Dilated cardiomyopathy 2J (CMD2J, OMIM 620635) is the recessive, early-infantile dilated cardiomyopathy caused by biallelic variants in FLII, which encodes flightless-I, a gelsolin-superfamily actin-remodelling protein. It was defined in 2023 in three unrelated families - one non-consanguineous Dutch, two consanguineous Saudi Arabian - whose children all presented within the first year of life, between two and five months, with severely reduced left ventricular ejection fractions of 23 to 32 percent and no extracardiac features. What makes the entity mechanistically interesting is that flightless-I is not a sarcomeric protein in the usual sense. It sits at the junction of three things a developing ventricle needs at once: it organises myofibrils, it is required for cardiomyocyte cell-adhesion complexes to concentrate into foci rather than smear along the membrane, and its loss dysregulates Notch and Hippo signalling in the compact myocardium. In zebrafish carrying the patients' own variants, knocked in by CRISPR/Cas9, all three arms fail together and the ventricle trabeculates poorly. So this is a cardiomyopathy of ventricular chamber *morphogenesis* as much as of contraction - which fits an onset within months of birth better than a purely sarcomeric lesion would. Independent mouse work reached the heart from a different direction and adds a fourth arm. A common FLII variant, R1243H, had turned up in cardiac-remodelling genome-wide association studies; knock-in and cardiac-deletion mice showed that Flii binds the sarcomeric actin thin filament and sets its length, acting with tropomodulin-1, and that Flii-deleted hearts develop cardiomyopathy through thin-filament shortening. Overexpressing leiomodin-2, which lengthens thin filaments, partially rescued them - which ties this entry directly to dilated cardiomyopathy 2G, the LMOD2 disease curated here, at the level of the same physical parameter approached from opposite sides. The two literatures should not be merged carelessly, and this entry keeps them apart. The human disease is recessive, biallelic, and infantile; the R1243H work concerns a common variant conferring population-level remodelling risk in the heterozygous state. They agree that flightless-I dosage matters to the myocardium; they are not the same genetic claim.
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Conditions with similar clinical presentations that must be differentiated from Dilated Cardiomyopathy 2J:
name: Dilated Cardiomyopathy 2J
creation_date: "2026-09-04T00:00:00Z"
category: Mendelian
disease_term:
preferred_term: cardiomyopathy, dilated, 2j
term:
id: MONDO:0957984
label: cardiomyopathy, dilated, 2j
synonyms:
- CMD2J
- cardiomyopathy, dilated, 2J
- FLII-related dilated cardiomyopathy
- flightless-I dilated cardiomyopathy
- FLII-related pediatric cardiomyopathy
description: >-
Dilated cardiomyopathy 2J (CMD2J, OMIM 620635) is the recessive,
early-infantile dilated cardiomyopathy caused by biallelic variants in FLII,
which encodes flightless-I, a gelsolin-superfamily actin-remodelling protein.
It was defined in 2023 in three unrelated families - one non-consanguineous
Dutch, two consanguineous Saudi Arabian - whose children all presented within
the first year of life, between two and five months, with severely reduced
left ventricular ejection fractions of 23 to 32 percent and no extracardiac
features.
What makes the entity mechanistically interesting is that flightless-I is not
a sarcomeric protein in the usual sense. It sits at the junction of three
things a developing ventricle needs at once: it organises myofibrils, it is
required for cardiomyocyte cell-adhesion complexes to concentrate into foci
rather than smear along the membrane, and its loss dysregulates Notch and
Hippo signalling in the compact myocardium. In zebrafish carrying the
patients' own variants, knocked in by CRISPR/Cas9, all three arms fail
together and the ventricle trabeculates poorly. So this is a cardiomyopathy of
ventricular chamber *morphogenesis* as much as of contraction - which fits an
onset within months of birth better than a purely sarcomeric lesion would.
Independent mouse work reached the heart from a different direction and adds a
fourth arm. A common FLII variant, R1243H, had turned up in cardiac-remodelling
genome-wide association studies; knock-in and cardiac-deletion mice showed that
Flii binds the sarcomeric actin thin filament and sets its length, acting with
tropomodulin-1, and that Flii-deleted hearts develop cardiomyopathy through
thin-filament shortening. Overexpressing leiomodin-2, which lengthens thin
filaments, partially rescued them - which ties this entry directly to dilated
cardiomyopathy 2G, the LMOD2 disease curated here, at the level of the same
physical parameter approached from opposite sides.
The two literatures should not be merged carelessly, and this entry keeps them
apart. The human disease is recessive, biallelic, and infantile; the R1243H
work concerns a common variant conferring population-level remodelling risk in
the heterozygous state. They agree that flightless-I dosage matters to the
myocardium; they are not the same genetic claim.
parents:
- Dilated Cardiomyopathy
- Genetic Disorder
classifications:
harrisons_chapter:
- classification_value: CARDIOVASCULAR
- classification_value: GENETICS_ENVIRONMENT_DISEASE
notes: >-
Curation level. CMD2J is curated as a standalone entry, in line with how this
knowledge base already handles the numbered dilated-cardiomyopathy loci -
CMD2G (LMOD2), CMD1GG (SDHA), CMD1R (ACTC1) and many others are separate
files. It is a distinct gene with a distinct mechanism and a distinct
inheritance pattern from its neighbours, not a severity band on a parent
entry.
The whole entity rests on one paper and three patients. Everything clinical
here comes from that report, and the numerators are given per phenotype
because with three patients a percentage would be theatre. No frequency band
is recorded on any phenotype for the same reason.
Two sources, two genetic claims, kept separate. The defining paper reports
biallelic, recessive, infantile disease. The mouse and GWAS paper concerns
R1243H, a common variant associated with cardiac remodelling in the general
population, studied in heterozygous-equivalent knock-in and in cardiac-specific
deletion mice. Both are cited here, but only the first establishes CMD2J. The
thin-filament-length mechanism is drawn from the second and is marked
PROVISIONAL in this entry precisely because it has not been shown in a patient
with biallelic FLII variants.
The LMOD2 connection is real and is worth following. In the mouse work,
overexpressing leiomodin-2 partially rescued cardiomyopathy caused by cardiac
Flii deletion. Leiomodin-2 is the gene of dilated cardiomyopathy 2G, curated
in this knowledge base as a thin-filament-length disease. That two of the
numbered DCM loci converge on the same physical parameter - from opposite
directions, one shortening and one failing to elongate - is the kind of
observation a grouping could be built on later. It is recorded here rather
than acted on.
What this entry does not contain. No `treatments:` block: nothing has been
published on treating CMD2J specifically, and importing standard heart-failure
management would put therapies in the exported graph that no FLII patient has
been reported to receive. No `biochemical:` block: no biomarker distinguishes
this entity. Both absences are decisions, not gaps in the search.
Two phenotypes are deliberately left unwired in the pathograph - the secundum
atrial septal defect and the tachycardia - each with its reason recorded in
its own `notes:`. Neither is an oversight.
GeneReviews scope. There is no FLII-specific GeneReviews chapter, but the
disease-level "Dilated Cardiomyopathy Overview" (PMID:20301486) applies and
is tagged accordingly in `references`. Its indexed PubMed record is
content_type abstract_only and carries only the chapter's purpose statement -
not the Clinical Characteristics, Management, Genetic Counseling or
Surveillance sections - so section-by-section GeneReviews mining is not
possible from the cache. The one substantive sentence it does carry, on the
proband evaluation strategy for nonsyndromic dilated cardiomyopathy, is
quoted on the sequencing `diagnosis` entry; nothing else in the chapter is
quotable. This follows the disposition already taken by the numbered-series
peers `Cardiomyopathy_Dilated_2G`, `Cardiomyopathy_Dilated_100`,
`Dilated_Cardiomyopathy_1AA` and `Dilated_Cardiomyopathy_1EE`, none of which
has a gene-specific chapter either. The clinical baseline for this entry is
therefore built entirely from the defining primary report.
On the deep-research report committed with this entry. A falcon report was run
with a disambiguating query naming FLII, the OMIM number and the recessive
biallelic mechanism. `just preflight-dr` PASSed - FLII mentioned 45 times, the
report's OMIM number matching MONDO's cross-reference - and the report
independently reached this entry's framing, including the point this entry is
most careful about: it states explicitly that the rs8821 p.Arg1243His
susceptibility allele studied in adults and mice is not one of the four family
alleles that define CMD2J.
Two of its details are recorded here as uncited leads rather than curated,
because they come from the defining paper's Table 1 rather than from any text
that can be quoted against the cached record: two of the three patients
presented with overt heart failure and one with a tachyarrhythmia, and the
ages at last review were 2, 6 and 9 years. Heart failure is consequently not
curated as a phenotype here, although it plainly belongs in the entity - a
curator with the table in front of them should add it.
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
All three reported patients carry two FLII variants, and in each family the
parents were heterozygous carriers with no clinical evidence of dilated
cardiomyopathy on cardiac screening. Two of the three families were
consanguineous. That combination - biallelic affected children, screened
unaffected heterozygous parents - is the segregation evidence for
recessiveness, and it is unusually complete for an entity defined on three
families.
evidence:
- reference: PMID:37561591
reference_title: Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Each of the parents was heterozygous for one of the FLII variants. None of
the parents showed clinical signs of DCM at cardiac screening.
explanation: >-
Carrier parents screened and unaffected, which is what distinguishes
recessive inheritance from reduced-penetrance dominant inheritance here.
- reference: PMID:37561591
reference_title: Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
We identified 3 unrelated patients with early-onset DCM and biallelic
variants in the FLII gene, including 1 nonconsanguineous family of Dutch
ancestry and 2 consanguineous families of Saudi Arabian ancestry
explanation: >-
Biallelic genotypes in three unrelated families, two of them
consanguineous.
pathophysiology:
- name: Biallelic FLII Variants
biological_scale: MOLECULAR
role: trigger
mechanism_confidence: ESTABLISHED
description: >-
The initiating lesion. Four variants were found across the three families:
one predicted to introduce a premature stop codon, three missense changes at
highly conserved residues. All were absent from gnomAD or present at very
low frequency in the heterozygous state.
The authors expected the mechanism to be hypomorphic rather than null, and
that expectation is load-bearing for the whole entry: complete loss of FLII
function is embryonic-lethal in Drosophila, zebrafish and mouse, so a viable
human recessive disease has to involve alleles that leave some protein
working. The zebrafish modelling is built around that distinction, with the
patient-mimicking knock-ins compared against a pre-existing severe truncating
line.
genes:
- preferred_term: FLII
term:
id: hgnc:3750
label: FLII
genetic_context:
functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
variant_origin: GERMLINE
description: >-
Curated as partial rather than complete loss of function on the authors'
own reasoning - null FLII is embryonic-lethal across three model species,
and these patients are alive with a cardiac-restricted phenotype - and on
the zebrafish result that the patient-mimicking alleles give a milder
phenotype than the severe truncating line. Note this is an inference about
the alleles' consequence, not a direct measurement of residual
flightless-I protein in a patient.
evidence:
- reference: PMID:37561591
reference_title: Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Here, we identified biallelic variants in the highly conserved
flightless-I (FLII) gene in 3 families with idiopathic, early-onset
dilated CM.
explanation: >-
The gene-disease assignment that defines this entity.
