip1 pages 7-7, hasumi2015folliculininteractingproteinsfnip1 pages 4-5, siggs2016mutationoffnip1 pages 1-1, siggs2016mutationoffnip1 pages 3-4, siggs2016mutationoffnip1 pages 4-5, siggs2016mutationoffnip1 pages 1-3) Primary animal model evidence High confidence; strong mechanistic relevance, though murine phenotypes cannot substitute for full human natural-history data
Evidence gaps Exact patient variants, ages, sex distribution, penetrance, prognosis, and treatment responses were not established in the retrieved accessible evidence and should not be inferred without the primary human case series/case reports (redmond2022novelgeneticdiscoveries pages 10-11, tangye2023inbornerrorsof pages 13-13) Evidence-quality assessment High confidence that these are current evidence gaps in the accessible corpus

Table: This table summarizes the strongest currently retrievable evidence for Immunodeficiency 93 with hypertrophic cardiomyopathy, focusing on established findings and explicit limitations. It is useful as a compact knowledge-base scaffold when primary human case details are sparse or inaccessible.

1. Disease information

Definition and classification

The disorder is a Mendelian, predominantly antibody-deficiency syndrome in which deficient FNIP1 function disrupts the metabolic checkpoints required for early B-cell development and also perturbs cardiomyocyte energy sensing. Recent authoritative reviews classify FNIP1 deficiency among monogenic inborn errors affecting B-cell development; the 2024 IUIS update emphasizes that IEIs are classified according to the most consistently reported phenotype and now encompasses more than 500 causal genes (redmond2022novelgeneticdiscoveries pages 10-11, tangye2023inbornerrorsof pages 13-13).

Preferred name: Immunodeficiency 93 with hypertrophic cardiomyopathy.
Synonyms: FNIP1 deficiency; FNIP1-related immunodeficiency; syndromic agammaglobulinemia due to FNIP1 deficiency; autosomal-recessive immunodeficiency with cardiomyopathy and pre-excitation syndrome; B-cell deficiency with cardiomyopathy.
OMIM: commonly catalogued as Immunodeficiency 93 with hypertrophic cardiomyopathy; the exact phenotype accession should be verified directly in OMIM before database import because an accessible OMIM record was not retrieved.
MONDO/Orphanet: no confidently verified disease-specific accession was recovered. A parent mapping to inborn error of immunity and predominantly antibody deficiency is appropriate until a dedicated MONDO record is confirmed.
ICD-10/ICD-11/MeSH: no unique code exists. Component coding would use congenital/predominantly antibody immunodeficiency and hypertrophic cardiomyopathy codes rather than a disease-specific code.

Evidence is aggregated disease-level literature, not EHR-derived. The tiny human evidence base consists of individual case reports/series.

2. Etiology, risk, and protective factors

Causal factor

The primary cause is germline biallelic FNIP1 loss of function, inherited autosomal recessively. FNIP1 encodes a cytoplasmic protein that binds folliculin (FLCN), FNIP2, AMPK subunits, and the Hsp90 chaperone machinery. Mouse studies demonstrate that a recessive splice-donor mutation generating aberrant transcripts and loss of detectable FNIP1 protein causes B-cell deficiency and cardiomyopathy (backe2022emerginglinkbetween pages 2-4, hasumi2015folliculininteractingproteinsfnip1 pages 1-2, siggs2016mutationoffnip1 pages 4-5, siggs2016mutationoffnip1 pages 1-3).

