Left Ventricular Noncompaction 8

Genetic MONDO:0014152 Pathograph 11 Show in embeddings browser Left Ventricular Noncompaction Dilated Cardiomyopathy Genetic Disorder

Left ventricular noncompaction 8 (LVNC8) is the PRDM16-associated form of inherited left ventricular noncompaction and dilated cardiomyopathy. PRDM16 encodes a zinc-finger transcription factor that is enriched in the compact myocardium of the developing left ventricle, where it activates compact-myocardial genes, represses trabecular-myocardial genes, restrains TGF-beta signaling to permit cardiomyocyte proliferation, opposes master regulators of ventricular conduction and atrial fate, and supports cardiac metabolic homeostasis. Haploinsufficient or truncating PRDM16 variants were first identified within the 1p36 deletion syndrome critical region and were subsequently shown to cause nonsyndromic LVNC and dilated cardiomyopathy (DCM), producing a ventricular phenotype that spans isolated noncompaction, noncompaction with dilation, and pure dilation without excess trabeculation. MONDO frames the entity through the PRDM16-dilated-cardiomyopathy axis ("any familial isolated dilated cardiomyopathy in which the cause of the disease is a mutation in the PRDM16 gene") while the disease label foregrounds noncompaction; both framings are correct descriptions of the same genotype and are reconciled below.

Ask OpenScientist

Ask a research question about Left Ventricular Noncompaction 8. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Mappings
1
Inheritance
11
Pathophys.
7
Phenotypes
1
Gaps
11
Pathograph
1
Genes
5
Medical Actions
2
Differentials
1
Datasets
1
References
1
Deep Research
🔗

Mappings

MONDO
MONDO:0014152 left ventricular noncompaction 8
skos:exactMatch
👪

Inheritance

1
Autosomal Dominant HP:0000006
Reported PRDM16 cardiomyopathy cases follow autosomal dominant transmission of a heterozygous variant; several cases, including the fetal presentation and one of two pediatric probands in the TGF-beta mechanistic study, arose de novo.
Autosomal dominant inheritance
Show evidence (2 references)
CGGV:assertion_c0a3445a-5bb0-4d77-a4f0-5b7cfceb837f-2025-05-30T160000.000Z SUPPORT Other
"PRDM16 | HGNC:14000 | dilated cardiomyopathy | MONDO:0005021 | AD | Strong"
ClinGen Hereditary Cardiovascular Disease GCEP records autosomal dominant inheritance for the PRDM16-dilated cardiomyopathy relationship with Strong clinical validity.
PMID:31965688 SUPPORT Human Clinical
"Exome sequencing (ES) identified a de novo unreported p.(Gln353*) heterozygous nonsense variant in PRDM16."
Documents a de novo heterozygous PRDM16 nonsense variant, consistent with autosomal dominant, often sporadic, transmission.
?

Discussions and Knowledge Gaps

1
Is PRDM16-associated cardiomyopathy best classified as a form of left ventricular noncompaction, a form of dilated cardiomyopathy, or a single genotype that produces a phenotypic spectrum spanning both labels?
INTERPRETATION OPEN gap_lvnc8_noncompaction_vs_dcm_nosology
Attached to
pathophysiology#Failed Ventricular Compaction pathophysiology#Left Ventricular Dilation and Systolic Dysfunction
MONDO:0014152 is defined through the DCM axis ("any familial isolated dilated cardiomyopathy...caused by...PRDM16") even though its label and OMIM entry (615373) foreground noncompaction. The primary literature resolves this as a genuine spectrum rather than a labeling error: the founding report found PRDM16 mutations in both nonsyndromic LVNC and DCM cohorts, a large systematic rare-variant study found PRDM16 (with MYH7 and ACTN2) uniquely enriched in LVNC specifically among cardiomyopathy genes, a contemporary review reports that missense variants track with DCM while nonsense/frameshift variants track with LVNC, and mouse/human mechanistic work shows PRDM16 loss produces both noncompaction (failure of compact-myocardium specification) and LV dilation (impaired cardiomyocyte proliferation and TGF-beta-driven remodeling) from the same lesion. This dismech entry curates LVNC8 as its own genotype-defined node distinct from the polygenic LVNC umbrella entry, modeling both the noncompaction and the dilation/heart-failure branches as parallel downstream consequences of the same PRDM16 lesion rather than picking one label over the other.
Show evidence (3 references)
PMID:23768516 SUPPORT Human Clinical
"In conclusion, mutation of PRDM16 causes the cardiomyopathy in 1p36 deletion syndrome as well as a proportion of nonsyndromic LVNC and DCM."
The founding genetic report establishes PRDM16 as causal for both LVNC and DCM cohorts, directly supporting a shared-genotype spectrum rather than two separate diseases.
PMID:33500567 SUPPORT Human Clinical
"In contrast, truncating variants in MYH7, ACTN2, and PRDM16 were uniquely associated with LVNC and may reflect a distinct LVNC etiology."
A large systematic rare-variant study specifically flags PRDM16 as one of few genes with LVNC-specific (rather than shared DCM/HCM) enrichment, supporting genuine noncompaction biology alongside the DCM framing.
PMID:39337275 SUPPORT Human Clinical
"Missense variants in PRDM16 were primarily associated with DCM, whereas nonsense and frameshift mutations were associated with LVNC"
A contemporary narrative review reports a variant-class-specific genotype-phenotype correlation (missense to DCM, nonsense/frameshift to LVNC) that directly explains why the same gene produces both labeled phenotypes rather than one being a misclassification of the other.
⚙