- reference: PMID:37561591
reference_title: Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
1 of the variants was predicted to result in a premature stop codon, and
the other 3 variants were missense, affecting highly conserved amino acids
explanation: >-
The allelic spectrum across the three families.
- reference: PMID:37561591
reference_title: Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: INDIRECT
snippet: >-
Gene knockout of FLII homologs leads to embryonic lethality in Drosophila,
zebrafish, and mouse
explanation: >-
Establishes that complete FLII loss is not survivable, which is the basis
for reading the patients' alleles as hypomorphic. Indirect: it is a
cross-species statement about null alleles, not a measurement on these
variants.
downstream:
- target: Reduced Flightless-I Function in Cardiomyocytes
causal_link_type: DIRECT
- name: Reduced Flightless-I Function in Cardiomyocytes
biological_scale: MOLECULAR
role: central_effector
mechanism_confidence: ESTABLISHED
description: >-
Flightless-I is a member of the gelsolin superfamily and was first described
as a regulator of actin dynamics; it also localises at cell-adhesion sites.
In the heart that combination gives it several jobs at once, and the three
edges out of this node are the three the defining paper measured, with a
fourth added from independent mouse work.
The authors' own summary of what the protein turned out to be doing is worth
keeping intact rather than paraphrasing: Flii dysfunction affects the
structural components of the ventricular myocardium - myofibrils and cell
adhesion complexes - *and* dysregulates DCM-related signalling pathways
during ventricular chamber morphogenesis. This is not a protein with one
downstream consequence.
biological_processes:
- preferred_term: actin filament organization
modifier: DECREASED
term:
id: GO:0007015
label: actin filament organization
cell_types:
- preferred_term: cardiomyocyte
term:
id: CL:0000746
label: cardiac muscle cell
evidence:
- reference: PMID:37561591
reference_title: Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization.
supports: SUPPORT
evidence_source: OTHER
directness: INDIRECT
snippet: >-
FLII, a member of the gelsolin superfamily, was initially described to be
involved in the regulation of actin dynamics
explanation: >-
Identifies the protein family and its canonical function. Indirect: it
states background biology rather than a finding in this disease.
- reference: PMID:37561591
reference_title: Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
snippet: >-
these data show that Flii dysfunction not only affects structural
components of the ventricular myocardium, including myofibrils and cell
adhesion complexes, but it also results in the dysregulation of
DCM-related signaling pathways during ventricular chamber morphogenesis
explanation: >-
The authors' summary of the three consequences this node branches into.
downstream:
- target: Myofibril Disorganization
causal_link_type: DIRECT
- target: Cardiomyocyte Cell Adhesion Complex Failure
causal_link_type: DIRECT
- target: Dysregulated Notch and Hippo Signaling
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Typed with unknown intermediates because the signalling changes were
measured as endpoints - reduced Notch reporter expression, reduced nuclear
Taz - without the steps connecting them to loss of an actin-remodelling
protein being established.
- target: Sarcomeric Thin Filament Shortening
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Typed with unknown intermediates, and note it comes from a different
genetic model: mouse cardiac Flii deletion and the R1243H/R1245H knock-in,
not a biallelic patient allele.
- name: Myofibril Disorganization
biological_scale: CELLULAR
role: effector
mechanism_confidence: ESTABLISHED
description: >-
Zebrafish carrying a patient-mimicking FLII missense allele have myofibrils
and intercalated discs that are less densely packed and irregularly
oriented, on transmission electron microscopy. The severe truncating line is
worse still, with poorly defined filament organisation - a dose relationship
that supports reading the patients' alleles as hypomorphic rather than null.
biological_processes:
- preferred_term: myofibril assembly
modifier: DECREASED
term:
id: GO:0030239
label: myofibril assembly
evidence:
- reference: PMID:37561591
reference_title: Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
snippet: >-
myofibrils and intercalated discs of fliiR1230C/R1230C larvae were less
densely packed and irregularly oriented
explanation: >-
The ultrastructural measurement, in the zebrafish line carrying the
knocked-in equivalent of a patient's missense variant.
downstream:
- target: Impaired Ventricular Contractility
causal_link_type: DIRECT
- name: Cardiomyocyte Cell Adhesion Complex Failure
biological_scale: CELLULAR
role: effector
mechanism_confidence: ESTABLISHED
description: >-
The finding the defining paper puts in its own title, and the one that
separates flightless-I from an ordinary sarcomeric protein. Vinculin, imaged
live as a fusion protein in zebrafish cardiomyocytes, normally concentrates
into discrete foci at the lateral membrane. In flii mutants it is dispersed
along the membrane instead. The adhesion machinery is present but no longer
organised into the discrete anchor points a cardiomyocyte needs to transmit
force to its neighbours.
Note what this claim rests on. The dispersal was measured in the severe
truncating line, not in the patient-mimicking knock-in - so the strength of
the evidence here is for flightless-I's role in adhesion-complex patterning,
with the extension to the hypomorphic patient alleles resting on the shared
myofibrillar and contractile phenotype rather than on a vinculin measurement
in those animals.
biological_processes:
- preferred_term: cell-cell adhesion
modifier: DECREASED
term:
id: GO:0098609
label: cell-cell adhesion
cell_types:
- preferred_term: cardiomyocyte
term:
id: CL:0000746
label: cardiac muscle cell
evidence:
- reference: PMID:37561591
reference_title: Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
snippet: >-
in flii+/? siblings, Vcl-EGFP was distinctly concentrated in foci (Figure
6A, left panel), whereas in fliiD110fs/D110fs embryos, Vcl-EGFP was
dispersed throughout the lateral cardiomyocyte membranes
explanation: >-
The direct in-vivo observation of adhesion-complex mispatterning, in the
severe truncating zebrafish line.
downstream:
- target: Impaired Ventricular Contractility
causal_link_type: DIRECT
- target: Defective Ventricular Trabeculation
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Dysregulated Notch and Hippo Signaling
biological_scale: CELLULAR
role: effector
mechanism_confidence: PROVISIONAL
description: >-
Two developmental signalling pathways, both independently linked to
trabeculation and to dilated cardiomyopathy, are disturbed in flii-deficient
myocardium. Notch reporter expression is strongly reduced in compact-layer
cardiomyocytes while being preserved in the atrioventricular canal and
outflow tract - a regionally specific loss rather than a global one. Nuclear
localisation of the Hippo effector Wwtr1/Taz is strongly reduced in the same
ventricular myocardium.
Marked PROVISIONAL for two reasons that should not be collapsed. Both
measurements come from the severe truncating zebrafish line rather than from
the patient-mimicking alleles; and both are readouts, not mechanisms - what
connects loss of an actin-remodelling protein to reduced Notch reporter
activity and to Taz nuclear exclusion is not established here. The likely
bridge is mechanotransduction, since Taz is a mechanosensitive effector and
the myofibrillar and adhesion lesions upstream both change how force is
generated and transmitted; but that is reasoning, not a result in this
paper, and it is stated as such.
biological_processes:
- preferred_term: Notch signaling pathway
modifier: DECREASED
term:
id: GO:0007219
label: Notch signaling pathway
- preferred_term: hippo signaling
modifier: DYSREGULATED
term:
id: GO:0035329
label: hippo signaling
evidence:
- reference: PMID:37561591
reference_title: Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
snippet: >-
Notch reporter expression was present in the AVC and OFT of
fliiD110fs/D110fs larvae, it was strongly reduced in compact layer
cardiomyocytes of the mutants
explanation: >-
The regionally specific loss of Notch reporter activity in the compact
myocardium.
- reference: PMID:37561591
reference_title: Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
snippet: >-
Immunohistochemical analyses showed that Wwtr1/Taz nuclear localization
was strongly reduced in the fliiD110fs/D110f ventricular myocardium at 60
hpf
explanation: >-
The Hippo-arm measurement. The source's spelling of the genotype is
retained in the quote.
downstream:
- target: Defective Ventricular Trabeculation
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Sarcomeric Thin Filament Shortening
biological_scale: MOLECULAR
role: modulator
mechanism_confidence: PROVISIONAL
description: >-
A fourth arm, reached from a different direction and in a different genetic
model. Mouse work driven by a common FLII variant found in cardiac-remodelling
genome-wide association studies showed that Flii binds the sarcomeric actin
thin filament and influences its length, acting together with
tropomodulin-1, and that deleting Flii from the heart - or introducing the
R1245H substitution - causes cardiomyopathy through thin-filament shortening.
The rescue is the part that makes this more than an association: overexpressing
leiomodin-2, which lengthens thin filaments, partially rescued the disease
caused by cardiac Flii deletion. That is a manipulation of the proposed
mechanism reversing the phenotype, which is stronger evidence than a
correlation - and it links this entry to dilated cardiomyopathy 2G, the
LMOD2 disease, at the level of one shared physical parameter.
PROVISIONAL for this entity all the same, and the reason is genetic rather
than experimental. The mouse work concerns a common heterozygous-state
variant and a cardiac-specific deletion; CMD2J is a recessive disease of
biallelic hypomorphic alleles in infants. Thin-filament length has not been
measured in a CMD2J patient or in the patient-mimicking zebrafish, and the
defining paper does not report it.
biological_processes:
- preferred_term: actin cytoskeleton organization
modifier: ABNORMAL
term:
id: GO:0030036
label: actin cytoskeleton organization
evidence:
- reference: PMID:37126682
reference_title: A human FLII gene variant alters sarcomeric actin thin filament length and predisposes to cardiomyopathy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
snippet: >-
Deletion of Flii from the heart, or mice with the R1245H amino acid
substitution, show cardiomyopathy due to shortening of the actin thin
filaments.
explanation: >-
The thin-filament mechanism and the cardiomyopathy it produces in mouse.
- reference: PMID:37126682
reference_title: A human FLII gene variant alters sarcomeric actin thin filament length and predisposes to cardiomyopathy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
snippet: >-
Mechanistically, Flii is a known actin binding protein that we show
associates with tropomodulin-1 (TMOD1) to regulate sarcomere thin filament
length.
explanation: >-
The molecular partnership through which flightless-I is proposed to set
thin-filament length.
- reference: PMID:37126682
reference_title: A human FLII gene variant alters sarcomeric actin thin filament length and predisposes to cardiomyopathy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
snippet: >-
Indeed, overexpression of leiomodin-2 in the heart, which lengthens the
actin-containing thin filaments, partially rescued disease due to
heart-specific deletion of Flii.
explanation: >-
The rescue experiment, which tests the thin-filament-length mechanism
rather than merely observing it, and which connects this entity to the
LMOD2 disease curated as dilated cardiomyopathy 2G.
downstream:
- target: Impaired Ventricular Contractility
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Defective Ventricular Trabeculation
biological_scale: TISSUE
role: effector
mechanism_confidence: ESTABLISHED
description: >-
Trabeculation is how the embryonic ventricle builds the muscular complexity
it needs before a coronary circulation exists. In flii mutant zebrafish it
fails: the patient-mimicking line has less organised, more primitive
trabeculae, and the severe truncating line has almost none, together with
cardiomyocytes extruding toward the abluminal side of the ventricle.