Genetic and environmental risk

  • Genetic risk: two pathogenic or likely pathogenic FNIP1 alleles in trans. Consanguinity increases the probability of homozygosity for a rare recessive allele but is not itself causal.
  • Susceptibility loci/modifiers: none established in humans. Fnip2 expression is tissue-dependent and can partly compensate for Fnip1 in mice, making FNIP2 a plausible modifier, but not a validated human modifier (hasumi2015folliculininteractingproteinsfnip1 pages 1-2, hasumi2015folliculininteractingproteinsfnip1 pages 4-4).
  • Environmental causes: none known. Infections expose the consequences of antibody deficiency rather than initiating the Mendelian disease.
  • Protective variants or exposures: none established.
  • Gene–environment interaction: nutrient and energetic stress are mechanistically relevant. Fnip1-deficient pre-B cells show abnormal mTOR localization and increased apoptosis during lysine or arginine deprivation, suggesting that cellular nutrient availability modifies survival downstream of the genetic defect; this has not been quantified clinically (ramirez2019folliculininteractingprotein pages 1-2).

3. Phenotypes

Human frequencies cannot be estimated reliably from six or slightly more reported patients. “Frequent” below means recurrent across reports/reviews, not a population percentage.

Phenotype Type and course Suggested HPO term
Profound reduction/absence of circulating B cells Laboratory abnormality; childhood presentation; severe and persistent B-cell lymphopenia (HP:0010976)
Agammaglobulinemia or marked hypogammaglobulinemia Laboratory abnormality; chronic; predisposes to infection Agammaglobulinemia (HP:0004432), Hypogammaglobulinemia (HP:0004313)
Recurrent infections, especially respiratory Symptom/clinical course; episodic on chronic susceptibility Recurrent respiratory infections (HP:0002205), Recurrent bacterial infections (HP:0002718)
Hypertrophic cardiomyopathy/LV hypertrophy Clinical and imaging sign; childhood onset reported; severity variable Hypertrophic cardiomyopathy (HP:0001639), Left ventricular hypertrophy (HP:0001712)
Ventricular pre-excitation ECG abnormality; reported in the defining human series Ventricular preexcitation (HP:0005136)
Neutropenia Laboratory finding in some later cases; prevalence unresolved Neutropenia (HP:0001875)
Altered skeletal-muscle phenotype Strong in mice; insufficiently characterized in humans Skeletal muscle abnormality (HP:0003011), if clinically demonstrated

The mouse phenotype directly demonstrates an early developmental block: homozygotes lacked peripheral and splenic B cells and bone marrow IgM⁺/IgD⁺ cells, while B220-low progenitors remained. Heterozygotes had reduced marginal-zone B cells, indicating gene-dose sensitivity (siggs2016mutationoffnip1 pages 3-4, siggs2016mutationoffnip1 pages 4-5, siggs2016mutationoffnip1 pages 1-3).

Quality of life: no disease-specific EQ-5D, SF-36, PROMIS, or pediatric quality-of-life study exists. Expected burdens include recurrent infection, lifelong replacement therapy, repeated cardiac surveillance, exercise restrictions where clinically indicated, arrhythmia anxiety, and possible heart-failure symptoms. These are clinically reasonable consequences, not measured FNIP1-specific outcomes.

4. Genetic and molecular information

Gene

  • Gene: FNIP1, folliculin-interacting protein 1.
  • Molecular role: FLCN-binding protein, AMPK regulator, Hsp90 co-chaperone, and regulator of mTORC1/TFE3-dependent lysosomal and autophagic programs.
  • Origin: pathogenic disease alleles are germline; there is no evidence that somatic FNIP1 mutation causes this immunodeficiency.
  • Mechanism: recessive loss of function. The disease architecture and null/near-null mouse phenotypes support haplosufficiency for the major syndrome, although heterozygous mice show subtle marginal-zone B-cell effects (backe2022emerginglinkbetween pages 2-4, siggs2016mutationoffnip1 pages 3-4).

Variants

The defining literature reports homozygous or compound-heterozygous variants, including truncating alleles; a review notes that one disease-associated missense change lies in a region important for Hsp90 interaction and FNIP1 stability. Exact patient-level HGVS expressions, ClinVar accessions, ACMG classifications, and gnomAD frequencies could not be validated from accessible full text and should be imported only after direct ClinVar/primary-paper review (backe2022emerginglinkbetween pages 2-4, redmond2022novelgeneticdiscoveries pages 10-11).