Pathophysiology

11
PRDM16 Loss-of-Function Variant
Heterozygous truncating (nonsense, frameshift) or missense PRDM16 variants reduce the dose or activity of the PRDM16 zinc-finger transcription factor. Variants cluster across the gene's 17 exons and were first mapped within the terminal 1p36 deletion syndrome critical region before being confirmed as an independent cause of nonsyndromic disease. A contemporary review reports a variant-class correlation: missense variants track with DCM, while nonsense and frameshift (loss-of-function) variants track with LVNC, and PRDM16 is predicted to be highly intolerant of loss-of-function variation.
Genetic context allele_type: SNV_INDEL variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION
heart left ventricle UBERON:0002084 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in heart left ventricle (UBERON:0002084). UBERON:0002084 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Loss of Compact Myocardium Transcriptional Identity Reduced PRDM16 dose removes its transcriptional activation of compact-myocardial genes and repression of trabecular-myocardial genes in left ventricular cardiomyocytes.
Cardiac Metabolic Dysregulation Independent of the compact-myocardium transcriptional program, monoallelic Prdm16 loss produces early, sex-modified metabolic and oxidative-stress changes in cardiac tissue.
Show evidence (4 references)
PMID:23768516 SUPPORT Human Clinical
"Resequencing of PRDM16 in a cohort of 75 nonsyndromic individuals with LVNC detected three mutations, including one truncation mutant, one frameshift null mutation, and a single missense mutant."
Directly documents the spectrum of PRDM16 loss-of-function and missense variants identified in nonsyndromic LVNC probands.
PMID:38113297 SUPPORT Human Clinical
"We report 2 probands with loss-of-function PRDM16 variants and pediatric left ventricular noncompaction cardiomyopathy."
Confirms loss-of-function PRDM16 variants as the proximate genetic lesion in two independently ascertained pediatric probands.
PMID:39337275 SUPPORT Human Clinical
"Missense variants in PRDM16 were primarily associated with DCM, whereas nonsense and frameshift mutations were associated with LVNC"
Establishes the variant-class-specific genotype-phenotype correlation that motivates classifying this node's loss-of-function variants as the LVNC-associated lesion class.
+ 1 more reference
Loss of Compact Myocardium Transcriptional Identity
PRDM16 is a compact-myocardium-enriched transcription factor that activates a compact-myocardial gene program while repressing a trabecular-myocardial gene program, in part through cooperation with the LV-enriched transcription factors TBX5 and HAND1. In cardiomyocyte-specific Prdm16 knockout mice, compact myocardial cardiomyocytes shift from a compact transcriptional identity toward one resembling trabecular myocardium or neurons, with reduced cardiomyocyte proliferation localized to the left ventricular compact layer and interventricular septum. Independently, single-cell RNA+ATAC sequencing shows PRDM16 favors ventricular working cardiomyocyte identity specifically by opposing the master regulators of ventricular conduction and atrial fate, so its loss also derepresses a conduction-system/atrial transcriptional program.
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
heart left ventricle UBERON:0002084 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in heart left ventricle (UBERON:0002084). UBERON:0002084 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
TGF-beta Signaling Dysregulation Loss of PRDM16-mediated repression of TGF-beta pathway genes, including direct repression of the TGFB3 promoter, de-represses TGF-beta receptor signaling in cardiomyocytes.
Failed Ventricular Compaction Loss of the compact-myocardial gene program directly impairs the structural maturation of the compact ventricular wall.
Ventricular Conduction System Hyperplasia and Atrial-Fate Derepression Loss of PRDM16-mediated suppression of conduction-system and atrial-fate master regulators allows ectopic conduction-system tissue to expand within the ventricular myocardium.
Show evidence (3 references)
PMID:34915728 SUPPORT Model Organism
"PRDM16 functioned mechanistically as a compact myocardium-enriched transcription factor that activated compact myocardial genes while repressing trabecular myocardial genes in LV compact myocardium."
Mouse cardiomyocyte-specific knockout study directly establishes the dual activator/repressor transcriptional role of PRDM16 in specifying compact versus trabecular cardiomyocyte identity.
PMID:34915728 SUPPORT Model Organism
"Prdm16cKO LV compact myocardial cardiomyocytes shifted from their normal transcriptomic identity to a transcriptional signature resembling trabecular myocardial cardiomyocytes or neurons."
Documents the specific transcriptional-identity-switch consequence of PRDM16 loss in LV compact myocardium.
PMID:39304345 SUPPORT Model Organism
"PRDM16 favors ventricular working cardiomyocyte identity, by opposing the activity of master regulators of ventricular conduction and atrial fate."
Independent single-cell RNA+ATAC-sequencing study in a mouse cardiomyocyte-specific Prdm16 deletion establishes that PRDM16 actively suppresses conduction-system and atrial cell-fate programs as part of maintaining ventricular working cardiomyocyte identity.
TGF-beta Signaling Dysregulation
PRDM16 normally binds the TGFB3 promoter and represses its transcription. Loss of PRDM16 releases this repression, producing increased TGF-beta receptor signaling in cardiomyocytes. Because TGF-beta signaling has an antiproliferative effect on cardiomyocytes, its dysregulated increase reduces cardiomyocyte proliferative capacity during the developmental window when compaction normally occurs.
transforming growth factor beta receptor signaling pathway GO:0007179 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased transforming growth factor beta receptor signaling pathway (GO:0007179). GO:0007179 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Impaired Cardiomyocyte Proliferation Increased TGF-beta receptor signaling suppresses the proliferative expansion of developing left ventricular cardiomyocytes.
Show evidence (2 references)
PMID:38113297 SUPPORT In Vitro
"Mechanistic studies were undertaken in H9c2 cardiomyoblasts to show that PRDM16 binds TGFB3 promoter and represses its transcription."
Direct biochemical evidence that PRDM16 represses TGFB3 transcription, establishing the molecular basis for TGF-beta pathway de-repression upon PRDM16 loss. H9c2 is a rat cardiomyoblast cell line, so this is cultured-cell (IN_VITRO) evidence, not a whole-animal model.
PMID:27642787 SUPPORT In Vitro
"TBX20 regulates the expression of TGF-β signalling modifiers including one known to be a genetic cause of LVNC, PRDM16, and genome editing of PRDM16 caused proliferation defects in iPSC-CMs."
Independent iPSC-cardiomyocyte genome-editing evidence that PRDM16 loss causes the same TGF-beta-linked proliferation defect seen in the PRDM16 patient-mutation studies.
Cardiac Metabolic Dysregulation
Independently of the compact-myocardium transcriptional program, monoallelic Prdm16 loss produces early metabolic dysregulation in cardiac tissue: reduced amino-acid, glycerol, glycolytic, and tricarboxylic-acid-cycle metabolites, diminished glutathione with increased inosine monophosphate (indicating oxidative stress and dysregulated energetics), and up-regulation of two novel candidate cardiac metabolic regulators, PYROXD2 and PBXIP1. The phenotype is sex-modified: cardiac dysfunction and reduced glucose utilization are more pronounced in female mice, while triacylglyceride accumulation and reduced fatty-acid utilization are male-specific.
cellular response to oxidative stress GO:0034599 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cellular response to oxidative stress (GO:0034599). GO:0034599 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Left Ventricular Dilation and Systolic Dysfunction Oxidative stress and dysregulated cardiac energetics contribute to diminished systolic performance independently of the compaction/TGF-beta axis.
Show evidence (3 references)
PMID:37842925 SUPPORT Model Organism
"Prdm16csp1/wt mice are viable up to 8 months, develop hypoplastic hearts, and diminished systolic performance that is more pronounced in female mice."
Establishes the sex-modified severity of the metabolic/functional cardiac phenotype in a monoallelic Prdm16 mouse model.
PMID:37842925 SUPPORT Model Organism
"Prdm16csp1/wt cardiac tissue revealed diminished glutathione (GSH) and increased inosine monophosphate (IMP) levels indicating oxidative stress and a dysregulated energetics, respectively."
Direct metabolomic evidence for oxidative stress and dysregulated cardiac energetics as an early consequence of PRDM16 loss.
PMID:37842925 SUPPORT Model Organism
"On the level of transcripts and protein expression, Prdm16csp1/wt hearts demonstrate an up-regulation of pyridine nucleotide-disulphide oxidoreductase domain 2 (Pyroxd2) and the transcriptional regulator pre-B-cell leukaemia transcription factor interacting protein 1 (Pbxip1)."
Identifies PYROXD2 and PBXIP1 as novel transcriptionally up-regulated candidate cardiac metabolic regulators downstream of PRDM16 loss.
Impaired Cardiomyocyte Proliferation
Cardiomyocytes carrying loss-of-function PRDM16 variants show reduced proliferative capacity and increased apoptosis. In induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) generated from a PRDM16-Q187X proband, proliferation was significantly reduced and apoptosis increased, with transcriptional dysregulation of cardiac maturation genes including TGF-beta-associated transcripts; homozygous Prdm16-Q187X knock-in mice were embryonic lethal with an underdeveloped compact myocardium.
cardiac muscle cell CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
Downstream
Failed Ventricular Compaction Reduced cardiomyocyte proliferation in the developing compact myocardium limits the thickening and maturation of the compact ventricular wall.
Left Ventricular Dilation and Systolic Dysfunction Reduced cardiomyocyte number and thinner compact/interventricular septal myocardium predispose to progressive ventricular dilation and contractile dysfunction.
Show evidence (2 references)
PMID:38113297 SUPPORT In Vitro
"Induced pluripotent stem cell-derived cardiomyocytes prepared from the PRDM16-Q187X proband demonstrated a statistically significant impairment in myocyte proliferation and increased apoptosis associated with transcriptional dysregulation of genes implicated in cardiac maturation, including..."
Patient-derived iPSC-cardiomyocyte data directly demonstrate the proliferation and apoptosis defect caused by a human loss-of-function PRDM16 variant.
PMID:38113297 SUPPORT Model Organism
"Homozygous Prdm16Q187X/Q187X mice demonstrated an underdeveloped compact myocardium and were embryonically lethal. Heterozygous Prdm16Q187X/WT mice demonstrated significantly smaller ventricular dimensions, heightened fibrosis, and age-dependent loss of TGF-β expression."
Knock-in mouse model carrying the human PRDM16-Q187X variant confirms dose-dependent impairment of compact myocardial development.
Failed Ventricular Compaction
Loss of PRDM16-driven compact myocardial specification and reduced compact-layer cardiomyocyte proliferation leave a thick, spongy trabeculated layer with deep intertrabecular recesses overlying a thinned compacted wall, predominantly affecting the left ventricle. In cardiomyocyte-specific Prdm16 knockout mice this produces biventricular noncompaction with LV-specific thinning of the compact myocardium and interventricular septum detectable from embryonic day 15.5.
cardiac ventricle morphogenesis GO:0003208 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves cardiac ventricle morphogenesis (GO:0003208). GO:0003208 is a biological process from the Gene Ontology.
heart left ventricle UBERON:0002084 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in heart left ventricle (UBERON:0002084). UBERON:0002084 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Left Ventricular Dilation and Systolic Dysfunction The structurally abnormal, thinned compact wall is predisposed to progressive dilation and reduced contractile function.
Show evidence (2 references)
PMID:34915728 SUPPORT Model Organism
"Cardiomyocyte-specific ablation of Prdm16 in mice caused LV-specific dilation and dysfunction, as well as biventricular noncompaction, which fully recapitulated LVNC in patients."
Mouse model directly recapitulates the human noncompaction phenotype following cardiomyocyte-specific PRDM16 loss.
PMID:31965688 SUPPORT Human Clinical
"Endocardial fibroelastosis was associated with non-compaction of the myocardium of the left ventricle."
Human fetal pathology report documents left ventricular non-compaction as the structural cardiac lesion in a de novo PRDM16 nonsense variant.
Ventricular Conduction System Hyperplasia and Atrial-Fate Derepression
PRDM16 loss removes its suppression of master regulators of ventricular conduction and atrial cell fate within ventricular working cardiomyocytes. In cardiomyocyte-specific Prdm16-deletion mice this produces hyperplasia of the distal ventricular conduction system and abnormal postnatal electrophysiology, providing a mechanistic node upstream of arrhythmia and pre-excitation phenotypes that is distinct from (and additional to) arrhythmia risk driven by ventricular dilation and remodeling.
cardiac conduction system development GO:0003161 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves cardiac conduction system development (GO:0003161). GO:0003161 is a biological process from the Gene Ontology.
central cardiac conduction system UBERON:2005074 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in central cardiac conduction system (UBERON:2005074). UBERON:2005074 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Arrhythmia and Ventricular Pre-excitation Ectopic/hyperplastic conduction-system tissue provides a structural substrate for accessory-pathway-type pre-excitation and other rhythm disturbances.
Show evidence (2 references)
PMID:39304345 SUPPORT Model Organism
"Myocardial loss of PRDM16 during development resulted in hyperplasia of the (distal) ventricular conduction system."
Direct histological/molecular evidence that PRDM16 loss during cardiac development produces conduction-system hyperplasia, the structural substrate for a PRDM16-linked arrhythmia mechanism.
PMID:39304345 SUPPORT Model Organism
"cardiomyocyte-specific deletion of Prdm16 during cardiac development results in contractile dysfunction and abnormal electrophysiology of the postnatal heart, resulting in premature death"
Confirms that cardiomyocyte-specific PRDM16 loss produces abnormal electrophysiology in vivo, consistent with an arrhythmogenic mechanism independent of remodeling-driven arrhythmia.
Left Ventricular Dilation and Systolic Dysfunction
A subset of PRDM16 carriers develop left ventricular dilation and reduced systolic function, either accompanying noncompaction or, in some pedigrees and cardiac biopsy cohorts, as an apparently isolated dilated cardiomyopathy phenotype without prominent trabeculation, consistent with the MONDO definition of LVNC8 as a PRDM16-caused form of familial isolated dilated cardiomyopathy. Corresponds to the dismech-level phenotypes "Left Ventricular Noncompaction" and "Dilated Cardiomyopathy".
Downstream
Congestive Heart Failure Progressive ventricular dilation and systolic dysfunction lead to symptomatic heart failure.
Thromboembolic Risk Blood stasis in a dilated, hypokinetic, structurally abnormal ventricle predisposes to intracardiac thrombus formation and embolism.
Arrhythmia and Ventricular Pre-excitation Ventricular dilation and remodeling independently increase arrhythmogenic risk, in addition to the conduction-system substrate described above.
Show evidence (2 references)
PMID:23768516 SUPPORT Human Clinical
"In addition, in a series of cardiac biopsies from 131 individuals with DCM, we found 5 individuals with 4 previously unreported nonsynonymous variants in the coding region of PRDM16."
Documents PRDM16 variants identified directly in a dilated cardiomyopathy biopsy cohort, supporting the DCM branch of the phenotype.
PMID:34915728 SUPPORT Model Organism
"we also observed dramatic dilation that occurred only in LV of Prdm16cKO mice"
Mouse model shows LV-specific dilation is a direct consequence of cardiomyocyte PRDM16 loss, independent of noncompaction.
Congestive Heart Failure
Affected individuals progress to congestive heart failure, often with early or infant onset in the more severe pediatric cases. A single-center pediatric LVNC cohort documented heart failure as an adverse outcome in a PRDM16-positive patient.
Show evidence (2 references)
PMID:38113297 SUPPORT Human Clinical
"One proband hosts a PRDM16-Q187X variant with left ventricular noncompaction cardiomyopathy and demonstrated infant-onset heart failure, which was selected for further study."
Documents infant-onset heart failure as a clinical outcome directly linked to a PRDM16 loss-of-function variant.
PMID:35893073 SUPPORT Human Clinical
"Among those who developed symptoms of HF (LVEF reduction and LV enlargement) were patients P9 (novel pathogenic PRDM16 complex rearrangement c.1286_1289delinsTTGCACTT p.(Gly429Valfs*176))"
A pediatric LVNC cohort documents heart failure as an adverse outcome in a PRDM16-positive patient.
Arrhythmia and Ventricular Pre-excitation
PRDM16-associated cardiomyopathy carries an increased risk of cardiac arrhythmia. Beyond the remodeling-driven arrhythmia risk shared with other dilated/noncompaction cardiomyopathies, one reported adolescent carrier presented with Wolff-Parkinson-White syndrome (ventricular pre-excitation via a complex accessory pathway), mechanistically consistent with the conduction-system-hyperplasia node above.
Show evidence (1 reference)
PMID:39895316 SUPPORT Human Clinical
"We report a 17-year-old girl with Wolff – Parkinson– White syndrome and left ventricular non-compaction cardiomyopathy due to a rare genetic variant in PR-domain containing protein 16."
Case report documents ventricular pre-excitation (Wolff-Parkinson-White syndrome) co-occurring with LVNC in a PRDM16 variant carrier.
Thromboembolic Risk
Thromboembolic complications, consistent with stasis in a dilated, hypokinetic, and structurally abnormal ventricle, have been documented in PRDM16-positive patients. A single-center pediatric LVNC cohort found two PRDM16-positive patients experienced adverse events (heart failure in one, a thromboembolic event in the other).
Show evidence (1 reference)
PMID:35893073 SUPPORT Human Clinical
"A thromboembolic event, without increasing symptoms of HF, was noted in P8 (novel PRDM16 pathogenic c.1336G>T p.(Glu446*) variant)"
Documents a thromboembolic event as an adverse clinical outcome in a pediatric patient with a novel pathogenic PRDM16 variant.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Left Ventricular Noncompaction 8 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