This node is why CMD2J reads as a morphogenetic disease rather than a
degenerative one. A ventricle that never trabeculated properly starts life
with a structural deficit, which is consistent with presentation at two to
five months rather than in later childhood.
biological_processes:
- preferred_term: heart morphogenesis
modifier: ABNORMAL
term:
id: GO:0003007
label: heart morphogenesis
evidence:
- reference: PMID:37561591
reference_title: Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
snippet: >-
we provided insights into the function of Flii during ventricular chamber
morphogenesis in vivo, including myofibril organization and cardiomyocyte
cell adhesion, as well as trabeculation
explanation: >-
Places trabeculation among the processes flightless-I is required for.
downstream:
- target: Impaired Ventricular Contractility
causal_link_type: DIRECT
- name: Impaired Ventricular Contractility
biological_scale: ORGANISM
role: effector
mechanism_confidence: ESTABLISHED
description: >-
The convergence point, and the thing measured in both species. Dilated
cardiomyopathy is by definition ventricular dilation with impaired
myocardial contractility, and the zebrafish carrying the patients' own
variants reproduced key functional abnormalities of the heart seen in the
patients.
Note this node is tagged ORGANISM rather than TISSUE: the claim is about
whole-heart pump function, which is what the ejection fraction measures and
what the patients present with, rather than about the state of the
myocardial tissue.
evidence:
- reference: PMID:37561591
reference_title: Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization.
supports: SUPPORT
evidence_source: OTHER
directness: INDIRECT
snippet: >-
Dilated CM (DCM), characterized by ventricular dilation and impaired
myocardial contractility, is the most prevalent subtype among children
explanation: >-
The definition of the phenotype this node names. Indirect: it defines
dilated cardiomyopathy in general, not this entity's physiology.
- reference: PMID:37561591
reference_title: Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
snippet: >-
We demonstrated that patient-specific FLII variants, when brought into the
zebrafish genome using CRISPR/Cas9 genome editing, resulted in the
manifestation of key aspects of morphological and functional abnormalities
of the heart, as observed in our patients.
explanation: >-
States that the animal model reproduces the patients' functional cardiac
abnormality, which is what makes the model informative for this node.
downstream:
- target: Dilated Cardiomyopathy
causal_link_type: DIRECT
- target: Reduced Left Ventricular Ejection Fraction
causal_link_type: DIRECT
phenotypes:
- name: Dilated Cardiomyopathy
category: Cardiovascular
description: >-
The defining phenotype, present in all three reported patients and the
reason each came to attention. Onset was within the first year of life in
every case, between two and five months.
No frequency band is recorded. Three patients is not a denominator, and the
cohort was ascertained by starting from children who already had idiopathic
early-onset dilated cardiomyopathy - so "3 of 3" describes the entry
criterion of the study rather than the penetrance of the genotype.
phenotype_term:
preferred_term: Dilated cardiomyopathy
term:
id: HP:0001644
label: Dilated cardiomyopathy
onset:
onset_category: INFANTILE
min_age_years: 0.17
max_age_years: 0.42
notes: >-
All three reported patients presented between two and five months of
age, which falls inside the HPO infantile-onset window (28 days to one
year). The bounds are the reported two- and five-month extremes
converted to years; they are the range across three patients, not a
distribution.
evidence:
- reference: PMID:37561591
reference_title: Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
All patients presented with signs of DCM within the first year of life
(age range: 2–5 months) with severely reduced left ventricular ejection
fraction (LVEF) (range 23%–32%).
explanation: >-
Dilated cardiomyopathy in all three patients, with the onset window.
- name: Reduced Left Ventricular Ejection Fraction
category: Cardiovascular
description: >-
Severely reduced in all three patients at presentation, in the range 23 to
32 percent against a normal floor of about 55 percent. Curated separately
from the dilated-cardiomyopathy diagnosis because it is the quantitative
measurement that tracks the disease and, in these patients, improved: at last
follow-up between two and nine years of age all three were alive with stable
or improved cardiac function.
phenotype_term:
preferred_term: Reduced left ventricular ejection fraction
term:
id: HP:0012664
label: Reduced left ventricular ejection fraction
evidence:
- reference: PMID:37561591
reference_title: Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
All patients presented with signs of DCM within the first year of life
(age range: 2–5 months) with severely reduced left ventricular ejection
fraction (LVEF) (range 23%–32%).
explanation: >-
The ejection fraction range at presentation in all three patients.
- reference: PMID:37561591
reference_title: Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
At last follow-up (age range 2–9 years), all patients were alive and
showed either stable disease or improved cardiac function.
explanation: >-
The follow-up course, which is what makes the presenting ejection fraction
a starting point rather than a prognosis.
- name: Secundum Atrial Septal Defect
category: Cardiovascular
description: >-
Reported in one of the three patients (patient 2-II:1). One patient of
three, so no frequency band; and a secundum atrial septal defect is common
enough in the general infant population that a single occurrence cannot
establish it as part of this syndrome. It is curated because it is a
structural cardiac malformation in a disorder whose mechanism is
morphogenetic, which makes it worth watching for in the next patient rather
than dismissing as coincidence.
notes: >-
Deliberately not wired into the pathograph. No node in this entry causes
atrial septation to fail: the morphogenetic lesion that is evidenced here is
ventricular - trabeculation, myofibril organisation, cardiomyocyte adhesion
in the ventricular wall - and nothing in either source connects flightless-I
loss to atrial septation. Drawing an edge from the ventricular
trabeculation node would assert a developmental relationship that no source
supports. It stays as an unattached observation until a second patient or a
mechanism supplies one.
phenotype_term:
preferred_term: Secundum atrial septal defect
term:
id: HP:0001684
label: Secundum atrial septal defect
evidence:
- reference: PMID:37561591
reference_title: Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Patient 2-II:1 also displayed a secondary atrial septal defect.
explanation: >-
The single reported septal defect. The source writes "secondary" for
secundum; the HPO binding is to the secundum term.
- name: Tachycardia
category: Cardiovascular
description: >-
Initial tachycardia in one of the three patients (1-II:2). Recorded together
with its context, which is the more informative half: apart from this,
none of the children showed signs of arrhythmia. An arrhythmia-free
presentation is a discriminating feature against several other pediatric
cardiomyopathies.
notes: >-
Deliberately not wired into the pathograph. Tachycardia in an infant with a
severely reduced ejection fraction is the expected compensatory response to
low cardiac output, and drawing that edge would be physiologically
reasonable - but the source reports the finding without asserting the
causal relationship, and this entry does not add causal edges that no cited
source states. The reasoning is recorded here so a later curator can wire it
against a source that does make the claim.
phenotype_term:
preferred_term: Tachycardia
term:
id: HP:0001649
label: Tachycardia
temporality: TRANSIENT
evidence:
- reference: PMID:37561591
reference_title: Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Aside from initial tachycardia in patient 1-II:2, none of the children
displayed signs of arrhythmias
explanation: >-
Tachycardia in one patient, and the absence of arrhythmia in the others.
genetic:
- name: FLII
gene_term:
preferred_term: FLII
term:
id: hgnc:3750
label: FLII
relationship_type: CAUSATIVE
variant_origin: GERMLINE
presence: PRESENT
notes: >-
FLII encodes flightless-I, a gelsolin-superfamily actin-remodelling protein
with an N-terminal leucine-rich repeat domain and C-terminal gelsolin-like
domains. Four alleles are reported across the three families: one predicted
premature stop, three missense changes at conserved residues, all rare or
absent in gnomAD.
Reading the FLII literature needs one distinction held firmly. There are two
separate genetic claims about FLII and the heart, and conflating them would
misstate both. This entry - CMD2J - is the recessive, biallelic, infantile
disease. Separately, a common FLII variant, R1243H, was associated with
cardiac remodelling in genome-wide association studies and studied in mice;
that is a population-level risk allele acting in the heterozygous state, not
a cause of CMD2J. Both bodies of work are cited here, and only the first
establishes this entity.
Two of the three families were previously published in a consanguineous
pediatric-cardiomyopathy cohort, where FLII appeared as a candidate gene
without functional validation. The 2023 paper is what converted the candidate
into a gene-disease relationship, by adding a third independent family and
modelling the patients' own alleles in zebrafish.
evidence:
- reference: PMID:37561591
reference_title: Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Taken together, our data provide experimental evidence for a role for FLII
in the pathogenesis of pediatric CM and report biallelic variants as a
genetic cause of pediatric CM.
explanation: >-
The gene-disease claim as the authors state it.
- reference: PMID:37126682
reference_title: A human FLII gene variant alters sarcomeric actin thin filament length and predisposes to cardiomyopathy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: >-
we identified a variant in the Flightless-I homolog (FLII) gene that
generates a R1243H missense change and predisposes to cardiac remodeling
across multiple previous human genome-wide association studies (GWAS)
explanation: >-
The separate, common-variant association with cardiac remodelling.
Indirect for CMD2J: it is a population risk allele in the heterozygous
state, and is cited here to keep the two FLII genetic claims distinct
rather than to support this entity's cause.
- reference: PMID:32870709
reference_title: Categorized Genetic Analysis in Childhood-Onset Cardiomyopathy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: >-
Homozygous variants were also detected in 7 novel candidates (ACACB,
AASDH, CASZ1, FLII, RHBDF1, RPL3L, ULK1).
explanation: >-
The earlier consanguineous childhood-onset cardiomyopathy cohort in which
FLII first appeared, as one of seven homozygous novel candidate genes.
Indirect: it is a candidate-gene listing without functional validation,
and does not by itself establish the gene-disease relationship - which is
exactly the distinction this entry's notes draw.
animal_models:
- name: flii R1230C knock-in zebrafish (patient-mimicking missense)
species: Zebrafish
genotype: flii R1230C homozygous, the zebrafish equivalent of the patient allele p.(R1240C)
publication: PMID:37561591
description: >-
CRISPR/Cas9 knock-in of the zebrafish residue corresponding to a patient's
missense variant, plus a compound-heterozygous line pairing the equivalent
of the second family's missense allele with a premature-stop allele. These
animals were viable to adulthood and morphologically normal at 120 hours
post-fertilisation, which is itself the point: the phenotype is cardiac and
subtle, as a hypomorphic allele should be.
modeled_mechanisms:
- target: Myofibril Disorganization
relationship: RECAPITULATES
fidelity: HIGH
description: >-
Transmission electron microscopy shows less densely packed, irregularly
oriented myofibrils and intercalated discs, in an animal carrying the
knocked-in equivalent of a patient's own allele.
limitations: >-
Zebrafish ventricular myocardium is two-layered and lacks the compact
wall thickness and coronary circulation of a mammalian heart, so
trabecular and wall-architecture findings do not transfer to human anatomy
one for one. The residue numbering also differs between species.
readouts:
- name: Myofibril and intercalated disc ultrastructure
target: Myofibril Disorganization
direction: ALTERED
interpretation: >-
Loss of the dense, regular packing seen in wild-type larvae is the
structural correlate of this node.
evidence:
- reference: PMID:37561591
reference_title: Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
snippet: >-
myofibrils and intercalated discs of fliiR1230C/R1230C larvae were
less densely packed and irregularly oriented
explanation: >-
The ultrastructural measurement behind this readout.
evidence:
- reference: PMID:37561591
reference_title: Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
snippet: >-
We demonstrated that patient-specific FLII variants, when brought into
the zebrafish genome using CRISPR/Cas9 genome editing, resulted in the
manifestation of key aspects of morphological and functional
abnormalities of the heart, as observed in our patients.
explanation: >-
Supports treating this line as informative for the patients' cardiac
phenotype, which is the claim the link makes.