No pathogenic chromosomal rearrangement, repeat expansion, mitochondrial-DNA variant, epigenetic signature, anticipation, or established germline mosaicism has been reported. No validated modifier gene or disease-specific methylation/proteomic/metabolomic biomarker is available.

5. Environmental and infectious information

There is no evidence that toxins, pollution, radiation, smoking, alcohol, diet, occupation, or exercise causes FNIP1 deficiency. Pathogens are secondary opportunists or recurrent infectious challenges, not causal agents. Published summaries support infection susceptibility resulting from severe humoral deficiency, but the retrieved evidence does not permit a reliable organism-by-organism infection spectrum.

Exercise down-regulates muscle FNIP1 in experimental systems, and myofiber-specific Fnip1 loss enhances PGC-1α-dependent macrophage recruitment and angiogenesis in mice. This is mechanistically interesting but does not establish exercise as protective or harmful in affected humans; exercise advice must instead follow individualized HCM assessment.

6. Mechanism and pathophysiology

Causal chain in B cells

  1. Biallelic FNIP1 loss disrupts the FLCN–FNIP metabolic/chaperone complex.
  2. Nutrient and energy sensing through AMPK and mTORC1 becomes improperly coordinated.
  3. In Fnip1-deficient pre-B cells, mTOR remains inappropriately localized at lysosomes during nutrient deprivation; AMPK and mTORC1 can both appear activated.
  4. TFE3 accumulates in nuclei, increasing lysosomal target-gene expression, lysosome number/function, and autophagic flux.
  5. Developing B cells are unusually vulnerable to metabolic stress and apoptosis, producing a block around the pre-B-cell stage.
  6. The downstream clinical result is profound B-cell lymphopenia, agammaglobulinemia, and recurrent infection (backe2022emerginglinkbetween pages 2-4, ramirez2019folliculininteractingprotein pages 1-2).

An important experimental caution is that neither genetic AMPK inhibition, pharmacologic mTORC1 inhibition, BCL-xL-mediated survival restoration, nor BCL2 overexpression fully corrected B-cell development. Thus, the mechanism is not reducible to a single linear “AMPK high” or “mTOR high” lesion (siggs2016mutationoffnip1 pages 7-7, ramirez2019folliculininteractingprotein pages 1-2).

Cardiac chain

Fnip1 loss increases activity of γ2-containing AMPK complexes in neonatal mouse myocardium, accompanied by cardiomyocyte glycogen accumulation and left-ventricular hypertrophy resembling PRKAG2-associated metabolic cardiomyopathy. FNIP1 therefore appears to restrain cardiac energy-sensing pathways in a tissue- and AMPK-complex-specific manner (siggs2016mutationoffnip1 pages 7-8, siggs2016mutationoffnip1 pages 7-7, siggs2016mutationoffnip1 pages 1-1).

Suggested ontology annotations

  • GO biological process: B-cell differentiation (GO:0030183); B-cell homeostasis (GO:0001782); cellular response to nutrient levels (GO:0031669); AMPK signaling; TOR signaling (GO:0031929); autophagy (GO:0006914); lysosome organization (GO:0007040); mitochondrial biogenesis; cardiac muscle-cell hypertrophy.
  • GO cellular component: lysosome (GO:0005764); cytosol (GO:0005829); AMPK complex; mTORC1 complex; mitochondrion (GO:0005739).
  • Cell Ontology: B-cell progenitor (CL:0000826); precursor B cell (CL:0000817); mature B cell (CL:0000785); cardiomyocyte (CL:0000746); skeletal muscle fiber (CL:0000187); macrophage (CL:0000235).

No human single-cell, spatial-transcriptomic, multi-omic, lipidomic, or disease-specific iPSC-cardiomyocyte dataset was identified. A 2024 CRISPR/Cas9 HL-60 abstract investigated neutropenia, but conference-abstract evidence is insufficient to define a mature granulopoietic mechanism.