7
Blood 1
Thromboembolic Event Thromboembolism HP:0001907 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thromboembolism (HP:0001907). HP:0001907 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:35893073 SUPPORT Human Clinical
"A thromboembolic event, without increasing symptoms of HF, was noted in P8 (novel PRDM16 pathogenic c.1336G>T p.(Glu446*) variant)"
Documents a thromboembolic event as an adverse clinical outcome in a pediatric patient with a novel pathogenic PRDM16 variant.
Cardiovascular 3
Dilated Cardiomyopathy HP:0001644 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dilated cardiomyopathy (HP:0001644). HP:0001644 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23768516 SUPPORT Human Clinical
"In addition, in a series of cardiac biopsies from 131 individuals with DCM, we found 5 individuals with 4 previously unreported nonsynonymous variants in the coding region of PRDM16."
Documents dilated cardiomyopathy as a clinical phenotype directly associated with PRDM16 variants, independent of a noncompaction diagnosis.
Congestive Heart Failure FREQUENT HP:0001635 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congestive heart failure (HP:0001635). HP:0001635 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38113297 SUPPORT Human Clinical
"One proband hosts a PRDM16-Q187X variant with left ventricular noncompaction cardiomyopathy and demonstrated infant-onset heart failure, which was selected for further study."
Confirms heart failure, with infant onset in the severe pediatric case reported, as a clinical feature of PRDM16-associated cardiomyopathy.
Wolff-Parkinson-White Syndrome HP:0001716 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Wolff-Parkinson-White syndrome (HP:0001716). HP:0001716 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39895316 SUPPORT Human Clinical
"We report a 17-year-old girl with Wolff – Parkinson– White syndrome and left ventricular non-compaction cardiomyopathy due to a rare genetic variant in PR-domain containing protein 16."
Case report documents Wolff-Parkinson-White syndrome co-occurring with LVNC in a PRDM16 variant carrier.
Metabolism 1
Fetal-Onset Cardiomegaly and Hydrops VERY_RARE Nonimmune hydrops fetalis HP:0001790 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nonimmune hydrops fetalis (HP:0001790). HP:0001790 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31965688 SUPPORT Human Clinical
"The third-trimester obstetric ultrasound revealed a hydropic fetus with hydramnios and expanded hypokinetic heart. After termination of pregnancy, foetopathology showed a eutrophic fetus with isolated cardiomegaly."
First reported fetal presentation of PRDM16-associated cardiomyopathy, establishing hydrops fetalis and cardiomegaly as a rare but documented severe end of the phenotypic spectrum.
Other 2
Left Ventricular Noncompaction HP:0030682 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Left ventricular noncompaction (HP:0030682). HP:0030682 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23768516 SUPPORT Human Clinical
"Resequencing of PRDM16 in a cohort of 75 nonsyndromic individuals with LVNC detected three mutations, including one truncation mutant, one frameshift null mutation, and a single missense mutant."
Establishes left ventricular noncompaction as a clinical phenotype directly associated with PRDM16 variants.
Myocardial Fibrosis HP:0001685 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myocardial fibrosis (HP:0001685). HP:0001685 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38113297 SUPPORT Model Organism
"Heterozygous Prdm16Q187X/WT mice demonstrated significantly smaller ventricular dimensions, heightened fibrosis, and age-dependent loss of TGF-β expression."
Documents heightened myocardial fibrosis as a feature of the heterozygous PRDM16-Q187X mouse model.
🧬

Genetic Associations

1
PRDM16 (Pathogenic Variants)
Gene: PRDM16 hgnc:14000 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PRDM16 (hgnc:14000). hgnc:14000 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (2 references)
PMID:23768516 SUPPORT Human Clinical
"PRDM16 has not previously been associated with cardiac disease but is localized in the nuclei of cardiomyocytes throughout murine and human development and in the adult heart."
Establishes PRDM16 as the founding causal gene for this entity and documents its cardiomyocyte nuclear localization.
CGGV:assertion_c0a3445a-5bb0-4d77-a4f0-5b7cfceb837f-2025-05-30T160000.000Z SUPPORT Other
"PRDM16 | HGNC:14000 | dilated cardiomyopathy | MONDO:0005021 | AD | Strong"
ClinGen classifies the PRDM16-dilated cardiomyopathy gene-disease relationship as strong with autosomal dominant inheritance.
💊

Medical Actions

5
Guideline-Directed Heart Failure Pharmacotherapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Standard heart failure pharmacotherapy (e.g., ACE inhibitors/ARBs or ARNI, beta-blockers, mineralocorticoid receptor antagonists, SGLT2 inhibitors) is used to manage systolic dysfunction in PRDM16-associated cardiomyopathy. There is no PRDM16- or LVNC8-specific pharmacotherapy; management follows the general phenotype-based approach used for LVNC and DCM.
Show evidence (1 reference)
PMID:25443708 SUPPORT Other
"Currently, there are no specific treatments for LVNC. Depending on the phenotype, patients are managed according to their clinical needs and corresponding guidelines (e.g., for congestive heart failure, arrhythmias)."
States directly that LVNC (and by extension LVNC8) has no disease-specific pharmacotherapy and is managed with standard phenotype-based guideline therapy. Evidence source is OTHER because this is a review.
Implantable Cardioverter-Defibrillator Placement
Action: Implantable Cardioverter-Defibrillator PlacementNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Implantable Cardioverter-Defibrillator Placement (NCIT:C80435). NCIT:C80435 is a clinical intervention from the NCI Thesaurus. NCIT:C80435
ICD implantation is considered for PRDM16-associated cardiomyopathy patients at risk of ventricular arrhythmia and sudden cardiac death, following conventional primary/secondary-prevention criteria for LVNC/DCM rather than a PRDM16-specific indication.
Show evidence (1 reference)
PMID:25443708 SUPPORT Human Clinical
"In 30 patients with LVNC who underwent implantable cardioverter defibrillator (ICD) implantation for secondary or primary prevention, 11 patients (37%) had appropriate ICD therapies in a mean follow-up period of 40 ± 34 months"
Reports outcome data for ICD implantation specifically in LVNC patients (37% received appropriate therapy), directly supporting ICD placement as a real intervention with documented efficacy signal in this cardiomyopathy.
Anticoagulation for Thromboembolic Risk
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: anticoagulant agent NCIT:C263 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses anticoagulant agent (NCIT:C263). NCIT:C263 is a therapeutic agent from the NCI Thesaurus.
Anticoagulant therapy is considered in patients with reduced systolic function or documented thromboembolic events, given the thromboembolic complications reported in PRDM16-positive LVNC patients. Routine anticoagulation for isolated trabeculation with normal ventricular function remains debated.
Show evidence (2 references)
PMID:25443708 SUPPORT Other
"Oral anticoagulation is a debated issue in subjects with normal LV function and absence of LV hypertrophy: patients are either treated on the basis of the phenotype (oral anticoagulation given independently on arrhythmias or LV dysfunction for primary prevention of embolic episodes) or in the..."
States the clinical indications for oral anticoagulation in LVNC directly. Evidence source is OTHER because this is a review.
PMID:35893073 SUPPORT Human Clinical
"A thromboembolic event, without increasing symptoms of HF, was noted in P8 (novel PRDM16 pathogenic c.1336G>T p.(Glu446*) variant)"
Documents a thromboembolic complication in a PRDM16-positive patient, the clinical indication anticoagulation is intended to prevent.
Cardiac Transplantation
Action: Organ TransplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Organ Transplantation (NCIT:C15289). NCIT:C15289 is a clinical intervention from the NCI Thesaurus. NCIT:C15289
Heart transplantation is the definitive treatment for end-stage heart failure in severe PRDM16-associated cardiomyopathy, following standard advanced-heart-failure criteria; there is no PRDM16-specific transplant indication or outcome data, so no evidence item is attached here (see CLAUDE.md evidence SOP §4 — description retained, claim not evidenced).
Cascade Genetic Testing and Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Genetic testing for the proband's PRDM16 variant and cascade testing of at-risk relatives is recommended given autosomal dominant transmission, given that a subset of first-degree relatives of PRDM16 probands may carry the variant.
Show evidence (2 references)
PMID:31965688 SUPPORT Human Clinical
"Exome sequencing (ES) identified a de novo unreported p.(Gln353*) heterozygous nonsense variant in PRDM16."
Documents molecular genetic testing (exome sequencing) as the diagnostic route to identifying a causal PRDM16 variant, supporting genetic testing and counseling as a management step.
PMID:20301486 SUPPORT Other
"Provide a basic view of genetic risk assessment of at-risk asymptomatic relatives of a proband with DCM to inform cardiac surveillance and allow early detection and treatment of DCM to improve long-term outcome."
The GeneReviews DCM overview frames genetic risk assessment of at-risk asymptomatic relatives, with cardiac surveillance for early detection, as the purpose of cascade evaluation — precisely this treatment. Evidence source is OTHER because GeneReviews is an expert-authored review resource.
🔬

Diagnosis

4
Echocardiography
First-line imaging modality for LVNC. The most widely used echocardiographic diagnostic criterion is a noncompacted-to-compacted (NC/C) myocardial thickness ratio greater than 2.0 measured at end-systole, though this threshold carries substantial interobserver and intraobserver variability and is not LVNC8-specific.
echocardiography NCIT:C16525 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:25443708 SUPPORT Other
"the most important echocardiographic criterion remains the ratio of noncompacted/compacted >2.0 in end-systole"
States the quantitative echocardiographic NC/C >2.0 criterion used to diagnose LVNC. Evidence source is OTHER because this is a review.
Cardiac Magnetic Resonance Imaging
CMR gives a 3-dimensional dataset that better resolves trabecular architecture than echocardiography. A noncompacted-to-compacted ratio greater than 2.3 measured at end-diastole on CMR is the commonly cited diagnostic cutoff, and CMR additionally assesses fibrosis via late gadolinium enhancement. Neither the echocardiographic nor the CMR threshold is sufficiently specific in isolation.
cardiac magnetic resonance imaging NCIT:C16809 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:25443708 SUPPORT Other
"A noncompacted/compacted ratio >2.3 on CMR is considered the cutoff for LVNC diagnosis"
States the quantitative CMR NC/C >2.3 criterion used to diagnose LVNC. Evidence source is OTHER because this is a review.
Natriuretic Peptide Measurement
BNP/NT-proBNP assesses heart failure severity and cardiomyocyte stretch but is not diagnostic of LVNC8 specifically. Heterozygous Prdm16 mutant mice show elevated plasma BNP, supporting its use as a marker of cardiac stretch/dysfunction downstream of PRDM16 loss rather than a disease-specific biomarker.
brain natriuretic peptide measurement NCIT:C74735 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:37842925 SUPPORT Model Organism
"We found an elevation of plasma levels of brain natriuretic peptide (Bnp) in both sexes, indicating cardiomyocyte stretch with impaired systolic and possibly diastolic LV dysfunction"
Mouse-model evidence that BNP is elevated downstream of PRDM16 loss; PARTIAL because this is a general heart-failure-stretch biomarker in a mouse model, not an LVNC8-specific human diagnostic marker.
Cardiomyopathy Multigene Panel Sequencing with Copy-Number Analysis
The confirmatory test is a clinically curated cardiomyopathy gene panel including PRDM16. Copy-number analysis (chromosomal microarray) is important alongside sequencing specifically to distinguish an intragenic PRDM16 variant (LVNC8) from a 1p36 deletion spanning PRDM16 (1p36 deletion syndrome), since the original mapping of the PRDM16 cardiac critical region was itself done by comparative genomic hybridization delineating the terminal 1p36 deletion interval.
cardiomyopathy multigene panel sequencing with copy-number analysis NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:20301486 SUPPORT Other
"Provide the evaluation strategy of a proband with nonsyndromic DCM"
The GeneReviews DCM overview exists to supply this proband evaluation strategy, of which gene-panel and copy-number testing is a component. Evidence source is OTHER because GeneReviews is an expert-authored review resource.
PMID:23768516 SUPPORT Human Clinical
"we identified a minimal deletion for the cardiomyopathy associated with 1p36del syndrome that included only the terminal 14 exons of the transcription factor PRDM16"
Comparative genomic hybridization (the copy-number method) was how the PRDM16 cardiac critical region within the 1p36 deletion was originally delineated, supporting copy-number analysis as the tool that distinguishes a 1p36 deletion from an intragenic PRDM16 variant.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Left Ventricular Noncompaction 8:

Left ventricular noncompaction (polygenic umbrella) MONDO:0018901
Overlapping Features Isolated LVNC of other or undetermined genetic cause, including sarcomeric (MYH7, ACTN2), cytoskeletal (NRAP), and mitochondrial (TAFAZZIN) etiologies modeled in the umbrella dismech entry.
Distinguishing Features
  • A confirmed PRDM16 loss-of-function variant identifies LVNC8 specifically, versus the broader genetically heterogeneous LVNC umbrella.
  • Truncating PRDM16 (along with MYH7 and ACTN2) variants show LVNC-specific enrichment in large rare-variant studies, unlike genes shared broadly across DCM/HCM/LVNC.
Show evidence (1 reference)
PMID:33500567 SUPPORT Human Clinical
"In contrast, truncating variants in MYH7, ACTN2, and PRDM16 were uniquely associated with LVNC and may reflect a distinct LVNC etiology."
Directly distinguishes PRDM16 (and MYH7/ACTN2) from the broader, LVNC-associated gene set as having LVNC-specific rare-variant enrichment.
1p36 deletion syndrome
Overlapping Features A contiguous-gene deletion syndrome of the terminal short arm of chromosome 1 that includes PRDM16 within its cardiomyopathy critical region, together with craniofacial anomalies, intellectual disability, seizures, and other syndromic features not present in isolated LVNC8.
Distinguishing Features
  • 1p36 deletion syndrome is a multigene contiguous deletion with extracardiac syndromic features; LVNC8 is a nonsyndromic, single-gene PRDM16 point-mutation or small-indel disorder confined to the cardiac phenotype.
  • Array CGH or chromosomal microarray identifying a terminal 1p36 deletion spanning PRDM16 (rather than an intragenic PRDM16 variant) indicates 1p36 deletion syndrome rather than LVNC8.
Show evidence (1 reference)
PMID:23768516 SUPPORT Human Clinical
"we identified a minimal deletion for the cardiomyopathy associated with 1p36del syndrome that included only the terminal 14 exons of the transcription factor PRDM16"
Establishes PRDM16 as the cardiomyopathy-critical gene within the larger 1p36 deletion syndrome region, distinguishing the contiguous-gene syndrome from isolated PRDM16 point-mutation disease.
📊

Related Datasets

1
PRDM16 Modulates Aspects of Cell-Cycle Dynamics and Maturation in Human iPSC-Derived Cardiomyocytes geo:GSE307782
human BULK RNA SEQ
siRNA knockdown and lentiviral overexpression of PRDM16 in hiPSC-derived cardiomyocytes, directly probing the proliferation-maturation axis implicated in the PRDM16 loss-of-function mechanism curated above (reduced PRDM16 impairs metabolic/structural maturation and sarcomeric protein ratios; no linked PMID at time of curation).
{ }

Source YAML

click to show 
name: Left Ventricular Noncompaction 8
creation_date: "2026-08-17T21:00:00Z"
category: Genetic
description: >-
  Left ventricular noncompaction 8 (LVNC8) is the PRDM16-associated form of
  inherited left ventricular noncompaction and dilated cardiomyopathy. PRDM16
  encodes a zinc-finger transcription factor that is enriched in the compact
  myocardium of the developing left ventricle, where it activates
  compact-myocardial genes, represses trabecular-myocardial genes, restrains
  TGF-beta signaling to permit cardiomyocyte proliferation, opposes master
  regulators of ventricular conduction and atrial fate, and supports cardiac
  metabolic homeostasis. Haploinsufficient or truncating PRDM16 variants were
  first identified within the 1p36 deletion syndrome critical region and were
  subsequently shown to cause nonsyndromic LVNC and dilated cardiomyopathy
  (DCM), producing a ventricular phenotype that spans isolated noncompaction,
  noncompaction with dilation, and pure dilation without excess trabeculation.
  MONDO frames the entity through the PRDM16-dilated-cardiomyopathy axis ("any
  familial isolated dilated cardiomyopathy in which the cause of the disease is
  a mutation in the PRDM16 gene") while the disease label foregrounds
  noncompaction; both framings are correct descriptions of the same genotype
  and are reconciled below.
synonyms:
- LVNC8
- left ventricular noncompaction type 8
- PRDM16 familial isolated dilated cardiomyopathy
- familial isolated dilated cardiomyopathy caused by mutation in PRDM16
- CMD1LL
disease_term:
  preferred_term: left ventricular noncompaction 8
  term:
    id: MONDO:0014152
    label: left ventricular noncompaction 8
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0014152
      label: left ventricular noncompaction 8
    mapping_predicate: skos:exactMatch
parents:
- Left Ventricular Noncompaction
- Dilated Cardiomyopathy
- Genetic Disorder
notes: >-
  Related entries: kb/disorders/Left_Ventricular_Noncompaction.yaml
  (MONDO:0018901, the polygenic umbrella LVNC entry) and
  kb/disorders/Dilated_Cardiomyopathy.yaml /
  Dilated_Cardiomyopathy_1AA.yaml (ACTN2, which models an analogous
  noncompaction-or-dilation dual phenotype). PRDM16 is also the gene
  underlying the cardiomyopathy component of 1p36 deletion syndrome
  (PMID:23768516); that syndromic, contiguous-gene-deletion context is
  distinct from this nonsyndromic, single-gene entity and is not modeled here.
  PRDM16 is independently well known as the master regulator of brown/beige
  adipocyte fate; that adipose biology is unrelated to the cardiac mechanism
  curated below and was excluded during literature triage (NEC risk noted on
  issue #8747).

  Sources fetched but deliberately not cited: DOI:10.1007/s12265-023-10459-6
  (Walsh 2023) and DOI:10.1016/j.jacc.2014.08.030 (Arbustini 2014) resolved to
  empty ("content_type: unavailable") DOI-keyed caches, so both were re-fetched
  and cited under their PMID identifiers instead (PMID:38019448, PMID:25443708)
  once full text was confirmed available and PMID citations are
  snippet-validated by tooling, unlike DOI citations (`DOI:` is in
  `skip_prefixes`). DOI:10.1038/ncb3411 (Kodo 2016) and
  DOI:10.1161/CIRCULATIONAHA.121.056666 (Wu 2022) are the same papers already
  cited here under PMID:27642787 and PMID:34915728 respectively,  so no
  separate DOI-keyed citation was added. DOI:10.17169/refubium-41680 (Theisen
  2024, an unpublished doctoral thesis) reports the same Prdm16csp1/wt mouse
  line and sex-specific metabolic phenotype as the peer-reviewed
  PMID:37842925 (Kuhnisch et al. 2023), which is cited instead. The ESC 2023
  cardiomyopathy-guidelines commentary (DOI:10.1093/eurheartjsupp/suae002) is
  a generic classification-scheme overview with no LVNC8- or PRDM16-specific
  quotable claim beyond what PMID:25443708 already supports with concrete
  criteria, so it was left uncited rather than cited for its abstract alone.
discussions:
- discussion_id: gap_lvnc8_noncompaction_vs_dcm_nosology
  prompt: >-
    Is PRDM16-associated cardiomyopathy best classified as a form of left
    ventricular noncompaction, a form of dilated cardiomyopathy, or a single
    genotype that produces a phenotypic spectrum spanning both labels?
  kind: INTERPRETATION
  status: OPEN
  attaches_to:
  - pathophysiology#Failed Ventricular Compaction
  - pathophysiology#Left Ventricular Dilation and Systolic Dysfunction
  rationale: >-
    MONDO:0014152 is defined through the DCM axis ("any familial isolated
    dilated cardiomyopathy...caused by...PRDM16") even though its label and
    OMIM entry (615373) foreground noncompaction. The primary literature
    resolves this as a genuine spectrum rather than a labeling error: the
    founding report found PRDM16 mutations in both nonsyndromic LVNC and DCM
    cohorts, a large systematic rare-variant study found PRDM16 (with MYH7 and
    ACTN2) uniquely enriched in LVNC specifically among cardiomyopathy genes,
    a contemporary review reports that missense variants track with DCM while
    nonsense/frameshift variants track with LVNC, and mouse/human mechanistic
    work shows PRDM16 loss produces both noncompaction (failure of
    compact-myocardium specification) and LV dilation (impaired cardiomyocyte
    proliferation and TGF-beta-driven remodeling) from the same lesion. This
    dismech entry curates LVNC8 as its own genotype-defined node distinct from
    the polygenic LVNC umbrella entry, modeling both the noncompaction and the
    dilation/heart-failure branches as parallel downstream consequences of the
    same PRDM16 lesion rather than picking one label over the other.
  evidence:
  - reference: PMID:23768516
    reference_title: Fine mapping of the 1p36 deletion syndrome identifies mutation of PRDM16 as a cause of cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In conclusion, mutation of PRDM16 causes the cardiomyopathy in 1p36
      deletion syndrome as well as a proportion of nonsyndromic LVNC and DCM.
    explanation: >-
      The founding genetic report establishes PRDM16 as causal for both LVNC
      and DCM cohorts, directly supporting a shared-genotype spectrum rather
      than two separate diseases.
  - reference: PMID:33500567
    reference_title: Systematic large-scale assessment of the genetic architecture of left ventricular noncompaction reveals diverse etiologies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast, truncating variants in MYH7, ACTN2, and PRDM16 were uniquely
      associated with LVNC and may reflect a distinct LVNC etiology.
    explanation: >-
      A large systematic rare-variant study specifically flags PRDM16 as one
      of few genes with LVNC-specific (rather than shared DCM/HCM) enrichment,
      supporting genuine noncompaction biology alongside the DCM framing.
  - reference: PMID:39337275
    reference_title: "Unveiling the Spectrum of Minor Genes in Cardiomyopathies: A Narrative Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Missense variants in PRDM16 were primarily associated with DCM, whereas
      nonsense and frameshift mutations were associated with LVNC
    explanation: >-
      A contemporary narrative review reports a variant-class-specific
      genotype-phenotype correlation (missense to DCM, nonsense/frameshift to
      LVNC) that directly explains why the same gene produces both labeled
      phenotypes rather than one being a misclassification of the other.
pathophysiology:
- name: PRDM16 Loss-of-Function Variant
  biological_scale: MOLECULAR
  description: >-
    Heterozygous truncating (nonsense, frameshift) or missense PRDM16 variants
    reduce the dose or activity of the PRDM16 zinc-finger transcription
    factor. Variants cluster across the gene's 17 exons and were first mapped
    within the terminal 1p36 deletion syndrome critical region before being
    confirmed as an independent cause of nonsyndromic disease. A contemporary
    review reports a variant-class correlation: missense variants track with
    DCM, while nonsense and frameshift (loss-of-function) variants track with
    LVNC, and PRDM16 is predicted to be highly intolerant of loss-of-function
    variation.
  genetic_context:
    functional_impact_category: LOSS_OF_FUNCTION
    allele_type: SNV_INDEL
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
  locations:
  - preferred_term: heart left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  evidence:
  - reference: PMID:23768516
    reference_title: Fine mapping of the 1p36 deletion syndrome identifies mutation of PRDM16 as a cause of cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Resequencing of PRDM16 in a cohort of 75 nonsyndromic individuals with
      LVNC detected three mutations, including one truncation mutant, one
      frameshift null mutation, and a single missense mutant.
    explanation: >-
      Directly documents the spectrum of PRDM16 loss-of-function and missense
      variants identified in nonsyndromic LVNC probands.
  - reference: PMID:38113297
    reference_title: Nonsense Variant PRDM16-Q187X Causes Impaired Myocardial Development and TGF-β Signaling Resulting in Noncompaction Cardiomyopathy in Humans and Mice.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report 2 probands with loss-of-function PRDM16 variants and
      pediatric left ventricular noncompaction cardiomyopathy.
    explanation: >-
      Confirms loss-of-function PRDM16 variants as the proximate genetic
      lesion in two independently ascertained pediatric probands.
  - reference: PMID:39337275
    reference_title: "Unveiling the Spectrum of Minor Genes in Cardiomyopathies: A Narrative Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Missense variants in PRDM16 were primarily associated with DCM, whereas
      nonsense and frameshift mutations were associated with LVNC
    explanation: >-
      Establishes the variant-class-specific genotype-phenotype correlation
      that motivates classifying this node's loss-of-function variants as the
      LVNC-associated lesion class.
  - reference: PMID:39337275
    reference_title: "Unveiling the Spectrum of Minor Genes in Cardiomyopathies: A Narrative Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PRDM16 is predicted to be highly intolerant to LOF
    explanation: >-
      Population-genetic constraint evidence supporting a dosage-sensitive,
      loss-of-function-intolerant gene consistent with dominant
      haploinsufficiency as the disease mechanism.
  downstream:
  - target: Loss of Compact Myocardium Transcriptional Identity
    description: >-
      Reduced PRDM16 dose removes its transcriptional activation of
      compact-myocardial genes and repression of trabecular-myocardial genes
      in left ventricular cardiomyocytes.
    causal_link_type: DIRECT
  - target: Cardiac Metabolic Dysregulation
    description: >-
      Independent of the compact-myocardium transcriptional program,
      monoallelic Prdm16 loss produces early, sex-modified metabolic and
      oxidative-stress changes in cardiac tissue.
    causal_link_type: DIRECT