- target: Impaired Ventricular Contractility
relationship: RECAPITULATES
fidelity: MODERATE
description: >-
Functional imaging of the beating embryonic heart reproduced key
functional abnormalities seen in the patients.
limitations: >-
Ejection fraction in a five-day-old zebrafish larva measured by high-speed
video is not the same measurement as a clinical echocardiogram, and the
larval heart is not yet load-bearing in the way an infant's is.
evidence:
- reference: PMID:37561591
reference_title: Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
snippet: >-
We demonstrated that patient-specific FLII variants, when brought into
the zebrafish genome using CRISPR/Cas9 genome editing, resulted in the
manifestation of key aspects of morphological and functional
abnormalities of the heart, as observed in our patients.
explanation: >-
States the functional recapitulation this link asserts.
- name: flii D110fs severe truncating zebrafish
species: Zebrafish
genotype: flii D110fs homozygous premature stop in exon 5, lacking functional gelsolin domains
publication: PMID:37561591
description: >-
A pre-existing severe truncating line, used as the strong end of an allelic
series rather than as a model of the patients. It carries most of the
mechanistic readouts in the paper - adhesion-complex patterning, Notch
reporter activity, Taz nuclear localisation - because the hypomorphic
knock-ins give changes too subtle to measure reliably.
modeled_mechanisms:
- target: Cardiomyocyte Cell Adhesion Complex Failure
relationship: RECAPITULATES
fidelity: MODERATE
description: >-
Live imaging of a vinculin-EGFP fusion shows the protein dispersed along
the lateral cardiomyocyte membrane instead of concentrated into foci.
limitations: >-
This is a severe truncating allele, not a patient allele. It demonstrates
what flightless-I does for adhesion-complex patterning; it does not show
that the patients' hypomorphic alleles disturb vinculin in the same way,
which was not measured.
readouts:
- name: Vinculin-EGFP focal concentration at the lateral membrane
target: Cardiomyocyte Cell Adhesion Complex Failure
direction: DECREASED
interpretation: >-
Loss of focal concentration, with the protein present but dispersed, is
a patterning failure rather than a loss of the adhesion machinery.
evidence:
- reference: PMID:37561591
reference_title: Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
snippet: >-
in flii+/? siblings, Vcl-EGFP was distinctly concentrated in foci
(Figure 6A, left panel), whereas in fliiD110fs/D110fs embryos,
Vcl-EGFP was dispersed throughout the lateral cardiomyocyte membranes
explanation: >-
The imaging measurement behind this readout.
- name: Cadherin2-GFP focal distribution at cell-cell junctions
target: Cardiomyocyte Cell Adhesion Complex Failure
direction: DECREASED
interpretation: >-
A second, independent junctional protein shows the same patterning
failure - uniform smear along the junction instead of discrete foci -
which is what distinguishes a general adhesion-complex localisation
defect from a vinculin-specific one. The authors ran this experiment
for exactly that reason.
evidence:
- reference: PMID:37561591
reference_title: Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
snippet: >-
mutant larvae displayed uniform distribution of cadherin2-GFP
expression along the cell-cell junctions in contrast to the cadherin
foci present in flii+/? siblings
explanation: >-
The second imaging measurement behind this node, on cadherin2 rather
than vinculin.
evidence:
- reference: PMID:37561591
reference_title: Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: INDIRECT
snippet: >-
these data show that Flii dysfunction not only affects structural
components of the ventricular myocardium, including myofibrils and cell
adhesion complexes, but it also results in the dysregulation of
DCM-related signaling pathways during ventricular chamber morphogenesis
explanation: >-
Supports treating this line as informative for the adhesion node.
Indirect: a summary across the paper's models, not a statement about
this line alone.
- target: Dysregulated Notch and Hippo Signaling
relationship: RECAPITULATES
fidelity: LOW
description: >-
Reduced Notch reporter expression in compact-layer cardiomyocytes, and
reduced nuclear Wwtr1/Taz in the ventricular myocardium.
limitations: >-
Fidelity is low for CMD2J specifically. These are severe-allele findings in
a fish embryo, the corresponding measurements have not been made in the
patient-mimicking lines, and no signalling readout has been obtained from
human FLII-deficient tissue.
readouts:
- name: Notch reporter expression in compact-layer cardiomyocytes
target: Dysregulated Notch and Hippo Signaling
direction: DECREASED
interpretation: >-
Regionally specific loss - preserved in atrioventricular canal and
outflow tract - which argues against a global reporter artefact.
evidence:
- reference: PMID:37561591
reference_title: Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
snippet: >-
Notch reporter expression was present in the AVC and OFT of
fliiD110fs/D110fs larvae, it was strongly reduced in compact layer
cardiomyocytes of the mutants
explanation: >-
The reporter measurement behind this readout.
- name: Nuclear Wwtr1/Taz localisation in ventricular myocardium
target: Dysregulated Notch and Hippo Signaling
direction: DECREASED
interpretation: >-
Reduced nuclear Taz is the standard readout of reduced Hippo-effector
activity.
evidence:
- reference: PMID:37561591
reference_title: Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
snippet: >-
Immunohistochemical analyses showed that Wwtr1/Taz nuclear
localization was strongly reduced in the fliiD110fs/D110f ventricular
myocardium at 60 hpf
explanation: >-
The immunohistochemical measurement behind this readout.
evidence:
- reference: PMID:37561591
reference_title: Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: INDIRECT
snippet: >-
In addition, we identified Flii function to be important for the
regulation of Notch and Hippo signaling, crucial pathways associated
with cardiac morphogenesis and function.
explanation: >-
Supports treating this line as informative for the signalling node.
Indirect: it states the conclusion across the paper's experiments.
- name: Cardiac-specific Flii deletion and R1245H knock-in mouse
species: Mouse
genotype: Cardiac Flii deletion; separately, Flii R1245H knock-in (syntenic to human R1243H)
publication: PMID:37126682
description: >-
Gain- and loss-of-function mice plus a knock-in of the residue syntenic to
the human common variant R1243H. This is the model that produced the
thin-filament-length mechanism and the leiomodin-2 rescue.
modeled_mechanisms:
- target: Sarcomeric Thin Filament Shortening
relationship: RECAPITULATES
fidelity: MODERATE
description: >-
Cardiac Flii deletion and the R1245H knock-in both produce cardiomyopathy
attributed to shortening of the sarcomeric actin thin filaments, with Flii
shown to bind the thin filament and to act with tropomodulin-1.
limitations: >-
This models a different genetic situation from CMD2J. The disease modelled
is a common-variant risk allele and a cardiac-specific deletion, not a
biallelic hypomorphic infantile genotype, and no thin-filament measurement
has been made in a CMD2J patient or in the patient-mimicking zebrafish.
Fidelity is moderate for the mechanism and low for the entity.
readouts:
- name: Sarcomeric actin thin filament length
target: Sarcomeric Thin Filament Shortening
direction: DECREASED
interpretation: >-
Shortened thin filaments reduce thin-thick overlap and therefore force
generation at a given sarcomere length.
evidence:
- reference: PMID:37126682
reference_title: A human FLII gene variant alters sarcomeric actin thin filament length and predisposes to cardiomyopathy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
snippet: >-
Deletion of Flii from the heart, or mice with the R1245H amino acid
substitution, show cardiomyopathy due to shortening of the actin thin
filaments.
explanation: >-
The thin-filament measurement and the phenotype it produces.
evidence:
- reference: PMID:37126682
reference_title: A human FLII gene variant alters sarcomeric actin thin filament length and predisposes to cardiomyopathy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
snippet: >-
showed that Flii protein binds the sarcomeric actin thin filament and
influences its length
explanation: >-
The molecular result on which the link rests.
- target: Impaired Ventricular Contractility
relationship: RESCUES
fidelity: MODERATE
description: >-
Overexpressing leiomodin-2, which lengthens thin filaments, partially
rescued the cardiomyopathy of cardiac Flii deletion - a manipulation of
the proposed mechanism reversing the phenotype.
limitations: >-
The rescue is partial, it is in the deletion model rather than in a
patient-allele model, and leiomodin-2 overexpression is not a therapy. Its
value here is as a mechanistic test, and as the link to the LMOD2 disease
curated as dilated cardiomyopathy 2G.
readouts:
- name: Cardiac function after cardiac leiomodin-2 overexpression
target: Impaired Ventricular Contractility
direction: RESTORED
interpretation: >-
Partial restoration by lengthening thin filaments is what makes
thin-filament shortening the operative lesion in this model rather than
an incidental finding.
evidence:
- reference: PMID:37126682
reference_title: A human FLII gene variant alters sarcomeric actin thin filament length and predisposes to cardiomyopathy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
snippet: >-
Indeed, overexpression of leiomodin-2 in the heart, which lengthens
the actin-containing thin filaments, partially rescued disease due to
heart-specific deletion of Flii.
explanation: >-
The rescue measurement behind this readout.
evidence:
- reference: PMID:37126682
reference_title: A human FLII gene variant alters sarcomeric actin thin filament length and predisposes to cardiomyopathy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: INDIRECT
snippet: >-
the identified FLII human variant likely increases cardiomyopathy risk
through an alteration in sarcomere structure and associated contractile
dynamics, like other sarcomere gene-based familial cardiomyopathies
explanation: >-
The authors' framing of how the lesion reaches contractile function.
Indirect and hedged in the source itself - "likely" - which is why the
corresponding pathophysiology node is PROVISIONAL.
progression:
- phase: Presentation in early infancy
age_range: 2-5 months
notes: >-
All three patients presented between two and five months of age with signs
of dilated cardiomyopathy and a severely reduced ejection fraction of 23 to
32 percent.
evidence:
- reference: PMID:37561591
reference_title: Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
All patients presented with signs of DCM within the first year of life
(age range: 2–5 months) with severely reduced left ventricular ejection
fraction (LVEF) (range 23%–32%).
explanation: >-
The presenting phase in all three patients.
- phase: Stabilisation or improvement in childhood
age_range: 2-9 years
notes: >-
Between two and nine years of age all three patients were alive, with either
stable disease or improved cardiac function. That is worth stating plainly
because a presenting ejection fraction of 23 percent in a two-month-old
would otherwise read as a terminal prognosis. On the available three
patients it is not - although three patients cannot establish a natural
history, and no patient has been followed into adolescence.
evidence:
- reference: PMID:37561591
reference_title: Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
At last follow-up (age range 2–9 years), all patients were alive and
showed either stable disease or improved cardiac function.
explanation: >-
The follow-up outcome in all three patients.
prevalence:
- population: Reported patients
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
Three patients from three unrelated families, in one 2023 paper. Two of the
three had already appeared as candidates in an earlier consanguineous
pediatric-cardiomyopathy cohort. No population estimate exists for CMD2J and
none can be built from three ascertained families.
