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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Conditions with similar clinical presentations that must be differentiated from Immunodeficiency 93 and Hypertrophic Cardiomyopathy:
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
directness: INDIRECT
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. Recorded with directness
INDIRECT 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 recorded with directness
INDIRECT accordingly.
evidence:
- reference: PMID:39537849
reference_title: "A novel mutation in FNIP1 associated with a syndromic immunodeficiency and cardiomyopathy."
supports: SUPPORT
directness: INDIRECT
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.
progression:
- phase: Onset in infancy with combined immune and cardiac disease
age_range: First months to years of life
notes: >
Recurrent infection and the laboratory antibody deficit manifest within
the first year of life, and cardiac involvement can present neonatally;
in one reported family an affected infant died of cardiogenic shock at 2
months, before any diagnosis could be made.
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: Places clinical onset 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: "and succumbed to cardiogenic shock at the age of 2 months, prior to genetic evaluation"
explanation: >
Documents the earliest and most severe end of the presentation
spectrum: fatal infantile cardiogenic shock before diagnosis.
- phase: Long-term course on immunoglobulin replacement
notes: >
Survival to adulthood is documented: the defining cohort included a
first known adult, and a separate patient managed with immunoglobulin
replacement and supportive cardiac therapy from infancy survived to 40
years, dying of heart failure associated with SARS-CoV-2 infection. The
cardiac arm is not corrected by immunoglobulin replacement and remains
the principal life-limiting axis over the long term.
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: "novel patients, including the first known adult, from unrelated families with agammaglobulinemia, recurrent infections, and hypertrophic cardiomyopathy (HCM)"
explanation: Documents survival of a FNIP1-deficient patient into adulthood.
- reference: PMID:37522988
reference_title: "A Case Report of Folliculin-Interacting Protein 1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The patient died at 40 years of age due to heart failure"
explanation: >
The longest-surviving reported patient died at 40 of heart failure,
identifying the cardiac arm as the long-term life-limiting axis.
clinical_burden:
burden_level: HIGH
rationale: >
The disorder combines two independently serious arms: an agammaglobulinemia
requiring lifelong immunoglobulin replacement from infancy, and a
hypertrophic — often obstructive — cardiomyopathy with pre-excitation that
is not corrected by any current therapy. Cardiac disease can be fatal in
infancy (cardiogenic shock at 2 months in an undiagnosed sibling) and
remains life-limiting in adulthood (death from heart failure at 40 in the
longest-surviving reported patient), so the burden is high even with good
infection control.
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: "and succumbed to cardiogenic shock at the age of 2 months, prior to genetic evaluation"
explanation: Documents infantile cardiac mortality in an undiagnosed affected sibling.
- reference: PMID:37522988
reference_title: "A Case Report of Folliculin-Interacting Protein 1 Deficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The patient died at 40 years of age due to heart failure"
explanation: >
Documents cardiac-driven mortality in adulthood despite decades of
managed immunodeficiency.
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."
Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.
Create: Immunodeficiency 93 and Hypertrophic Cardiomyopathy (FNIP1) · 2026-08-01T19:09:44Z · View source
De-novo curation of IMD93 / FNIP1 deficiency, MONDO:0030528, OMIM 619705. NEC preflight passed: OAK MONDO record confirms xref OMIM:619705 and RO:0004003 HGNC:29418 FNIP1, plus synonym IMD93; causal gene independently confirmed as FNIP1 against primary literature before any deep-research content was used. Deep research provider: Edison/falcon via just research-disorder falcon; the report was read in full and cross-checked - it named FNIP1 throughout and cited only DOIs that resolve to papers independently fetched and verified, so it passed the NEC and hallucination checks, but it had missed the three most informative human sources and it proposed HP:0005136 for ventricular preexcitation, which OAK shows is actually Mitral annular calcification, so that suggested term was rejected. Curation is therefore anchored on independently fetched primary literature: Saettini Blood 2021 PMID 32905580, Niehues Eur J Immunol 2020 PMID 32181500, Moreno-Corona J Clin Immunol 2023 PMID 37522988, Spivak Immunogenetics 2024 PMID 39537849, Ulas J Pediatr Hematol Oncol 2024 PMID 38748614, Roncareggi review 2025 PMID 40699689, Siggs PNAS 2016 PMID 27303042, Ramirez J Immunol 2019 PMID 31676673, Reyes PNAS 2015 PMID 25548157, and IUIS 2022 PMID 35748970. Modelled an eight-node pathograph running FNIP1 loss of function to dysregulated AMPK/mTORC1 nutrient sensing, then branching to a pre-B-cell metabolic checkpoint failure arm giving absent B cells, agammaglobulinemia and recurrent infection, a cardiomyocyte glycogen accumulation arm giving hypertrophic cardiomyopathy and ventricular pre-excitation as a PRKAG2 phenocopy, and a variable neutropenia arm. Twelve phenotypes, four treatments, three diagnostics, three differential diagnoses, one mouse model, and two discussions. Respected the OMIM/MONDO caveat that rare myopathic and neurologic features are not consistently part of the disorder: these are deliberately NOT curated as core phenotypes and are instead recorded as a KNOWLEDGE_GAP discussion citing the primary statement that they were seen only in consanguineous pedigrees. IUIS category set to predominantly antibody deficiency, sourced from the IUIS 2022 Table 3 row. Validation: just validate, just validate-terms and just validate-references all pass, with 68 of 68 snippets verified against cached references.
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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.
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.
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).
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.
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.
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.
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).
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).
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.
Primary systems: immune/hematopoietic and cardiovascular systems.
The cardiac and immune abnormalities are systemic rather than lateralized.
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.
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.
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.
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.
There is no approved FNIP1-directed therapy and no relevant disease-specific interventional trial was found.
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).
Primary prevention by lifestyle change is impossible because the condition is germline. Effective prevention is genetic and complication-focused:
No population newborn or carrier-screening program is currently justified by prevalence data, although targeted familial screening is appropriate.
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.
The best-characterized models are constitutive Fnip1-null mice and the recessive ENU-induced hamel splice allele. They reproduce the two defining disease axes:
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).
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.
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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