- name: Loss of Compact Myocardium Transcriptional Identity
  biological_scale: CELLULAR
  role: effector
  description: >-
    PRDM16 is a compact-myocardium-enriched transcription factor that
    activates a compact-myocardial gene program while repressing a
    trabecular-myocardial gene program, in part through cooperation with the
    LV-enriched transcription factors TBX5 and HAND1. In cardiomyocyte-specific
    Prdm16 knockout mice, compact myocardial cardiomyocytes shift from a
    compact transcriptional identity toward one resembling trabecular
    myocardium or neurons, with reduced cardiomyocyte proliferation localized
    to the left ventricular compact layer and interventricular septum.
    Independently, single-cell RNA+ATAC sequencing shows PRDM16 favors
    ventricular working cardiomyocyte identity specifically by opposing the
    master regulators of ventricular conduction and atrial fate, so its loss
    also derepresses a conduction-system/atrial transcriptional program.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: heart left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  evidence:
  - reference: PMID:34915728
    reference_title: PRDM16 Is a Compact Myocardium-Enriched Transcription Factor Required to Maintain Compact Myocardial Cardiomyocyte Identity in Left Ventricle.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      PRDM16 functioned mechanistically as a compact myocardium-enriched
      transcription factor that activated compact myocardial genes while
      repressing trabecular myocardial genes in LV compact myocardium.
    explanation: >-
      Mouse cardiomyocyte-specific knockout study directly establishes the
      dual activator/repressor transcriptional role of PRDM16 in specifying
      compact versus trabecular cardiomyocyte identity.
  - reference: PMID:34915728
    reference_title: PRDM16 Is a Compact Myocardium-Enriched Transcription Factor Required to Maintain Compact Myocardial Cardiomyocyte Identity in Left Ventricle.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Prdm16cKO LV compact myocardial cardiomyocytes shifted from their normal
      transcriptomic identity to a transcriptional signature resembling
      trabecular myocardial cardiomyocytes or neurons.
    explanation: >-
      Documents the specific transcriptional-identity-switch consequence of
      PRDM16 loss in LV compact myocardium.
  - reference: PMID:39304345
    reference_title: PRDM16 determines specification of ventricular cardiomyocytes by suppressing alternative cell fates.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      PRDM16 favors ventricular working cardiomyocyte identity, by opposing
      the activity of master regulators of ventricular conduction and atrial
      fate.
    explanation: >-
      Independent single-cell RNA+ATAC-sequencing study in a mouse
      cardiomyocyte-specific Prdm16 deletion establishes that PRDM16 actively
      suppresses conduction-system and atrial cell-fate programs as part of
      maintaining ventricular working cardiomyocyte identity.
  downstream:
  - target: TGF-beta Signaling Dysregulation
    description: >-
      Loss of PRDM16-mediated repression of TGF-beta pathway genes,
      including direct repression of the TGFB3 promoter, de-represses
      TGF-beta receptor signaling in cardiomyocytes.
    causal_link_type: DIRECT
  - target: Failed Ventricular Compaction
    description: >-
      Loss of the compact-myocardial gene program directly impairs the
      structural maturation of the compact ventricular wall.
    causal_link_type: DIRECT
  - target: Ventricular Conduction System Hyperplasia and Atrial-Fate Derepression
    description: >-
      Loss of PRDM16-mediated suppression of conduction-system and
      atrial-fate master regulators allows ectopic conduction-system tissue
      to expand within the ventricular myocardium.
    causal_link_type: DIRECT

- name: TGF-beta Signaling Dysregulation
  biological_scale: MOLECULAR
  role: effector
  description: >-
    PRDM16 normally binds the TGFB3 promoter and represses its transcription.
    Loss of PRDM16 releases this repression, producing increased TGF-beta
    receptor signaling in cardiomyocytes. Because TGF-beta signaling has an
    antiproliferative effect on cardiomyocytes, its dysregulated increase
    reduces cardiomyocyte proliferative capacity during the developmental
    window when compaction normally occurs.
  biological_processes:
  - preferred_term: transforming growth factor beta receptor signaling pathway
    modifier: INCREASED
    term:
      id: GO:0007179
      label: transforming growth factor beta receptor signaling pathway
  evidence:
  - reference: PMID:38113297
    reference_title: Nonsense Variant PRDM16-Q187X Causes Impaired Myocardial Development and TGF-β Signaling Resulting in Noncompaction Cardiomyopathy in Humans and Mice.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Mechanistic studies were undertaken in H9c2 cardiomyoblasts to show that
      PRDM16 binds TGFB3 promoter and represses its transcription.
    explanation: >-
      Direct biochemical evidence that PRDM16 represses TGFB3 transcription,
      establishing the molecular basis for TGF-beta pathway de-repression
      upon PRDM16 loss. H9c2 is a rat cardiomyoblast cell line, so this is
      cultured-cell (IN_VITRO) evidence, not a whole-animal model.
  - reference: PMID:27642787
    reference_title: iPSC-derived cardiomyocytes reveal abnormal TGF-β signalling in left ventricular non-compaction cardiomyopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      TBX20 regulates the expression of TGF-β signalling modifiers including
      one known to be a genetic cause of LVNC, PRDM16, and genome editing of
      PRDM16 caused proliferation defects in iPSC-CMs.
    explanation: >-
      Independent iPSC-cardiomyocyte genome-editing evidence that PRDM16 loss
      causes the same TGF-beta-linked proliferation defect seen in the PRDM16
      patient-mutation studies.
  downstream:
  - target: Impaired Cardiomyocyte Proliferation
    description: >-
      Increased TGF-beta receptor signaling suppresses the proliferative
      expansion of developing left ventricular cardiomyocytes.
    causal_link_type: DIRECT

- name: Cardiac Metabolic Dysregulation
  biological_scale: MOLECULAR
  role: effector
  description: >-
    Independently of the compact-myocardium transcriptional program,
    monoallelic Prdm16 loss produces early metabolic dysregulation in cardiac
    tissue: reduced amino-acid, glycerol, glycolytic, and
    tricarboxylic-acid-cycle metabolites, diminished glutathione with
    increased inosine monophosphate (indicating oxidative stress and
    dysregulated energetics),
    and up-regulation of two novel candidate cardiac metabolic regulators,
    PYROXD2 and PBXIP1. The phenotype is sex-modified: cardiac dysfunction
    and reduced glucose utilization are more pronounced in female mice, while
    triacylglyceride accumulation and reduced fatty-acid utilization are
    male-specific.
  biological_processes:
  - preferred_term: cellular response to oxidative stress
    modifier: INCREASED
    term:
      id: GO:0034599
      label: cellular response to oxidative stress
  evidence:
  - reference: PMID:37842925
    reference_title: Prdm16 mutation determines sex-specific cardiac metabolism and identifies two novel cardiac metabolic regulators.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Prdm16csp1/wt mice are viable up to 8 months, develop hypoplastic
      hearts, and diminished systolic performance that is more pronounced in
      female mice.
    explanation: >-
      Establishes the sex-modified severity of the metabolic/functional
      cardiac phenotype in a monoallelic Prdm16 mouse model.
  - reference: PMID:37842925
    reference_title: Prdm16 mutation determines sex-specific cardiac metabolism and identifies two novel cardiac metabolic regulators.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Prdm16csp1/wt cardiac tissue revealed diminished glutathione (GSH) and
      increased inosine monophosphate (IMP) levels indicating oxidative
      stress and a dysregulated energetics, respectively.
    explanation: >-
      Direct metabolomic evidence for oxidative stress and dysregulated
      cardiac energetics as an early consequence of PRDM16 loss.
  - reference: PMID:37842925
    reference_title: Prdm16 mutation determines sex-specific cardiac metabolism and identifies two novel cardiac metabolic regulators.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      On the level of transcripts and protein expression, Prdm16csp1/wt
      hearts demonstrate an up-regulation of pyridine nucleotide-disulphide
      oxidoreductase domain 2 (Pyroxd2) and the transcriptional regulator
      pre-B-cell leukaemia transcription factor interacting protein 1
      (Pbxip1).
    explanation: >-
      Identifies PYROXD2 and PBXIP1 as novel transcriptionally up-regulated
      candidate cardiac metabolic regulators downstream of PRDM16 loss.
  downstream:
  - target: Left Ventricular Dilation and Systolic Dysfunction
    description: >-
      Oxidative stress and dysregulated cardiac energetics contribute to
      diminished systolic performance independently of the
      compaction/TGF-beta axis.
    causal_link_type: DIRECT

- name: Impaired Cardiomyocyte Proliferation
  biological_scale: CELLULAR
  role: effector
  description: >-
    Cardiomyocytes carrying loss-of-function PRDM16 variants show reduced
    proliferative capacity and increased apoptosis. In induced pluripotent
    stem cell-derived cardiomyocytes (iPSC-CMs) generated from a PRDM16-Q187X
    proband, proliferation was significantly reduced and apoptosis increased,
    with transcriptional dysregulation of cardiac maturation genes including
    TGF-beta-associated transcripts; homozygous Prdm16-Q187X knock-in mice were
    embryonic lethal with an underdeveloped compact myocardium.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:38113297
    reference_title: Nonsense Variant PRDM16-Q187X Causes Impaired Myocardial Development and TGF-β Signaling Resulting in Noncompaction Cardiomyopathy in Humans and Mice.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Induced pluripotent stem cell-derived cardiomyocytes prepared from the
      PRDM16-Q187X proband demonstrated a statistically significant impairment
      in myocyte proliferation and increased apoptosis associated with
      transcriptional dysregulation of genes implicated in cardiac maturation,
      including TGF-β-associated transcripts.
    explanation: >-
      Patient-derived iPSC-cardiomyocyte data directly demonstrate the
      proliferation and apoptosis defect caused by a human loss-of-function
      PRDM16 variant.
  - reference: PMID:38113297
    reference_title: Nonsense Variant PRDM16-Q187X Causes Impaired Myocardial Development and TGF-β Signaling Resulting in Noncompaction Cardiomyopathy in Humans and Mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Homozygous Prdm16Q187X/Q187X mice demonstrated an underdeveloped compact
      myocardium and were embryonically lethal. Heterozygous
      Prdm16Q187X/WT mice demonstrated significantly smaller ventricular
      dimensions, heightened fibrosis, and age-dependent loss of TGF-β
      expression.
    explanation: >-
      Knock-in mouse model carrying the human PRDM16-Q187X variant confirms
      dose-dependent impairment of compact myocardial development.
  downstream:
  - target: Failed Ventricular Compaction
    description: >-
      Reduced cardiomyocyte proliferation in the developing compact
      myocardium limits the thickening and maturation of the compact
      ventricular wall.
    causal_link_type: DIRECT
  - target: Left Ventricular Dilation and Systolic Dysfunction
    description: >-
      Reduced cardiomyocyte number and thinner compact/interventricular
      septal myocardium predispose to progressive ventricular dilation and
      contractile dysfunction.
    causal_link_type: DIRECT