For the denominator rather than for this entity: pediatric cardiomyopathy as
a whole is estimated at about 1 in 100,000 children per year, and dilated
cardiomyopathy is its commonest subtype. FLII is one gene among many within
that, and it was only established as a cause in 2023 - so the published
count is a floor.
evidence:
- reference: PMID:37561591
reference_title: Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
We identified 3 unrelated patients with early-onset DCM and biallelic
variants in the FLII gene, including 1 nonconsanguineous family of Dutch
ancestry and 2 consanguineous families of Saudi Arabian ancestry
explanation: >-
The size and structure of the founding cohort.
- reference: PMID:37561591
reference_title: Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization.
supports: SUPPORT
evidence_source: OTHER
directness: INDIRECT
snippet: >-
Pediatric CM is estimated to occur in 1 in 100,000 children per year.
explanation: >-
The incidence of the disease class, which is the denominator - not of this
entity.
diagnosis:
- name: Exome or Genome Sequencing in Idiopathic Early-Onset Dilated Cardiomyopathy
description: >-
CMD2J is reached by broad sequencing in an infant with idiopathic dilated
cardiomyopathy, not by clinical suspicion: the phenotype has no feature that
points at FLII specifically. Two of the three families were found by
family-based whole-exome sequencing, and the third by the same approach in a
non-consanguineous family.
Two practical points for a laboratory encountering a novel FLII variant.
The absence of extracardiac features is informative - it argues against the
syndromic and metabolic causes that dominate the infantile dilated
cardiomyopathy differential. And the parents should be screened
echocardiographically as well as genotyped: in all three families the
heterozygous parents were clinically unaffected, which is the observation
that supports a recessive interpretation of a novel biallelic genotype.
evidence:
- reference: PMID:37561591
reference_title: Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
No additional extracardiac features were detected.
explanation: >-
The cardiac-restricted phenotype, which is what narrows the differential.
- reference: PMID:37561591
reference_title: Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: DIRECT
snippet: >-
Each of the parents was heterozygous for one of the FLII variants. None of
the parents showed clinical signs of DCM at cardiac screening.
explanation: >-
The parental screening that makes a novel biallelic FLII genotype
interpretable.
- reference: PMID:20301486
reference_title: Dilated Cardiomyopathy Overview.
supports: SUPPORT
evidence_source: OTHER
directness: INDIRECT
snippet: >-
Provide the evaluation strategy of a proband with nonsyndromic DCM
explanation: >-
The GeneReviews dilated cardiomyopathy overview states that its purpose is
to set out the proband evaluation strategy for nonsyndromic dilated
cardiomyopathy, which is the workup an infant reaches CMD2J through.
Graded OTHER because the source is an expert overview, and INDIRECT
because the chapter is disease-level and says nothing about FLII.
differential_diagnoses:
- name: Other genetic causes of infantile dilated cardiomyopathy
description: >-
An infant presenting at two to five months with a severely reduced ejection
fraction has a long differential spanning sarcomeric, cytoskeletal,
mitochondrial, metabolic and syndromic causes, and CMD2J is not clinically
separable from them - only by genotype. What narrows the list here is the
absence of extracardiac features and the absence of arrhythmia, which
together argue against the metabolic and channelopathy-adjacent causes.
evidence:
- reference: PMID:37561591
reference_title: Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization.
supports: SUPPORT
evidence_source: OTHER
directness: INDIRECT
snippet: >-
Pediatric cardiomyopathy (CM) corresponds to a group of clinically and
genetically heterogeneous structural and functional disorders affecting the
myocardium.
explanation: >-
Establishes the heterogeneity that makes this a genotype-level
differential. Indirect: a class-level statement.
- name: Dilated cardiomyopathy 2G (LMOD2)
description: >-
Worth separating out from the general differential, because the two entities
are mechanistically linked rather than merely adjacent. LMOD2 lengthens
sarcomeric thin filaments; flightless-I, in mouse, sets their length with
tropomodulin-1, and leiomodin-2 overexpression partially rescues cardiac
Flii deletion. Both present as severe early-onset recessive dilated
cardiomyopathy.
Clinically they separate on course rather than on presentation: CMD2G is
frequently lethal in the first weeks to months, whereas all three CMD2J
patients were alive and stable or improved at two to nine years. That is
three patients against a small series, so it is a difference to watch rather
than a rule.
evidence:
- reference: PMID:37126682
reference_title: A human FLII gene variant alters sarcomeric actin thin filament length and predisposes to cardiomyopathy.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
directness: DIRECT
snippet: >-
Indeed, overexpression of leiomodin-2 in the heart, which lengthens the
actin-containing thin filaments, partially rescued disease due to
heart-specific deletion of Flii.
explanation: >-
The experimental link between the two entities' gene products.
discussions:
- discussion_id: cmd2j_mechanism_measured_in_severe_allele_not_patient_allele
kind: HUMAN_MODEL_MISMATCH
status: OPEN
prompt: >-
Do the patients' hypomorphic FLII alleles disturb cardiomyocyte
adhesion-complex patterning and Notch/Hippo signalling, or are those
findings properties of a severe truncating allele that the patient alleles
do not reach?
attaches_to:
- "pathophysiology#Cardiomyocyte Cell Adhesion Complex Failure"
- "pathophysiology#Dysregulated Notch and Hippo Signaling"
rationale: >-
Curated as HUMAN_MODEL_MISMATCH rather than KNOWLEDGE_GAP because the
evidence exists and is good - it just comes from the wrong allele. The
vinculin dispersal, the reduced Notch reporter expression and the reduced
nuclear Taz were all measured in the fliiD110fs severe truncating line. The
patient-mimicking knock-ins carry the myofibrillar and contractile
phenotypes, and were not assayed for adhesion patterning or signalling.
The paper is explicit about why: the biallelic patient variants were expected
to be hypomorphic and to give subtle phenotypic differences, which is
precisely what makes the severe line the practical vehicle for mechanism.
That is a reasonable experimental choice and a real limitation at the same
time, and the two should not be conflated.
What is at stake is not academic. If adhesion-complex patterning fails only
at severe loss of function, then the patients' disease is principally a
myofibrillar and thin-filament one, and the title claim of the defining paper
over-reaches for this entity. If it fails at hypomorphic dosage too, then
CMD2J is genuinely an adhesion disease and belongs alongside the
intercalated-disc cardiomyopathies rather than the sarcomeric ones.
proposed_experiments:
- experiment_id: exp_cmd2j_vinculin_in_patient_allele_zebrafish
name: Assay adhesion-complex patterning in the patient-mimicking zebrafish lines
description: >-
Cross the fliiR1230C/R1230C and fliiS449fs/R1158W lines into the
Tg myl7:vcla-EGFP background and quantify focal concentration of
vinculin-EGFP at the lateral cardiomyocyte membrane against wild-type
siblings, using the same quantification applied to the severe line. Repeat
for the Notch reporter and for nuclear Wwtr1/Taz. A negative result in the
hypomorphic lines would be as informative as a positive one.
- discussion_id: cmd2j_two_genetic_claims_about_flii
kind: KNOWLEDGE_GAP
status: OPEN
prompt: >-
Is thin-filament shortening part of the mechanism of recessive CMD2J, or a
property of the separate common-variant FLII association with cardiac
remodelling?
attaches_to:
- "pathophysiology#Sarcomeric Thin Filament Shortening"
rationale: >-
Two independent 2023 papers put FLII in the heart, and they do not describe
the same genetic situation. One reports biallelic hypomorphic variants
causing infantile recessive dilated cardiomyopathy in three families. The
other reports a common variant, R1243H, associated with cardiac remodelling
in genome-wide association studies, and studies it in cardiac-deletion and
knock-in mice, where the mechanism is thin-filament shortening with
tropomodulin-1.
It would be easy, and wrong, to read across. Nobody has measured sarcomeric
thin-filament length in a CMD2J patient's myocardium, in patient-derived
cardiomyocytes, or in the patient-mimicking zebrafish; and the defining paper
does not report it. Equally, nobody has shown that the mouse mechanism does
*not* operate in the patients - the measurement simply has not been made.
The question is worth resolving beyond tidiness, because it would say which
disease family CMD2J belongs to. If thin-filament length is the operative
lesion, CMD2J is a thin-filament cardiomyopathy adjacent to the LMOD2 and
TMOD1 diseases, and leiomodin-2 biology becomes a rational therapeutic
direction. If it is not, the entity is a morphogenetic and adhesion disease
that happens to share a gene with a common remodelling variant.
proposed_experiments:
- experiment_id: exp_cmd2j_thin_filament_length_patient_cells
name: Measure thin-filament length in CMD2J patient-derived cardiomyocytes
description: >-
Derive induced pluripotent stem cell cardiomyocytes from a patient with
biallelic FLII variants, or use the patient-mimicking zebrafish, and
measure sarcomeric actin thin-filament length by super-resolution imaging
against isogenic controls, alongside tropomodulin-1 and leiomodin-2
localisation. Test whether leiomodin-2 overexpression rescues contractile
function as it does in the mouse deletion model.
references:
- reference: PMID:37561591
title: Biallelic variants in FLII cause pediatric cardiomyopathy by disrupting cardiomyocyte cell adhesion and myofibril organization.
- reference: PMID:37126682
title: A human FLII gene variant alters sarcomeric actin thin filament length and predisposes to cardiomyopathy.
- reference: PMID:32870709
title: Categorized Genetic Analysis in Childhood-Onset Cardiomyopathy.
- reference: PMID:20301486
title: Dilated Cardiomyopathy Overview.
tags:
- GeneReviews
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.