7. Anatomical structures affected

Primary systems: immune/hematopoietic and cardiovascular systems.

  • Bone marrow—early B-cell progenitor compartment; UBERON:0002371.
  • Peripheral blood, spleen, lymphoid tissue—markedly depleted mature B-cell compartment; spleen UBERON:0002106.
  • Heart/myocardium, particularly left ventricular muscle—hypertrophy and metabolic/glycogen abnormalities; heart UBERON:0000948, myocardium UBERON:0002349, left ventricle UBERON:0002084.
  • Skeletal muscle—altered oxidative-fiber and mitochondrial phenotype is well demonstrated in mice but incompletely defined clinically.
  • Subcellular sites: cytoplasm, lysosome, mitochondria, nucleus of TFE3-responsive cells, and the AMPK/mTOR complexes.

The cardiac and immune abnormalities are systemic rather than lateralized.

8. Temporal development and natural history

The recognized syndrome is predominantly pediatric and chronic/lifelong. Immunodeficiency may become evident after loss of maternally acquired antibody or during recurrent childhood infections. Cardiac hypertrophy and pre-excitation may be detected concurrently or through syndromic screening. Onset and progression vary, and there are insufficient longitudinal data to define stages, median age at onset, annual progression, remission, or critical treatment windows.

There is no evidence of spontaneous genetic remission. Immunoglobulin therapy can reduce infection burden but does not restore endogenous B-cell development. Cardiac disease requires continued surveillance because HCM and conduction abnormalities can evolve independently of infectious control.

9. Inheritance and population

  • Inheritance: autosomal recessive.
  • Penetrance: probably high for severe biallelic loss of function, but cannot be quantified.
  • Expressivity: variable, particularly for cardiomyopathy, conduction disease, neutropenia, and residual immune function.
  • Prevalence/incidence: unknown; no cases-per-100,000 estimate exists. The literature base of approximately six individuals in five families through early reviews supports classification as ultra-rare (redmond2022novelgeneticdiscoveries pages 10-11).
  • Sex ratio, ancestry distribution, carrier frequency, founder effects: not established.
  • Consanguinity: relevant to recurrence of rare homozygous alleles but no universal requirement.
  • Anticipation: not expected and not reported.
  • Recurrence risk: when both parents are confirmed carriers, each pregnancy has a 25% probability of an affected child, 50% probability of a heterozygous carrier, and 25% probability of inheriting neither familial allele.

10. Diagnostics

Recommended clinical work-up

  1. Immune evaluation: CBC with differential; absolute lymphocyte subsets including CD19/CD20 B cells; IgG, IgA, IgM and IgE; vaccine-specific antibody titers where safe and interpretable; infection history; and assessment for bronchiectasis or chronic lung injury when indicated.
  2. Cardiac evaluation: ECG for pre-excitation or conduction abnormalities; echocardiography for wall thickness, outflow obstruction and systolic/diastolic function; ambulatory rhythm monitoring; cardiac MRI when echocardiography is insufficient; biomarkers such as BNP/troponin only as clinically indicated.
  3. Genetic confirmation: sequencing plus deletion/duplication analysis of FNIP1, with parental phasing to demonstrate biallelic variants in trans. A comprehensive IEI/agammaglobulinemia panel, WES, or WGS is preferable when the phenotype is atypical or single-gene testing is negative.
  4. Variant interpretation: ACMG/AMP criteria, population frequency, predicted loss of function, segregation, RNA studies for splice variants, and protein/functional assays where available.

WES/WGS is particularly useful because the combined immune–cardiac phenotype can be mistaken for two independent disorders. CMA, karyotyping, FISH, mitochondrial sequencing, and repeat-expansion testing are not first-line unless other findings suggest those mechanisms.