- name: Failed Ventricular Compaction
  biological_scale: TISSUE
  role: effector
  description: >-
    Loss of PRDM16-driven compact myocardial specification and reduced
    compact-layer cardiomyocyte proliferation leave a thick, spongy
    trabeculated layer with deep intertrabecular recesses overlying a thinned
    compacted wall, predominantly affecting the left ventricle. In
    cardiomyocyte-specific Prdm16 knockout mice this produces biventricular
    noncompaction with LV-specific thinning of the compact myocardium and
    interventricular septum detectable from embryonic day 15.5.
  locations:
  - preferred_term: heart left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  biological_processes:
  - preferred_term: cardiac ventricle morphogenesis
    term:
      id: GO:0003208
      label: cardiac ventricle morphogenesis
  evidence:
  - reference: PMID:34915728
    reference_title: PRDM16 Is a Compact Myocardium-Enriched Transcription Factor Required to Maintain Compact Myocardial Cardiomyocyte Identity in Left Ventricle.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Cardiomyocyte-specific ablation of Prdm16 in mice caused LV-specific
      dilation and dysfunction, as well as biventricular noncompaction, which
      fully recapitulated LVNC in patients.
    explanation: >-
      Mouse model directly recapitulates the human noncompaction phenotype
      following cardiomyocyte-specific PRDM16 loss.
  - reference: PMID:31965688
    reference_title: "Cardiomyopathy due to PRDM16 mutation: First description of a fetal presentation, with possible modifier genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Endocardial fibroelastosis was associated with non-compaction of the
      myocardium of the left ventricle.
    explanation: >-
      Human fetal pathology report documents left ventricular non-compaction
      as the structural cardiac lesion in a de novo PRDM16 nonsense variant.
  downstream:
  - target: Left Ventricular Dilation and Systolic Dysfunction
    description: >-
      The structurally abnormal, thinned compact wall is predisposed to
      progressive dilation and reduced contractile function.
    causal_link_type: DIRECT

- name: Ventricular Conduction System Hyperplasia and Atrial-Fate Derepression
  biological_scale: TISSUE
  role: effector
  description: >-
    PRDM16 loss removes its suppression of master regulators of ventricular
    conduction and atrial cell fate within ventricular working
    cardiomyocytes. In cardiomyocyte-specific Prdm16-deletion mice this
    produces hyperplasia of the distal ventricular conduction system and
    abnormal postnatal electrophysiology, providing a mechanistic node
    upstream of arrhythmia and pre-excitation phenotypes that is distinct
    from (and additional to) arrhythmia risk driven by ventricular dilation
    and remodeling.
  locations:
  - preferred_term: central cardiac conduction system
    term:
      id: UBERON:2005074
      label: central cardiac conduction system
  biological_processes:
  - preferred_term: cardiac conduction system development
    term:
      id: GO:0003161
      label: cardiac conduction system development
  evidence:
  - reference: PMID:39304345
    reference_title: PRDM16 determines specification of ventricular cardiomyocytes by suppressing alternative cell fates.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Myocardial loss of PRDM16 during development resulted in hyperplasia of
      the (distal) ventricular conduction system.
    explanation: >-
      Direct histological/molecular evidence that PRDM16 loss during cardiac
      development produces conduction-system hyperplasia, the structural
      substrate for a PRDM16-linked arrhythmia mechanism.
  - reference: PMID:39304345
    reference_title: PRDM16 determines specification of ventricular cardiomyocytes by suppressing alternative cell fates.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      cardiomyocyte-specific deletion of Prdm16 during cardiac development
      results in contractile dysfunction and abnormal electrophysiology of
      the postnatal heart, resulting in premature death
    explanation: >-
      Confirms that cardiomyocyte-specific PRDM16 loss produces abnormal
      electrophysiology in vivo, consistent with an arrhythmogenic mechanism
      independent of remodeling-driven arrhythmia.
  downstream:
  - target: Arrhythmia and Ventricular Pre-excitation
    description: >-
      Ectopic/hyperplastic conduction-system tissue provides a structural
      substrate for accessory-pathway-type pre-excitation and other rhythm
      disturbances.
    causal_link_type: DIRECT

- name: Left Ventricular Dilation and Systolic Dysfunction
  biological_scale: ORGANISM
  role: effector
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling"
  description: >-
    A subset of PRDM16 carriers develop left ventricular dilation and reduced
    systolic function, either accompanying noncompaction or, in some pedigrees
    and cardiac biopsy cohorts, as an apparently isolated dilated
    cardiomyopathy phenotype without prominent trabeculation, consistent with
    the MONDO definition of LVNC8 as a PRDM16-caused form of familial isolated
    dilated cardiomyopathy. Corresponds to the dismech-level phenotypes
    "Left Ventricular Noncompaction" and "Dilated Cardiomyopathy".
  evidence:
  - reference: PMID:23768516
    reference_title: Fine mapping of the 1p36 deletion syndrome identifies mutation of PRDM16 as a cause of cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, in a series of cardiac biopsies from 131 individuals with
      DCM, we found 5 individuals with 4 previously unreported nonsynonymous
      variants in the coding region of PRDM16.
    explanation: >-
      Documents PRDM16 variants identified directly in a dilated
      cardiomyopathy biopsy cohort, supporting the DCM branch of the
      phenotype.
  - reference: PMID:34915728
    reference_title: PRDM16 Is a Compact Myocardium-Enriched Transcription Factor Required to Maintain Compact Myocardial Cardiomyocyte Identity in Left Ventricle.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      we also observed dramatic dilation that occurred only in LV of
      Prdm16cKO mice
    explanation: >-
      Mouse model shows LV-specific dilation is a direct consequence of
      cardiomyocyte PRDM16 loss, independent of noncompaction.
  downstream:
  - target: Congestive Heart Failure
    description: >-
      Progressive ventricular dilation and systolic dysfunction lead to
      symptomatic heart failure.
    causal_link_type: DIRECT
  - target: Thromboembolic Risk
    description: >-
      Blood stasis in a dilated, hypokinetic, structurally abnormal
      ventricle predisposes to intracardiac thrombus formation and embolism.
    causal_link_type: DIRECT
  - target: Arrhythmia and Ventricular Pre-excitation
    description: >-
      Ventricular dilation and remodeling independently increase
      arrhythmogenic risk, in addition to the conduction-system substrate
      described above.
    causal_link_type: DIRECT

- name: Congestive Heart Failure
  biological_scale: ORGANISM
  role: effector
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Structural Cardiac Impairment and Heart Failure"
  description: >-
    Affected individuals progress to congestive heart failure, often with
    early or infant onset in the more severe pediatric cases. A single-center
    pediatric LVNC cohort documented heart failure as an adverse outcome in a
    PRDM16-positive patient.
  evidence:
  - reference: PMID:38113297
    reference_title: Nonsense Variant PRDM16-Q187X Causes Impaired Myocardial Development and TGF-β Signaling Resulting in Noncompaction Cardiomyopathy in Humans and Mice.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One proband hosts a PRDM16-Q187X variant with left ventricular
      noncompaction cardiomyopathy and demonstrated infant-onset heart
      failure, which was selected for further study.
    explanation: >-
      Documents infant-onset heart failure as a clinical outcome directly
      linked to a PRDM16 loss-of-function variant.
  - reference: PMID:35893073
    reference_title: Genetic Profile of Left Ventricular Noncompaction Cardiomyopathy in Children-A Single Reference Center Experience.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among those who developed symptoms of HF (LVEF reduction and LV
      enlargement) were patients P9 (novel pathogenic PRDM16 complex
      rearrangement c.1286_1289delinsTTGCACTT p.(Gly429Valfs*176))
    explanation: >-
      A pediatric LVNC cohort documents heart failure as an adverse outcome
      in a PRDM16-positive patient.

- name: Arrhythmia and Ventricular Pre-excitation
  biological_scale: ORGANISM
  role: effector
  description: >-
    PRDM16-associated cardiomyopathy carries an increased risk of cardiac
    arrhythmia. Beyond the remodeling-driven arrhythmia risk shared with
    other dilated/noncompaction cardiomyopathies, one reported adolescent
    carrier presented with Wolff-Parkinson-White syndrome (ventricular
    pre-excitation via a complex accessory pathway), mechanistically
    consistent with the conduction-system-hyperplasia node above.
  evidence:
  - reference: PMID:39895316
    reference_title: A rare genetic variant in PRDM16 is associated with Wolff-Parkinson-White syndrome with complex accessory pathway characteristics and left ventricular non-compaction cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a 17-year-old girl with Wolff – Parkinson– White syndrome and
      left ventricular non-compaction cardiomyopathy due to a rare genetic
      variant in PR-domain containing protein 16.
    explanation: >-
      Case report documents ventricular pre-excitation (Wolff-Parkinson-White
      syndrome) co-occurring with LVNC in a PRDM16 variant carrier.

- name: Thromboembolic Risk
  biological_scale: ORGANISM
  role: effector
  description: >-
    Thromboembolic complications, consistent with stasis in a dilated,
    hypokinetic, and structurally abnormal ventricle, have been documented in
    PRDM16-positive patients. A single-center pediatric LVNC cohort found two
    PRDM16-positive patients experienced adverse events (heart failure in
    one, a thromboembolic event in the other).
  evidence:
  - reference: PMID:35893073
    reference_title: Genetic Profile of Left Ventricular Noncompaction Cardiomyopathy in Children-A Single Reference Center Experience.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A thromboembolic event, without increasing symptoms of HF, was noted in
      P8 (novel PRDM16 pathogenic c.1336G>T p.(Glu446*) variant)
    explanation: >-
      Documents a thromboembolic event as an adverse clinical outcome in a
      pediatric patient with a novel pathogenic PRDM16 variant.

phenotypes:
- name: Left Ventricular Noncompaction
  category: Cardiovascular
  description: >-
    Excessive left ventricular trabeculation with deep intertrabecular
    recesses over a thinned compacted myocardial layer, the structural
    hallmark of the noncompaction branch of the PRDM16 phenotype.
  phenotype_term:
    preferred_term: Left ventricular noncompaction
    term:
      id: HP:0030682
      label: Left ventricular noncompaction
  evidence:
  - reference: PMID:23768516
    reference_title: Fine mapping of the 1p36 deletion syndrome identifies mutation of PRDM16 as a cause of cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Resequencing of PRDM16 in a cohort of 75 nonsyndromic individuals with
      LVNC detected three mutations, including one truncation mutant, one
      frameshift null mutation, and a single missense mutant.
    explanation: >-
      Establishes left ventricular noncompaction as a clinical phenotype
      directly associated with PRDM16 variants.