Record notes
Curation level. CMD2J is curated as a standalone entry, in line with how this knowledge base already handles the numbered dilated-cardiomyopathy loci - CMD2G (LMOD2), CMD1GG (SDHA), CMD1R (ACTC1) and many others are separate files. It is a distinct gene with a distinct mechanism and a distinct inheritance pattern from its neighbours, not a severity band on a parent entry. The whole entity rests on one paper and three patients. Everything clinical here comes from that report, and the numerators are given per phenotype because with three patients a percentage would be theatre. No frequency band is recorded on any phenotype for the same reason. Two sources, two genetic claims, kept separate. The defining paper reports biallelic, recessive, infantile disease. The mouse and GWAS paper concerns R1243H, a common variant associated with cardiac remodelling in the general population, studied in heterozygous-equivalent knock-in and in cardiac-specific deletion mice. Both are cited here, but only the first establishes CMD2J. The thin-filament-length mechanism is drawn from the second and is marked PROVISIONAL in this entry precisely because it has not been shown in a patient with biallelic FLII variants. The LMOD2 connection is real and is worth following. In the mouse work, overexpressing leiomodin-2 partially rescued cardiomyopathy caused by cardiac Flii deletion. Leiomodin-2 is the gene of dilated cardiomyopathy 2G, curated in this knowledge base as a thin-filament-length disease. That two of the numbered DCM loci converge on the same physical parameter - from opposite directions, one shortening and one failing to elongate - is the kind of observation a grouping could be built on later. It is recorded here rather than acted on. What this entry does not contain. No `treatments:` block: nothing has been published on treating CMD2J specifically, and importing standard heart-failure management would put therapies in the exported graph that no FLII patient has been reported to receive. No `biochemical:` block: no biomarker distinguishes this entity. Both absences are decisions, not gaps in the search. Two phenotypes are deliberately left unwired in the pathograph - the secundum atrial septal defect and the tachycardia - each with its reason recorded in its own `notes:`. Neither is an oversight. GeneReviews scope. There is no FLII-specific GeneReviews chapter, but the disease-level "Dilated Cardiomyopathy Overview" (PMID:20301486) applies and is tagged accordingly in `references`. Its indexed PubMed record is content_type abstract_only and carries only the chapter's purpose statement - not the Clinical Characteristics, Management, Genetic Counseling or Surveillance sections - so section-by-section GeneReviews mining is not possible from the cache. The one substantive sentence it does carry, on the proband evaluation strategy for nonsyndromic dilated cardiomyopathy, is quoted on the sequencing `diagnosis` entry; nothing else in the chapter is quotable. This follows the disposition already taken by the numbered-series peers `Cardiomyopathy_Dilated_2G`, `Cardiomyopathy_Dilated_100`, `Dilated_Cardiomyopathy_1AA` and `Dilated_Cardiomyopathy_1EE`, none of which has a gene-specific chapter either. The clinical baseline for this entry is therefore built entirely from the defining primary report. On the deep-research report committed with this entry. A falcon report was run with a disambiguating query naming FLII, the OMIM number and the recessive biallelic mechanism. `just preflight-dr` PASSed - FLII mentioned 45 times, the report's OMIM number matching MONDO's cross-reference - and the report independently reached this entry's framing, including the point this entry is most careful about: it states explicitly that the rs8821 p.Arg1243His susceptibility allele studied in adults and mice is not one of the four family alleles that define CMD2J. Two of its details are recorded here as uncited leads rather than curated, because they come from the defining paper's Table 1 rather than from any text that can be quoted against the cached record: two of the three patients presented with overt heart failure and one with a tachyarrhythmia, and the ages at last review were 2, 6 and 9 years. Heart failure is consequently not curated as a phenotype here, although it plainly belongs in the entity - a curator with the table in front of them should add it.
Create: Dilated Cardiomyopathy 2J (MONDO:0957984, FLII) · 2026-09-04T21:45:34Z · View source
New standalone Disease entry for CMD2J (OMIM 620635), the FLII-related recessive infantile dilated cardiomyopathy. entry_type decision: DISEASE. dismech already curates the numbered DCM loci as standalone files - CMD2G (LMOD2), CMD1GG (SDHA), CMD1R (ACTC1) and roughly forty others are separate entries. MONDO records no descendants for MONDO:0957984 and a single causal gene, so this is a leaf. Confirmed there is no existing kb/ coverage under a different term by grepping origin/main for the MONDO ID and for FLII. The mechanism, and why it is not just another sarcomeric DCM. Flightless-I is a gelsolin-superfamily actin-remodelling protein, and the defining paper measured three separable consequences of losing it in the heart: myofibril disorganisation, failure of cardiomyocyte cell-adhesion complexes to concentrate into foci, and dysregulated Notch and Hippo signalling in the compact myocardium, all converging on defective ventricular trabeculation. That makes CMD2J a disease of ventricular chamber morphogenesis as much as of contraction, which fits presentation at 2-5 months. Two separate genetic claims about FLII, deliberately kept apart. PMID:37561591 reports biallelic hypomorphic variants causing recessive infantile DCM in three families - that is CMD2J. PMID:37126682 reports the common variant R1243H associated with cardiac remodelling in GWAS, studied in cardiac-deletion and knock-in mice, where the mechanism is sarcomeric thin-filament shortening with TMOD1 and where LMOD2 overexpression partially rescues. The thin-filament node is curated but marked PROVISIONAL and its edge typed INDIRECT_UNKNOWN_INTERMEDIATES for exactly that reason, and a KNOWLEDGE_GAP discussion asks whether it operates in the recessive disease at all. The LMOD2 rescue links this entry to Cardiomyopathy_Dilated_2G, curated here as a thin-filament-length disease; that convergence is recorded in notes and as a differential rather than acted on. A second discussion records a HUMAN_MODEL_MISMATCH that is easy to miss when reading the paper: the adhesion-complex and Notch/Hippo findings were all measured in the severe truncating fliiD110fs zebrafish line, not in the patient-mimicking knock-ins, which carry only the myofibrillar and contractile phenotypes. The paper is explicit about why - hypomorphic alleles give subtle differences - but that means the entry's title-level claim about adhesion is an extrapolation across alleles. animal_models: three linked models with modeled_mechanisms, readouts and per-link limitations - the patient-mimicking flii R1230C knock-in zebrafish (RECAPITULATES, HIGH/MODERATE), the severe flii D110fs line (RECAPITULATES at MODERATE for adhesion and LOW for signalling, with the allele mismatch stated in limitations), and the mouse cardiac Flii deletion / R1245H knock-in, which carries both a RECAPITULATES link for thin-filament shortening and a RESCUES link for the LMOD2 experiment. Evidence: 44/44 snippets verified. No DOI-prefixed citations, so nothing skipped by prefix. Sources: PMID:37561591 (defining paper, full text cached), PMID:37126682 (mouse/GWAS thin-filament work), PMID:32870709 (the earlier consanguineous cohort in which two of the three families first appeared, listed under references only). Phenotype wiring: dilated cardiomyopathy and reduced LVEF are wired from Impaired Ventricular Contractility. The secundum atrial septal defect and the tachycardia are deliberately left unwired, each with the reason in its own notes - no evidenced node in this entry causes atrial septation to fail, and the tachycardia-from-low-output edge is physiologically reasonable but is not asserted by the source. No frequency bands on any phenotype: three patients ascertained by starting from children who already had idiopathic early-onset DCM, so a proportion would describe the study design. Numerators are given per phenotype instead. No treatments block and no biochemical block, both by decision and both stated in notes. Deep research: falcon, disambiguated query. preflight-dr PASS (FLII x45, report OMIM 620635 matches MONDO). The report independently reached the same framing and explicitly makes the same R1243H distinction this entry insists on. Its Table 1 details - two of three patients presenting in overt heart failure, one with tachyarrhythmia, ages at last review 2, 6 and 9 years - are recorded in notes as uncited leads, and heart failure is consequently not curated as a phenotype. Validation: just validate, validate-terms, count-verified-snippets, validate-disorders, check-entity-refs, check-duplicate-keys, check-causal-targets, check-enum-values, check-qualifier-terms, check-stubs all pass; whole-KB check-title-snippets passes. Pathograph orphan audit: no orphan downstream, target_mechanisms or animal-model targets; every model readout target repeats its link target; no isolated nodes.
Question: You are an expert researcher providing comprehensive, well-cited information.
Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies
Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.
Please provide a comprehensive research report on Dilated cardiomyopathy 2J, CMD2J, OMIM 620635 — an autosomal recessive pediatric dilated cardiomyopathy caused by biallelic variants in FLII, the human flightless-I homolog, a gelsolin-family actin-remodelling protein. Not FLNC, not FLII-adjacent LRRFIP genes. covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.
For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.
Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed
Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Search first: CTD, PubMed, PheGenI, GxE databases
Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC
For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities
For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype
Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser
Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Search first: CDC databases, WHO, PubMed, NHANES
Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON
Present this section as an ordered causal chain first, then the detail below. Open with a numbered sequence of mechanistic steps running from the initiating lesion (mutation, exposure, infection) to the clinical manifestation, one step per line, each naming what it causes next. State the causal verb explicitly ("leads to", "results in") and say where a step is inferred rather than demonstrated. Where the mechanism branches, show the branch. The categories below are a checklist of what to cover within those steps, not the organizing structure — a step may draw on several of them, and a category may contribute to several steps.
Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Search first: PubMed, Gene Ontology, Reactome
Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types
Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Search first: OMIM, Orphanet, HPO, PubMed
Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.
Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Search first: NSGC resources, ACMG guidelines, GeneReviews
Search first: Clinical guidelines, FDA approvals, PubMed
Search first: NCBI Taxonomy
Search first: VBO (Vertebrate Breed Ontology)
Search first: NCBI Gene
Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease
This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details
Dilated cardiomyopathy 2J is a newly delineated, autosomal-recessive infantile cardiomyopathy caused by biallelic germline variants in FLII, encoding flightless-I homolog, a gelsolin-family actin-remodeling protein. It is not FLNC-related cardiomyopathy, not disease caused by the adjacent LRRFIP genes, and not FLI1, the unrelated ETS-family transcription factor. The defining evidence comprises only three affected children from three unrelated families, supplemented by patient-variant zebrafish models and independent mouse cardiac studies. Consequently, its core gene–disease relationship is compelling, but penetrance, complete phenotypic spectrum, population frequency, and prognosis remain poorly quantified. (ruijmbeek2023biallelicvariantsin pages 2-4, ruijmbeek2023biallelicvariantsin pages 1-2, lipov2023exploringthecomplex pages 3-4)
The primary disease report is Ruijmbeek et al., JCI Insight, published 5 September 2023, DOI 10.1172/jci.insight.168247. Its abstract states: “we identified biallelic variants in the highly conserved flightless-I (FLII) gene in 3 families with idiopathic, early-onset dilated CM” and concludes that the data “report biallelic variants as a genetic cause of pediatric CM.” (ruijmbeek2023biallelicvariantsin pages 1-2)
The compact case and model-evidence audit is shown below.