Differential diagnosis

Important alternatives include BTK-related X-linked agammaglobulinemia, autosomal-recessive agammaglobulinemias involving IGHM, CD79A/B, BLNK, PIK3R1, TCF3 and SLC39A7/ZIP7, combined immunodeficiencies, PRKAG2 glycogen-storage cardiomyopathy with pre-excitation, Danon disease, Pompe disease, mitochondrial cardiomyopathy, RASopathy-associated HCM, and sarcomeric HCM. The combination of severe early B-cell deficiency plus HCM/pre-excitation and biallelic FNIP1 variants is the key discriminator.

There are no validated standardized clinical criteria, newborn-screening analyte, liquid biopsy, or diagnostic metabolomic signature.

11. Outcome and prognosis

No reliable survival curve, mortality rate, median life expectancy, or five-/ten-year outcome is available. Principal morbidity risks are severe or recurrent infection, chronic pulmonary damage, arrhythmia, progressive HCM, heart failure, and potentially sudden cardiac death by extrapolation from HCM—not from quantified FNIP1-specific cohorts.

Prognosis is likely influenced by residual B-cell/antibody function, infection burden before immunoglobulin replacement, ventricular wall thickness and function, outflow obstruction, arrhythmia/pre-excitation, and access to multidisciplinary care. None is validated as an FNIP1-specific prognostic biomarker.

12. Treatment and real-world implementation

There is no approved FNIP1-directed therapy and no relevant disease-specific interventional trial was found.

Current management

  • Immunoglobulin replacement—intravenous or subcutaneous—to maintain protective IgG exposure and reduce bacterial infections. Suggested NCIT concepts: Intravenous Immunoglobulin Therapy and Subcutaneous Immunoglobulin Therapy.
  • Prompt antimicrobial treatment and, for recurrent infections despite adequate replacement, individualized antibacterial prophylaxis. Live vaccines are generally avoided in profound immunodeficiency until immune competence is defined.
  • Pulmonary care: surveillance for bronchiectasis, airway clearance where required, and culture-directed treatment.
  • HCM management: pediatric/adult cardiology follow-up; beta blocker or nondihydropyridine calcium-channel blocker when clinically indicated; conventional management of heart failure or outflow obstruction; exercise advice based on HCM risk assessment.
  • Pre-excitation/arrhythmia: electrophysiology evaluation, ambulatory monitoring, and catheter ablation when indicated by pathway properties or clinical arrhythmia.
  • Advanced cardiac interventions: implantable cardioverter-defibrillator, septal reduction, or transplantation only under standard HCM indications; no FNIP1-specific outcome data exist.

Hematopoietic stem-cell transplantation has no established evidence base for this disorder and would not be expected to correct cardiomyocyte-intrinsic FNIP1 deficiency. Likewise, mTOR inhibitors, AMPK modulators, gene replacement, CRISPR editing, RNA therapy, and Hsp90-directed treatment remain experimental concepts. Failure of simple AMPK or mTOR manipulation to rescue murine B-cell development argues against premature pathway-targeted clinical use (siggs2016mutationoffnip1 pages 7-7, ramirez2019folliculininteractingprotein pages 1-2).

13. Prevention

Primary prevention by lifestyle change is impossible because the condition is germline. Effective prevention is genetic and complication-focused:

  • Genetic counseling, carrier testing of at-risk relatives, and cascade testing.
  • Reproductive options: prenatal diagnosis and preimplantation genetic testing for a known familial variant pair.
  • Secondary prevention: early immune and cardiac assessment of genetically affected siblings, ideally before serious infection or cardiac symptoms.
  • Tertiary prevention: immunoglobulin replacement, antimicrobial prophylaxis when indicated, pulmonary surveillance, ECG/echocardiographic follow-up, rhythm management, and individualized HCM precautions.
  • Vaccination: household contacts should be appropriately immunized; patient vaccine decisions require immunology review. Inactivated vaccines are generally safe but may be poorly immunogenic; live vaccines may be contraindicated depending on the breadth of immune dysfunction.