- name: Dilated Cardiomyopathy
  category: Cardiovascular
  description: >-
    Ventricular dilation with impaired systolic function, the phenotype MONDO
    uses to define LVNC8 ("familial isolated dilated cardiomyopathy...caused by
    ...PRDM16"), occurring either with or without accompanying noncompaction.
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
  evidence:
  - reference: PMID:23768516
    reference_title: Fine mapping of the 1p36 deletion syndrome identifies mutation of PRDM16 as a cause of cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, in a series of cardiac biopsies from 131 individuals with
      DCM, we found 5 individuals with 4 previously unreported nonsynonymous
      variants in the coding region of PRDM16.
    explanation: >-
      Documents dilated cardiomyopathy as a clinical phenotype directly
      associated with PRDM16 variants, independent of a noncompaction
      diagnosis.

- name: Congestive Heart Failure
  category: Cardiovascular
  frequency: FREQUENT
  description: >-
    Symptomatic heart failure, sometimes with infant onset in severe pediatric
    cases, is a common outcome of PRDM16-associated cardiomyopathy.
  phenotype_term:
    preferred_term: Congestive heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  evidence:
  - reference: PMID:38113297
    reference_title: Nonsense Variant PRDM16-Q187X Causes Impaired Myocardial Development and TGF-β Signaling Resulting in Noncompaction Cardiomyopathy in Humans and Mice.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One proband hosts a PRDM16-Q187X variant with left ventricular
      noncompaction cardiomyopathy and demonstrated infant-onset heart
      failure, which was selected for further study.
    explanation: >-
      Confirms heart failure, with infant onset in the severe pediatric case
      reported, as a clinical feature of PRDM16-associated cardiomyopathy.

- name: Wolff-Parkinson-White Syndrome
  category: Cardiovascular
  description: >-
    Ventricular pre-excitation via a complex accessory conduction pathway,
    reported in one adolescent PRDM16-LVNC carrier and mechanistically
    consistent with the PRDM16-dependent conduction-system-hyperplasia node
    (PMID:39304345). The specific Wolff-Parkinson-White term is used here
    rather than the generic arrhythmia term because the description and the
    sole supporting evidence are specifically about this syndrome.
  phenotype_term:
    preferred_term: Wolff-Parkinson-White syndrome
    term:
      id: HP:0001716
      label: Wolff-Parkinson-White syndrome
  evidence:
  - reference: PMID:39895316
    reference_title: A rare genetic variant in PRDM16 is associated with Wolff-Parkinson-White syndrome with complex accessory pathway characteristics and left ventricular non-compaction cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report a 17-year-old girl with Wolff – Parkinson– White syndrome and
      left ventricular non-compaction cardiomyopathy due to a rare genetic
      variant in PR-domain containing protein 16.
    explanation: >-
      Case report documents Wolff-Parkinson-White syndrome co-occurring with
      LVNC in a PRDM16 variant carrier.

- name: Thromboembolic Event
  category: Cardiovascular
  description: >-
    Thromboembolic complications, consistent with stasis in a dilated,
    hypokinetic, and structurally abnormal ventricle, have been documented in
    PRDM16-positive patients.
  phenotype_term:
    preferred_term: Thromboembolism
    term:
      id: HP:0001907
      label: Thromboembolism
  evidence:
  - reference: PMID:35893073
    reference_title: Genetic Profile of Left Ventricular Noncompaction Cardiomyopathy in Children-A Single Reference Center Experience.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A thromboembolic event, without increasing symptoms of HF, was noted in
      P8 (novel PRDM16 pathogenic c.1336G>T p.(Glu446*) variant)
    explanation: >-
      Documents a thromboembolic event as an adverse clinical outcome in a
      pediatric patient with a novel pathogenic PRDM16 variant.

- name: Myocardial Fibrosis
  category: Cardiovascular
  description: >-
    Heightened myocardial fibrosis has been reported in a heterozygous
    Prdm16-Q187X knock-in mouse model, and endocardial fibroelastosis was
    reported in the fetal-onset human case, mirroring the fibrotic component
    of the ventricular remodeling described above.
  phenotype_term:
    preferred_term: Myocardial fibrosis
    term:
      id: HP:0001685
      label: Myocardial fibrosis
  evidence:
  - reference: PMID:38113297
    reference_title: Nonsense Variant PRDM16-Q187X Causes Impaired Myocardial Development and TGF-β Signaling Resulting in Noncompaction Cardiomyopathy in Humans and Mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Heterozygous Prdm16Q187X/WT mice demonstrated significantly smaller
      ventricular dimensions, heightened fibrosis, and age-dependent loss of
      TGF-β expression.
    explanation: >-
      Documents heightened myocardial fibrosis as a feature of the
      heterozygous PRDM16-Q187X mouse model.

- name: Fetal-Onset Cardiomegaly and Hydrops
  category: Cardiovascular
  frequency: VERY_RARE
  description: >-
    The most severe reported presentation is prenatal: a third-trimester fetus
    with a de novo PRDM16 nonsense variant showed hydrops, hydramnios, and an
    expanded hypokinetic heart with cardiomegaly and endocardial
    fibroelastosis, leading to termination of pregnancy.
  phenotype_term:
    preferred_term: Nonimmune hydrops fetalis
    term:
      id: HP:0001790
      label: Nonimmune hydrops fetalis
  evidence:
  - reference: PMID:31965688
    reference_title: "Cardiomyopathy due to PRDM16 mutation: First description of a fetal presentation, with possible modifier genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The third-trimester obstetric ultrasound revealed a hydropic fetus with
      hydramnios and expanded hypokinetic heart. After termination of
      pregnancy, foetopathology showed a eutrophic fetus with isolated
      cardiomegaly.
    explanation: >-
      First reported fetal presentation of PRDM16-associated cardiomyopathy,
      establishing hydrops fetalis and cardiomegaly as a rare but documented
      severe end of the phenotypic spectrum.

genetic:
- name: PRDM16
  gene_term:
    preferred_term: PRDM16
    term:
      id: hgnc:14000
      label: PRDM16
  association: Pathogenic Variants
  case_fractions:
  - population: Single-center pediatric LVNC cohort (Poland)
    case_fraction_percent: 12.5
    cohort_size: 16
    notes: >-
      2 of 16 patients with a confirmed molecular defect in a pediatric LVNC
      referral cohort carried a PRDM16 variant, tied with MYH7 as the second
      most frequent gene after HCN4.
    evidence:
    - reference: PMID:35893073
      reference_title: Genetic Profile of Left Ventricular Noncompaction Cardiomyopathy in Children-A Single Reference Center Experience.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The most frequent defects in our cohort were found in the genes HCN4
        (n = 4), MYH7 (n = 2) and PRDM16 (n = 2).
      explanation: >-
        Quantifies the PRDM16 share of molecularly confirmed cases in a
        pediatric LVNC cohort.
  - population: Large multicenter LVNC rare-variant case-control cohort vs. gnomAD population controls
    case_fraction_percent: 1.35
    notes: >-
      PRDM16 truncating variants were significantly enriched in a large LVNC
      case-control rare-variant association study relative to gnomAD
      population controls (p = 4.0E-12), a far larger and better-controlled
      estimate than the single-center pediatric cohort above; the two are
      recorded separately because they measure different populations
      (pediatric referral cohort vs. multicenter case-control).
    evidence:
    - reference: PMID:38019448
      reference_title: "The Trouble with Trabeculation: How Genetics Can Help to Unravel a Complex and Controversial Phenotype."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        population controls, i.e. no enrichment was observed in similar
        analyses with HCM or DCM cohorts ... These were truncating variants
        in ... PRDM16 (1.35% vs 0.006%,
      explanation: >-
        Reports the PRDM16 truncating-variant case frequency (1.35% of LVNC
        cases vs 0.006% in gnomAD controls) from a large rare-variant
        association study cited in a 2023 review of LVNC genetics.
  notes: >-
    ClinGen classifies the PRDM16-dilated cardiomyopathy gene-disease
    relationship as Strong with autosomal dominant inheritance (see
    Dilated_Cardiomyopathy.yaml for the shared ClinGen assertion). A
    contemporary review reports a variant-class genotype-phenotype
    correlation: missense variants track with DCM, nonsense/frameshift
    (loss-of-function) variants track with LVNC, and PRDM16 is predicted to
    be highly loss-of-function-intolerant (see the discussions entry above
    and the PRDM16 Loss-of-Function Variant pathophysiology node).
  evidence:
  - reference: PMID:23768516
    reference_title: Fine mapping of the 1p36 deletion syndrome identifies mutation of PRDM16 as a cause of cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PRDM16 has not previously been associated with cardiac disease but is
      localized in the nuclei of cardiomyocytes throughout murine and human
      development and in the adult heart.
    explanation: >-
      Establishes PRDM16 as the founding causal gene for this entity and
      documents its cardiomyocyte nuclear localization.
  - reference: CGGV:assertion_c0a3445a-5bb0-4d77-a4f0-5b7cfceb837f-2025-05-30T160000.000Z
    reference_title: "PRDM16 / dilated cardiomyopathy (Strong)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PRDM16 | HGNC:14000 | dilated cardiomyopathy | MONDO:0005021 | AD | Strong"
    explanation: >-
      ClinGen classifies the PRDM16-dilated cardiomyopathy gene-disease
      relationship as strong with autosomal dominant inheritance.

inheritance:
- name: Autosomal Dominant
  description: >-
    Reported PRDM16 cardiomyopathy cases follow autosomal dominant
    transmission of a heterozygous variant; several cases, including the
    fetal presentation and one of two pediatric probands in the TGF-beta
    mechanistic study, arose de novo.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: CGGV:assertion_c0a3445a-5bb0-4d77-a4f0-5b7cfceb837f-2025-05-30T160000.000Z
    reference_title: "PRDM16 / dilated cardiomyopathy (Strong)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "PRDM16 | HGNC:14000 | dilated cardiomyopathy | MONDO:0005021 | AD | Strong"
    explanation: >-
      ClinGen Hereditary Cardiovascular Disease GCEP records autosomal
      dominant inheritance for the PRDM16-dilated cardiomyopathy relationship
      with Strong clinical validity.
  - reference: PMID:31965688
    reference_title: "Cardiomyopathy due to PRDM16 mutation: First description of a fetal presentation, with possible modifier genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Exome sequencing (ES) identified a de novo unreported p.(Gln353*)
      heterozygous nonsense variant in PRDM16.
    explanation: >-
      Documents a de novo heterozygous PRDM16 nonsense variant, consistent
      with autosomal dominant, often sporadic, transmission.

diagnosis:
- name: Echocardiography
  description: >-
    First-line imaging modality for LVNC. The most widely used echocardiographic
    diagnostic criterion is a noncompacted-to-compacted (NC/C) myocardial
    thickness ratio greater than 2.0 measured at end-systole, though this
    threshold carries substantial interobserver and intraobserver variability
    and is not LVNC8-specific.
  diagnosis_term:
    preferred_term: echocardiography
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  evidence:
  - reference: PMID:25443708
    reference_title: "Left ventricular noncompaction: a distinct cardiomyopathy or a trait shared by different cardiac diseases?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      the most important echocardiographic criterion remains the ratio of
      noncompacted/compacted >2.0 in end-systole
    explanation: >-
      States the quantitative echocardiographic NC/C >2.0 criterion used to
      diagnose LVNC. Evidence source is OTHER because this is a review.