| Evidence type | Subject / finding | Core evidence | Genotype / frequency | Outcome or interpretation | Citation |
|---|---|---|---|---|---|
| Human—disease definition | CMD2J / dilated cardiomyopathy 2J | Autosomal-recessive, early-onset pediatric DCM caused by biallelic variants in FLII (flightless-I homolog); initially established in three unrelated families. This is FLII, not FLNC, FLI1, or an adjacent LRRFIP gene. | OMIM 620635 | Newly delineated ultra-rare Mendelian cardiomyopathy | (ruijmbeek2023biallelicvariantsin pages 2-4, ruijmbeek2023biallelicvariantsin pages 1-2) |
| Human—patient 1 | Family 1, Dutch, nonconsanguineous; individual II:2, female | Presented at 2 months with tachyarrhythmia and DCM; reported cohort LVEF range was 23%–32%, but the exact patient-specific value was not available in the extracted evidence | NM_002018.3: compound heterozygous c.1360C>T, p.(Gln454Ter) and c.3502C>T, p.(Arg1168Trp); gnomAD: truncating allele not reported in extracted table, p.Arg1168Trp MAF 0.000024 | Alive at 2 years; cardiac function stable or improved; no reported extracardiac phenotype | (ruijmbeek2023biallelicvariantsin pages 4-5, ruijmbeek2023biallelicvariantsin pages 2-4) |
| Human—patient 2 | Family 2, Saudi Arabian, consanguineous; individual II:1, female | Presented at 5 months with heart failure, DCM, and secundum atrial septal defect; cohort LVEF 23%–32%, individual value unavailable | NM_002018.3: homozygous c.2020C>G, p.(Leu674Val); gnomAD not reported/absent in the study table | Alive at 6 years; cardiac function stable or improved; ASD-II was the only additional reported structural feature | (ruijmbeek2023biallelicvariantsin pages 4-5, ruijmbeek2023biallelicvariantsin pages 2-4) |
| Human—patient 3 | Family 3, Saudi Arabian, consanguineous; individual II:1, male | Presented at 3 months with heart failure and DCM; cohort LVEF 23%–32%, individual value unavailable | NM_002018.3: homozygous c.3718C>T, p.(Arg1240Cys); gnomAD MAF 0.000057 | Alive at 9 years; cardiac function stable or improved; no reported extracardiac phenotype | (ruijmbeek2023biallelicvariantsin pages 4-5, ruijmbeek2023biallelicvariantsin pages 2-4) |
| Human—inheritance and segregation | Three families | Recessive segregation: affected children carried biallelic variants, whereas heterozygous parents were reportedly unaffected by DCM | One protein-truncating and three conserved missense alleles; variants absent or extremely rare in gnomAD and predicted damaging | Supports autosomal-recessive causation; penetrance and expressivity cannot be estimated from three affected individuals | (ruijmbeek2023biallelicvariantsin pages 2-4, lipov2023exploringthecomplex pages 3-4) |
| Model—direct disease evidence | CRISPR/Cas9 zebrafish carrying patient-mimicking flii alleles | Patient-specific alleles caused reduced ventricular fractional-area change/ejection fraction, abnormal trabeculation, myofibrillar disorganization, and altered cardiomyocyte adhesion; Flii localized to intercalated-disk and costamere-like adhesions | Modeled alleles included flii p.Arg1158Trp and p.Arg1230Cys plus a truncating allele; these are zebrafish equivalents, not human HGVS designations | Recapitulated key human cardiac abnormalities and supported hypomorphic pathogenic effects | (ruijmbeek2023biallelicvariantsin pages 12-13, ruijmbeek2023biallelicvariantsin pages 8-11) |
| Model—direct mechanistic branch | Zebrafish flii loss of function | Disrupted focal-adhesion/cell-junction organization: vinculin became diffuse and cadherin-2 lost punctate membrane localization; Notch reporter activity and nuclear Wwtr1/Taz were reduced, linking adhesion/myofibril defects to altered Notch and Hippo signaling | Null-like flii p.Asp110fs caused a more severe phenotype than patient-specific alleles | Severe trabeculation and ventricular-wall morphogenesis defects led to systolic failure and larval lethality; patient-specific alleles were milder | (ruijmbeek2023biallelicvariantsin pages 12-13, ruijmbeek2023biallelicvariantsin pages 8-11) |
| Model—complementary FLII mechanism | Cardiac-specific knockout and human-variant knock-in mice | Flii regulates sarcomeric actin thin-filament length through interaction/sequestration of tropomodulin-1; cardiac deletion shortened thin filaments and caused hypertrophy, impaired ventricular function, lung congestion, and early death. The syntenic p.Arg1245His knock-in also shortened thin filaments and increased cardiomyopathy susceptibility | Human low-frequency allele rs8821, p.Arg1243His; overall MAF 0.0175, European MAF 0.0267. This susceptibility allele is not one of the CMD2J family alleles | Independently establishes FLII as a cardiac sarcomere regulator; LMOD2 overexpression partially rescued knockout disease in mice, but this is not a validated human therapy | (kuwabara2023ahumanflii pages 2-3, kuwabara2023ahumanflii pages 1-2) |
| Evidence limitations | Current knowledge base | Only three affected children from three families were available in the defining report; no disease-specific prevalence, incidence, sex ratio, penetrance estimate, validated biomarker, histopathologic signature, quality-of-life measurement, or FLII-targeted treatment trial was identified | ACMG/AMP classifications and complete ancestry-stratified carrier frequencies were not available in the extracted primary evidence | Clinical management must presently follow general pediatric DCM/heart-failure guidance; zebrafish and mouse mechanisms should not be treated as demonstrated human myocardial pathology | (ruijmbeek2023biallelicvariantsin pages 4-5, ruijmbeek2023biallelicvariantsin pages 2-4, malinow2024pediatricdilatedcardiomyopathy pages 9-10) |
Table: Compact audit table of the defining human cases, segregation evidence, direct zebrafish validation, complementary mouse mechanism, and principal evidence gaps for FLII-related CMD2J.
Definition. CMD2J is a Mendelian myocardial disorder presenting in early infancy with left-ventricular dilation and severe systolic dysfunction in the absence of a sufficient loading condition or another identified cause. The reported phenotype is predominantly isolated DCM; one child had a secundum atrial septal defect. (ruijmbeek2023biallelicvariantsin pages 2-4, ruijmbeek2023biallelicvariantsin pages 12-13)
Identifiers and terminology. The disease identifier specified for this entity is OMIM 620635, with preferred names dilated cardiomyopathy 2J, CMD2J, FLII-related dilated cardiomyopathy, and autosomal-recessive pediatric cardiomyopathy due to FLII. A confidently disease-specific MONDO, Orphanet, MeSH, ICD-10, or ICD-11 code was not identified in the retrieved literature. Until such mappings are curated, generic DCM codes should not be represented as uniquely identifying CMD2J. Suggested knowledge-base mapping is a provisional child of MONDO “dilated cardiomyopathy” with causal gene FLII and autosomal-recessive inheritance.
Evidence provenance. Current clinical information is a published, aggregated disease-level case series derived from three individually evaluated probands—not EHR-derived population data. Evaluations included examination, 12-lead ECG, transthoracic echocardiography, exome sequencing, and Sanger confirmation. (ruijmbeek2023biallelicvariantsin pages 12-13)
The necessary initiating factor is biallelic germline variation in FLII. One family was nonconsanguineous and compound heterozygous; two Saudi families were consanguineous and had homozygous variants. Unaffected heterozygous parents support recessive inheritance. (ruijmbeek2023biallelicvariantsin pages 4-5, ruijmbeek2023biallelicvariantsin pages 2-4)
No validated susceptibility modifier, protective allele, environmental cause, toxin, infectious trigger, diet, lifestyle factor, or FLII-specific gene–environment interaction has been reported. Consanguinity increases the probability that a rare recessive allele becomes homozygous but is not itself a biological cause. Viral illness and toxins belong in the differential diagnosis of pediatric DCM; they are not established triggers of CMD2J. Likewise, the common/low-frequency rs8821, p.Arg1243His susceptibility allele studied in adults and mice is not one of the four family alleles defining CMD2J. (kuwabara2023ahumanflii pages 2-3, kuwabara2023ahumanflii pages 1-2)
No genetic or environmental protective factor is established. Partial rescue of cardiac Flii-deletion phenotypes by LMOD2 overexpression in mice is mechanistic proof of principle, not evidence of a protective human allele or available therapy. (kuwabara2023ahumanflii pages 1-2)
All three known patients developed severe disease between 2 and 5 months, making infantile onset the defining temporal feature. LVEF across the cohort was 23%–32%. Two presented with overt heart failure and one with tachyarrhythmia; no subsequent arrhythmias or extracardiac abnormalities were reported. All were alive with stable or improved function at last review, ages 2, 6, and 9 years. (ruijmbeek2023biallelicvariantsin pages 4-5, ruijmbeek2023biallelicvariantsin pages 2-4)
Suggested HPO annotations are:
No skeletal-muscle weakness, neurodevelopmental abnormality, dysmorphism, inflammatory syndrome, behavioral phenotype, or reproducible laboratory abnormality was described. “Not reported” should not be encoded as “absent” unless the source explicitly examined and excluded it. No disease-specific quality-of-life instrument, functional score, school-impact assessment, or caregiver-burden measure is available.
Gene. The causal gene is FLII (flightless-I homolog), represented in the primary report by transcript NM_002018.3. FLII combines an N-terminal leucine-rich-repeat region with six gelsolin-homology domains. The gelsolin-like region binds actin; FLII participates in actin capping/remodeling, focal adhesions, and sarcomeric organization. (kuwabara2023ahumanflii pages 2-3, strudwick2020multifunctionalrolesof pages 4-6, strudwick2020multifunctionalrolesof pages 3-4)
Reported disease alleles. Four germline alleles were observed:
The missense substitutions affect conserved residues and were predicted damaging; CADD scores were 27, 31, and 26.1 for p.Arg1168Trp, p.Leu674Val, and p.Arg1240Cys, respectively. The source did not supply definitive ClinVar/ClinGen assertions or complete ACMG/AMP rule combinations in the extracted evidence. They should therefore not automatically be labeled “pathogenic” variant-by-variant solely because the gene–disease relationship is supported. (ruijmbeek2023biallelicvariantsin pages 4-5, ruijmbeek2023biallelicvariantsin pages 2-4)
The alleles are inherited constitutional variants, not somatic mutations. No CMD2J-associated copy-number variant, translocation, inversion, aneuploidy, repeat expansion, mitochondrial variant, epigenetic signature, modifier gene, or founder haplotype is established. There is also no disease-specific methylome, transcriptome, proteome, metabolome, lipidome, single-cell, spatial-transcriptomic, or human myocardial multi-omic dataset.
No environmental, occupational, nutritional, behavioral, radiation, medication, or infectious cause has been associated specifically with FLII-related CMD2J. Smoking and alcohol are irrelevant as causal exposures in the reported infants. Standard investigation should nevertheless exclude myocarditis, metabolic disease, nutritional deficiency, toxic exposure, and abnormal loading conditions because these can phenocopy pediatric DCM; exclusion does not imply a demonstrated interaction with FLII.
FLII is a multifunctional actin-associated protein. Its gelsolin-homology domains bind G-actin/F-actin and can cap filament barbed ends; biochemical work indicates inhibition of polymerization without robust severing in several contexts. Its LRR region mediates protein interactions, including LRRFIP1/2, but the human disease alleles and causal locus here are FLII itself. (gorog2026flightlessiand pages 15-17, strudwick2020multifunctionalrolesof pages 4-6, strudwick2020multifunctionalrolesof pages 3-4)
The most relevant proposed GO biological-process terms are actin filament organization, actin filament polymerization/depolymerization regulation, sarcomere organization, myofibril assembly, cell–cell adhesion, cell–matrix adhesion, cardiac muscle contraction, ventricular trabecula morphogenesis, Notch signaling, and Hippo signaling. Suggested cellular components are sarcomere, actin cytoskeleton, myofibril, focal adhesion, costamere, intercalated disc, adherens junction, and Z disc. Exact GO identifiers should be ontology-validated before ingestion.
Primary cell type: cardiomyocyte (CL:0000746), especially ventricular cardiomyocytes. Cardiac fibroblasts, endothelial cells, and immune cells have not been implicated directly in CMD2J. There is no demonstrated disease-specific apoptosis, autophagy, mitochondrial failure, metabolic reprogramming, fibrosis, inflammation, or immune activation in human tissue.