No population newborn or carrier-screening program is currently justified by prevalence data, although targeted familial screening is appropriate.

14. Other species and natural disease

No naturally occurring veterinary FNIP1-deficiency syndrome was identified in companion animals, livestock, or wildlife, and there is no zoonotic or cross-species transmission. Relevant orthologues are evolutionarily conserved, particularly mouse Fnip1, but model-organism phenotypes are experimentally induced rather than naturally transmitted disease.

15. Model organisms and experimental systems

Mouse models

The best-characterized models are constitutive Fnip1-null mice and the recessive ENU-induced hamel splice allele. They reproduce the two defining disease axes:

  • nearly absent peripheral B cells and developmental arrest before mature IgM⁺/IgD⁺ stages;
  • left-ventricular hypertrophy/cardiomyopathy with cardiomyocyte glycogen accumulation;
  • elevated γ2-containing AMPK activity in neonatal myocardium;
  • altered skeletal-muscle fiber composition and mitochondrial metabolism (siggs2016mutationoffnip1 pages 7-8, siggs2016mutationoffnip1 pages 7-7, siggs2016mutationoffnip1 pages 1-1, siggs2016mutationoffnip1 pages 3-4, siggs2016mutationoffnip1 pages 4-5).

The accessible primary mouse paper’s central conclusion is accurately captured by its title: “Mutation of Fnip1 is associated with B-cell deficiency, cardiomyopathy, and elevated AMPK activity.” Published June 2016, DOI: 10.1073/pnas.1607592113 (siggs2016mutationoffnip1 pages 1-1).

A second primary study provides the following abstract-level statement: “constitutive disruption of Fnip1 in mice resulted in a lack of peripheral B cells because of a block in B cell development at the pre–B cell stage.” It further reports increased nuclear TFE3, lysosome number/function, and autophagic flux. Published November 1, 2019, DOI: 10.4049/jimmunol.1900395 (ramirez2019folliculininteractingprotein pages 1-2).

Strengths and limitations

These models have excellent face validity for B-cell deficiency and cardiomyopathy and are suitable for studying metabolic checkpoints, lineage-specific AMPK complexes, lysosomal signaling, autophagy, and candidate rescue strategies. Limitations include species differences in immunoglobulin biology and cardiac physiology, incomplete replication of the human infection history, and the inability of constitutive null models to separate developmental from adult maintenance functions.

Recent developments, 2023–2024

  1. A 2023 synthesis of human B-cell IEIs continued to recognize FNIP1 deficiency as an early B-cell developmental defect and emphasized that human bone-marrow evidence remains limited (tangye2023inbornerrorsof pages 13-13).
  2. Recent metabolic work has expanded FNIP1 biology beyond AMPK alone, implicating FLCN/FNIP chaperoning, TFE3/TFEB, lysosomal function, mitochondrial homeostasis, PGC-1α and tissue-specific responses. These findings refine—but do not yet change—clinical care (backe2022emerginglinkbetween pages 2-4, ramirez2019folliculininteractingprotein pages 1-2).
  3. A new homozygous-FNIP1 patient report appeared in May 2024, confirming continued expansion of the phenotype, but accessible evidence did not support reliable recalculation of frequencies or genotype–phenotype relationships.
  4. A 2024 CRISPR/Cas9 HL-60 conference study began investigating neutropenia, representing functional-genomics follow-up rather than validated clinical evidence.
  5. The 2024 IUIS classification update, published in 2025, describes a rapidly expanding IEI landscape of 508 genes and 17 phenocopies, reinforcing the need to interpret FNIP1 through expert IEI frameworks rather than as nonspecific CVID (poli2025humaninbornerrors pages 29-30).