The primary organ is the heart, particularly ventricular myocardium, left ventricle, ventricular wall/trabeculae, and cardiomyocyte contractile/adhesion structures. Suggested anatomy mappings include UBERON:0000948 heart, UBERON:0002084 heart left ventricle, ventricular myocardium, interventricular/cardiac septal structures, and atrial septum for the single ASD-II case. Laterality is not applicable. Secondary lung, liver, or kidney involvement from congestion was not reported in the three patients.
At subcellular resolution, relevant sites are sarcomeric thin filaments, myofibrils, intercalated-disk/costamere-like adhesion complexes, focal adhesions, and adherens junctions. Flii localized to cardiac sarcomeres in mouse studies and to intercalated-disk/costamere-like adhesions in zebrafish. (ruijmbeek2023biallelicvariantsin pages 2-4, kuwabara2023ahumanflii pages 2-3)
Onset was uniformly early and clustered at 2–5 months. The presentation may be acute—heart failure or tachyarrhythmia—but the underlying developmental cytoskeletal defect is congenital. Patient-specific zebrafish alleles behaved as milder hypomorphs, whereas a null-like allele caused severe wall-morphogenesis defects, systolic failure, and larval death. This supports a dosage/severity continuum but does not establish a human stage system. (ruijmbeek2023biallelicvariantsin pages 8-11)
The three children survived to ages 2–9 with stable or improved cardiac function; therefore, CMD2J is not invariably lethal in infancy. Remission rates, relapse, adult course, pregnancy risk, arrhythmia burden, and critical treatment windows remain unknown. Early infancy is the clearest period of vulnerability.
Inheritance is autosomal recessive. For two confirmed heterozygous carrier parents, each pregnancy has a theoretical 25% affected, 50% carrier, and 25% noncarrier probability, subject to confirmation of parental phase and molecular diagnosis. Heterozygous parents were clinically unaffected, and heterozygous Flii-null mice lacked a reported cardiac phenotype. (ruijmbeek2023biallelicvariantsin pages 2-4, kuwabara2023ahumanflii pages 2-3)
Only three affected individuals—two females and one male—are known from the defining series, precluding sex-ratio, penetrance, expressivity, anticipation, germline-mosaicism, prevalence, or incidence estimates. Two children were Saudi Arabian from consanguineous families and one was Dutch from a nonconsanguineous family. This is ascertainment evidence, not proof of ethnic predisposition or founder effect. (ruijmbeek2023biallelicvariantsin pages 4-5, ruijmbeek2023biallelicvariantsin pages 2-4)
For context only, general pediatric DCM prevalence is estimated at 0.57–1.13 per 100,000 children, rising to 8.34 per 100,000 infants; these values must not be assigned to CMD2J. General pediatric DCM has a median diagnosis age of 1.5 years, with 41% diagnosed in the first year. (malinow2024pediatricdilatedcardiomyopathy pages 2-3)
Echocardiographic measurements should include LV dimensions/z-scores, fractional shortening, LVEF, mitral regurgitation, and serial remodeling. ECG/Holter monitoring is reasonable given the tachyarrhythmia in one patient. CMR can characterize anatomy, function, edema, inflammation, iron, or fibrosis but is not mandatory for diagnosis and lacks fully standardized pediatric monitoring methods. BNP/NT-proBNP and troponin can support heart-failure assessment but are not CMD2J-specific biomarkers. (malinow2024pediatricdilatedcardiomyopathy pages 9-10, malinow2024pediatricdilatedcardiomyopathy pages 3-4)
RNA sequencing may help resolve suspected splice variants or variants of uncertain significance but has not been reported for CMD2J. CMA, karyotyping, FISH, mtDNA testing, and repeat-expansion assays are not first-line FLII tests unless clinical findings suggest an alternative diagnosis. No biochemical FLII enzyme assay, biopsy hallmark, newborn screen, or liquid-biopsy test exists.
Differential diagnosis. Important genetic alternatives include other infantile sarcomeric/cytoskeletal DCMs, metabolic and mitochondrial cardiomyopathies, Barth syndrome, neuromuscular disease, myocarditis, and congenital structural lesions. FLNC-related DCM is generally a different gene–disease entity and must not be conflated with FLII.
All three reported CMD2J patients were alive with stable or improved function at last follow-up, but three observations cannot support survival estimates. No transplant, ventricular-assist-device use, sudden death, or extracardiac disability was reported in the extracted cases. (ruijmbeek2023biallelicvariantsin pages 4-5, ruijmbeek2023biallelicvariantsin pages 2-4)
General pediatric DCM has substantially worse aggregate outcomes: nearly 40% undergo transplantation or die within two years, while reported transplant-free survival is 69%, 54%, and 46% at 1, 5, and 10 years. These figures are contextual and may overstate risk for treated CMD2J, whose known patients improved or stabilized. (malinow2024pediatricdilatedcardiomyopathy pages 1-2, malinow2024pediatricdilatedcardiomyopathy pages 7-8)
General prognostic markers include larger LVEDD, lower LVEF/fractional shortening, and severe mitral regurgitation. Disease-specific prognostic biomarkers are unavailable. (malinow2024pediatricdilatedcardiomyopathy pages 7-8)
There is no FLII-directed approved therapy, genotype-specific clinical protocol, pharmacogenomic recommendation, gene therapy, RNA therapy, CRISPR trial, or registered FLII cardiomyopathy trial identified.
Management should follow pediatric systolic-heart-failure practice under a specialist cardiomyopathy team. Depending on congestion, blood pressure, renal function, and age, treatment commonly includes diuretics, ACE inhibitors/ARBs, beta-blockers, and mineralocorticoid-receptor antagonists. Ivabradine, sacubitril/valsartan, and SGLT2 inhibitors may be considered in selected children, but pediatric evidence is limited and much practice is extrapolated from adults. Acute decompensation may require inotropes such as milrinone; refractory stage-D disease may require ECMO, VAD, transplantation, or palliation. (malinow2024pediatricdilatedcardiomyopathy pages 9-10, malinow2024pediatricdilatedcardiomyopathy pages 8-9)
Suggested NCIT intervention concepts include heart-failure pharmacotherapy, diuretic therapy, ACE-inhibitor therapy, beta-blocker therapy, mineralocorticoid-receptor-antagonist therapy, mechanical circulatory support, ventricular-assist device, extracorporeal membrane oxygenation, and heart transplantation; exact NCIT codes should be validated before ingestion.
In general pediatric DCM cohorts, transplant occurred in 22%, 27%, and 29% by 1, 3, and 5 years, with post-transplant survival of 92% at one year and 80% at five years. These are not CMD2J-specific response rates. (malinow2024pediatricdilatedcardiomyopathy pages 8-9)
The LMOD2 rescue experiment and manipulation of FLII–TMOD1 biology are attractive research directions, but systemic alteration of actin regulation could have substantial safety risks. No human efficacy or toxicology data justify clinical use. (kuwabara2023ahumanflii pages 1-2)
Primary prevention cannot eliminate a spontaneously inherited allele through lifestyle change. Reproductive options after molecular confirmation include genetic counseling, carrier testing of relatives, prenatal diagnosis, and preimplantation genetic testing for monogenic disease. Population carrier screening and newborn screening are not established.
Secondary prevention consists of presymptomatic cascade testing and cardiac surveillance in at-risk siblings. General familial-DCM guidance suggests screening first-degree relatives annually at ages 0–5, every 1–2 years at 6–12, and every 1–3 years at 13–19, individualized for genotype and family course. (malinow2024pediatricdilatedcardiomyopathy pages 3-4)
Tertiary prevention includes early guideline-directed heart-failure therapy, rhythm surveillance, vaccination and prompt treatment of intercurrent infection according to routine pediatric practice, avoidance of cardiotoxic exposures, and timely referral for advanced support. Vaccination prevents infection-related decompensation but does not prevent the genetic disorder.
No naturally occurring FLII-related CMD2J-like veterinary disorder, breed predisposition, zoonotic transmission, or cross-species infectious risk was identified. The disorder is noncommunicable.
Relevant experimental taxa are Homo sapiens (NCBI Taxon 9606), Danio rerio (7955), Mus musculus (10090), and historically Drosophila melanogaster (7227). Orthologous flightless-I proteins are evolutionarily conserved, supporting comparative functional inference, but model phenotypes are induced genetically rather than documented natural veterinary disease.
Zebrafish—strongest disease-specific model. CRISPR/Cas9 patient-mimicking alleles reproduced reduced ventricular contractility, abnormal trabeculation, myofibril disorganization, and adhesion defects. Null-like flii loss caused more severe systolic failure and larval lethality, while patient-specific alleles allowed survival, supporting hypomorphic effects. Altered vinculin, cadherin-2, Notch, and Wwtr1/Taz localization/activity supplied mechanistic resolution. Limitations include the two-chambered fish heart, regenerative capacity, and differences in hemodynamic load. (ruijmbeek2023biallelicvariantsin pages 12-13, ruijmbeek2023biallelicvariantsin pages 8-11)
Mouse—complementary cardiac model. Cardiac Flii deletion shortened sarcomeric actin filaments and caused hypertrophy, impaired ventricular performance, pulmonary congestion, heart failure, and early death. The syntenic knock-in corresponding to human rs8821 p.Arg1243His also shortened thin filaments and increased susceptibility to cardiomyopathy. The PNAS abstract summarizes: “the Flii gene regulates sarcomeric actin thin filament length by sequestering tropomodulin-1.” These models establish a cardiac structural role for FLII but do not model the exact three CMD2J genotypes or prove the same thin-filament lesion in human myocardium. Published May 2023; DOI 10.1073/pnas.2213696120. (kuwabara2023ahumanflii pages 2-3, kuwabara2023ahumanflii pages 1-2)
Drosophila. Flightless-I studies support conserved barbed-end/Z-disc actin regulation and myofibril growth, but they are more remote comparative-mechanistic evidence. LRRFIP cooperation in flies does not make LRRFIP a demonstrated cause of CMD2J. (gorog2026flightlessiand pages 21-28, gorog2026flightlessiand pages 15-17, gorog2026flightlessiand pages 12-15)
No patient-derived iPSC-cardiomyocyte, cardiac organoid, humanized exact-variant mouse, large-animal model, or therapeutic CRISPR screen was identified.
CMD2J is best represented as a very rare, autosomal-recessive, infantile-onset, predominantly isolated DCM caused by biallelic FLII variants. The mechanistic center is defective cardiomyocyte actin/myofibril organization and adhesion, with downstream ventricular morphogenesis, Notch/Hippo, and contractile abnormalities. Evidence is strongest for gene causality and zebrafish phenocopy; human tissue-level mechanism and long-term clinical behavior remain uncertain. (ruijmbeek2023biallelicvariantsin pages 2-4, ruijmbeek2023biallelicvariantsin pages 8-11)
The highest priorities are additional case ascertainment, standardized ACMG/ClinVar deposition, longitudinal rhythm and imaging surveillance, patient-derived cardiomyocytes, direct measurement of human thin-filament length and adhesion complexes, and development of exact-variant mammalian models. Disease-specific prevalence, penetrance, carrier frequency, quality of life, adult outcomes, and treatment-response data are currently unavailable.
References
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