Knowledge-base conclusions

The highest-confidence annotations are: biallelic FNIP1 loss of function → disturbed FLCN/AMPK/mTORC1/TFE3 metabolic control → early pre-B-cell developmental failure → profound B-cell/antibody deficiency, with a parallel cardiomyocyte metabolic defect producing HCM and sometimes pre-excitation. Human case numbers remain too small for dependable phenotype frequencies, penetrance, epidemiology, prognosis, or treatment-response statistics. Exact HGVS variants, MONDO/OMIM accessions, and ClinVar classifications should be verified directly against the primary case reports and current databases before automated ingestion.

References

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  11. (hasumi2015folliculininteractingproteinsfnip1 pages 1-2): Hisashi Hasumi, Masaya Baba, Yukiko Hasumi, Martin Lang, Ying Huang, HyoungBin F. Oh, Masayuki Matsuo, Maria J. Merino, Masahiro Yao, Yusuke Ito, Mitsuko Furuya, Yasuhiro Iribe, Tatsuhiko Kodama, Eileen Southon, Lino Tessarollo, Kunio Nagashima, Diana C. Haines, W. Marston Linehan, and Laura S. Schmidt. Folliculin-interacting proteins fnip1 and fnip2 play critical roles in kidney tumor suppression in cooperation with flcn. Proceedings of the National Academy of Sciences, 112:E1624-E1631, Mar 2015. URL: https://doi.org/10.1073/pnas.1419502112, doi:10.1073/pnas.1419502112. This article has 127 citations and is from a highest quality peer-reviewed journal.

  12. (hasumi2015folliculininteractingproteinsfnip1 pages 4-5): Hisashi Hasumi, Masaya Baba, Yukiko Hasumi, Martin Lang, Ying Huang, HyoungBin F. Oh, Masayuki Matsuo, Maria J. Merino, Masahiro Yao, Yusuke Ito, Mitsuko Furuya, Yasuhiro Iribe, Tatsuhiko Kodama, Eileen Southon, Lino Tessarollo, Kunio Nagashima, Diana C. Haines, W. Marston Linehan, and Laura S. Schmidt. Folliculin-interacting proteins fnip1 and fnip2 play critical roles in kidney tumor suppression in cooperation with flcn. Proceedings of the National Academy of Sciences, 112:E1624-E1631, Mar 2015. URL: https://doi.org/10.1073/pnas.1419502112, doi:10.1073/pnas.1419502112. This article has 127 citations and is from a highest quality peer-reviewed journal.

  13. (hasumi2015folliculininteractingproteinsfnip1 pages 4-4): Hisashi Hasumi, Masaya Baba, Yukiko Hasumi, Martin Lang, Ying Huang, HyoungBin F. Oh, Masayuki Matsuo, Maria J. Merino, Masahiro Yao, Yusuke Ito, Mitsuko Furuya, Yasuhiro Iribe, Tatsuhiko Kodama, Eileen Southon, Lino Tessarollo, Kunio Nagashima, Diana C. Haines, W. Marston Linehan, and Laura S. Schmidt. Folliculin-interacting proteins fnip1 and fnip2 play critical roles in kidney tumor suppression in cooperation with flcn. Proceedings of the National Academy of Sciences, 112:E1624-E1631, Mar 2015. URL: https://doi.org/10.1073/pnas.1419502112, doi:10.1073/pnas.1419502112. This article has 127 citations and is from a highest quality peer-reviewed journal.

  14. (poli2025humaninbornerrors pages 29-30): M. Cecilia Poli, Ivona Aksentijevich, Ahmed Aziz Bousfiha, Charlotte Cunningham-Rundles, Sophie Hambleton, Christoph Klein, Tomohiro Morio, Capucine Picard, Anne Puel, Nima Rezaei, Mikko R.J. Seppänen, Raz Somech, Helen C. Su, Kathleen E. Sullivan, Troy R. Torgerson, Isabelle Meyts, and Stuart G. Tangye. Human inborn errors of immunity: 2024 update on the classification from the international union of immunological societies expert committee. Journal of Human Immunity, Apr 2025. URL: https://doi.org/10.70962/jhi.20250003, doi:10.70962/jhi.20250003. This article has 398 citations.

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