- name: Cardiac Magnetic Resonance Imaging
  description: >-
    CMR gives a 3-dimensional dataset that better resolves trabecular
    architecture than echocardiography. A noncompacted-to-compacted ratio
    greater than 2.3 measured at end-diastole on CMR is the commonly cited
    diagnostic cutoff, and CMR additionally assesses fibrosis via late
    gadolinium enhancement. Neither the echocardiographic nor the CMR
    threshold is sufficiently specific in isolation.
  diagnosis_term:
    preferred_term: cardiac magnetic resonance imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:25443708
    reference_title: "Left ventricular noncompaction: a distinct cardiomyopathy or a trait shared by different cardiac diseases?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A noncompacted/compacted ratio >2.3 on CMR is considered the cutoff for
      LVNC diagnosis
    explanation: >-
      States the quantitative CMR NC/C >2.3 criterion used to diagnose LVNC.
      Evidence source is OTHER because this is a review.

- name: Natriuretic Peptide Measurement
  description: >-
    BNP/NT-proBNP assesses heart failure severity and cardiomyocyte stretch
    but is not diagnostic of LVNC8 specifically. Heterozygous Prdm16
    mutant mice show elevated plasma BNP, supporting its use as a marker of
    cardiac stretch/dysfunction downstream of PRDM16 loss rather than a
    disease-specific biomarker.
  diagnosis_term:
    preferred_term: brain natriuretic peptide measurement
    term:
      id: NCIT:C74735
      label: Brain Natriuretic Peptide Measurement
  evidence:
  - reference: PMID:37842925
    reference_title: Prdm16 mutation determines sex-specific cardiac metabolism and identifies two novel cardiac metabolic regulators.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We found an elevation of plasma levels of brain natriuretic peptide
      (Bnp) in both sexes, indicating cardiomyocyte stretch with impaired
      systolic and possibly diastolic LV dysfunction
    explanation: >-
      Mouse-model evidence that BNP is elevated downstream of PRDM16 loss;
      PARTIAL because this is a general heart-failure-stretch biomarker in a
      mouse model, not an LVNC8-specific human diagnostic marker.

- name: Cardiomyopathy Multigene Panel Sequencing with Copy-Number Analysis
  description: >-
    The confirmatory test is a clinically curated cardiomyopathy gene panel
    including PRDM16. Copy-number analysis (chromosomal microarray) is
    important alongside sequencing specifically to distinguish an intragenic
    PRDM16 variant (LVNC8) from a 1p36 deletion spanning PRDM16 (1p36
    deletion syndrome), since the original mapping of the PRDM16 cardiac
    critical region was itself done by comparative genomic hybridization
    delineating the terminal 1p36 deletion interval.
  diagnosis_term:
    preferred_term: cardiomyopathy multigene panel sequencing with copy-number analysis
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:20301486
    reference_title: Dilated Cardiomyopathy Overview.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Provide the evaluation strategy of a proband with nonsyndromic DCM
    explanation: >-
      The GeneReviews DCM overview exists to supply this proband evaluation
      strategy, of which gene-panel and copy-number testing is a component.
      Evidence source is OTHER because GeneReviews is an expert-authored
      review resource.
  - reference: PMID:23768516
    reference_title: Fine mapping of the 1p36 deletion syndrome identifies mutation of PRDM16 as a cause of cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified a minimal deletion for the cardiomyopathy associated with
      1p36del syndrome that included only the terminal 14 exons of the
      transcription factor PRDM16
    explanation: >-
      Comparative genomic hybridization (the copy-number method) was how the
      PRDM16 cardiac critical region within the 1p36 deletion was originally
      delineated, supporting copy-number analysis as the tool that
      distinguishes a 1p36 deletion from an intragenic PRDM16 variant.

differential_diagnoses:
- name: Left ventricular noncompaction (polygenic umbrella)
  description: >-
    Isolated LVNC of other or undetermined genetic cause, including sarcomeric
    (MYH7, ACTN2), cytoskeletal (NRAP), and mitochondrial (TAFAZZIN) etiologies
    modeled in the umbrella dismech entry.
  distinguishing_features:
  - A confirmed PRDM16 loss-of-function variant identifies LVNC8 specifically,
    versus the broader genetically heterogeneous LVNC umbrella.
  - Truncating PRDM16 (along with MYH7 and ACTN2) variants show LVNC-specific
    enrichment in large rare-variant studies, unlike genes shared broadly
    across DCM/HCM/LVNC.
  disease_term:
    preferred_term: left ventricular noncompaction
    term:
      id: MONDO:0018901
      label: left ventricular noncompaction
  evidence:
  - reference: PMID:33500567
    reference_title: Systematic large-scale assessment of the genetic architecture of left ventricular noncompaction reveals diverse etiologies.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast, truncating variants in MYH7, ACTN2, and PRDM16 were uniquely
      associated with LVNC and may reflect a distinct LVNC etiology.
    explanation: >-
      Directly distinguishes PRDM16 (and MYH7/ACTN2) from the broader,
      LVNC-associated gene set as having LVNC-specific rare-variant
      enrichment.

- name: 1p36 deletion syndrome
  description: >-
    A contiguous-gene deletion syndrome of the terminal short arm of
    chromosome 1 that includes PRDM16 within its cardiomyopathy critical
    region, together with craniofacial anomalies, intellectual disability,
    seizures, and other syndromic features not present in isolated LVNC8.
  distinguishing_features:
  - 1p36 deletion syndrome is a multigene contiguous deletion with
    extracardiac syndromic features; LVNC8 is a nonsyndromic, single-gene
    PRDM16 point-mutation or small-indel disorder confined to the cardiac
    phenotype.
  - Array CGH or chromosomal microarray identifying a terminal 1p36 deletion
    spanning PRDM16 (rather than an intragenic PRDM16 variant) indicates 1p36
    deletion syndrome rather than LVNC8.
  evidence:
  - reference: PMID:23768516
    reference_title: Fine mapping of the 1p36 deletion syndrome identifies mutation of PRDM16 as a cause of cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified a minimal deletion for the cardiomyopathy associated with
      1p36del syndrome that included only the terminal 14 exons of the
      transcription factor PRDM16
    explanation: >-
      Establishes PRDM16 as the cardiomyopathy-critical gene within the larger
      1p36 deletion syndrome region, distinguishing the contiguous-gene
      syndrome from isolated PRDM16 point-mutation disease.

treatments:
- name: Guideline-Directed Heart Failure Pharmacotherapy
  description: >-
    Standard heart failure pharmacotherapy (e.g., ACE inhibitors/ARBs or
    ARNI, beta-blockers, mineralocorticoid receptor antagonists, SGLT2
    inhibitors) is used to manage systolic dysfunction in PRDM16-associated
    cardiomyopathy. There is no PRDM16- or LVNC8-specific pharmacotherapy;
    management follows the general phenotype-based approach used for LVNC and
    DCM.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:25443708
    reference_title: "Left ventricular noncompaction: a distinct cardiomyopathy or a trait shared by different cardiac diseases?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Currently, there are no specific treatments for LVNC. Depending on the
      phenotype, patients are managed according to their clinical needs and
      corresponding guidelines (e.g., for congestive heart failure,
      arrhythmias).
    explanation: >-
      States directly that LVNC (and by extension LVNC8) has no
      disease-specific pharmacotherapy and is managed with standard
      phenotype-based guideline therapy. Evidence source is OTHER because
      this is a review.

- name: Implantable Cardioverter-Defibrillator Placement
  description: >-
    ICD implantation is considered for PRDM16-associated cardiomyopathy
    patients at risk of ventricular arrhythmia and sudden cardiac death,
    following conventional primary/secondary-prevention criteria for
    LVNC/DCM rather than a PRDM16-specific indication.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: Implantable Cardioverter-Defibrillator Placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
  evidence:
  - reference: PMID:25443708
    reference_title: "Left ventricular noncompaction: a distinct cardiomyopathy or a trait shared by different cardiac diseases?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 30 patients with LVNC who underwent implantable cardioverter
      defibrillator (ICD) implantation for secondary or primary prevention,
      11 patients (37%) had appropriate ICD therapies in a mean follow-up
      period of 40 ± 34 months
    explanation: >-
      Reports outcome data for ICD implantation specifically in LVNC
      patients (37% received appropriate therapy), directly supporting ICD
      placement as a real intervention with documented efficacy signal in
      this cardiomyopathy.

- name: Anticoagulation for Thromboembolic Risk
  description: >-
    Anticoagulant therapy is considered in patients with reduced systolic
    function or documented thromboembolic events, given the thromboembolic
    complications reported in PRDM16-positive LVNC patients. Routine
    anticoagulation for isolated trabeculation with normal ventricular
    function remains debated.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: anticoagulant agent
      term:
        id: NCIT:C263
        label: Anticoagulant Agent
  evidence:
  - reference: PMID:25443708
    reference_title: "Left ventricular noncompaction: a distinct cardiomyopathy or a trait shared by different cardiac diseases?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Oral anticoagulation is a debated issue in subjects with normal LV
      function and absence of LV hypertrophy: patients are either treated on
      the basis of the phenotype (oral anticoagulation given independently on
      arrhythmias or LV dysfunction for primary prevention of embolic
      episodes) or in the presence of LV dysfunction, arrhythmias, prior
      embolic events, or proven atrial or ventricular thrombi.
    explanation: >-
      States the clinical indications for oral anticoagulation in LVNC
      directly. Evidence source is OTHER because this is a review.
  - reference: PMID:35893073
    reference_title: Genetic Profile of Left Ventricular Noncompaction Cardiomyopathy in Children-A Single Reference Center Experience.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A thromboembolic event, without increasing symptoms of HF, was noted in
      P8 (novel PRDM16 pathogenic c.1336G>T p.(Glu446*) variant)
    explanation: >-
      Documents a thromboembolic complication in a PRDM16-positive patient,
      the clinical indication anticoagulation is intended to prevent.

- name: Cardiac Transplantation
  description: >-
    Heart transplantation is the definitive treatment for end-stage heart
    failure in severe PRDM16-associated cardiomyopathy, following standard
    advanced-heart-failure criteria; there is no PRDM16-specific transplant
    indication or outcome data, so no evidence item is attached here (see
    CLAUDE.md evidence SOP §4 — description retained, claim not evidenced).
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Organ Transplantation
    term:
      id: NCIT:C15289
      label: Organ Transplantation

- name: Cascade Genetic Testing and Counseling
  description: >-
    Genetic testing for the proband's PRDM16 variant and cascade testing of
    at-risk relatives is recommended given autosomal dominant transmission,
    given that a subset of first-degree relatives of PRDM16 probands may carry
    the variant.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:31965688
    reference_title: "Cardiomyopathy due to PRDM16 mutation: First description of a fetal presentation, with possible modifier genes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Exome sequencing (ES) identified a de novo unreported p.(Gln353*)
      heterozygous nonsense variant in PRDM16.
    explanation: >-
      Documents molecular genetic testing (exome sequencing) as the diagnostic
      route to identifying a causal PRDM16 variant, supporting genetic
      testing and counseling as a management step.
  - reference: PMID:20301486
    reference_title: Dilated Cardiomyopathy Overview.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Provide a basic view of genetic risk assessment of at-risk asymptomatic
      relatives of a proband with DCM to inform cardiac surveillance and allow
      early detection and treatment of DCM to improve long-term outcome.
    explanation: >-
      The GeneReviews DCM overview frames genetic risk assessment of at-risk
      asymptomatic relatives, with cardiac surveillance for early detection,
      as the purpose of cascade evaluation — precisely this treatment.
      Evidence source is OTHER because GeneReviews is an expert-authored
      review resource.

datasets:
- accession: geo:GSE307782
  title: PRDM16 Modulates Aspects of Cell-Cycle Dynamics and Maturation in Human iPSC-Derived Cardiomyocytes
  data_type: BULK_RNA_SEQ
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: >-
    siRNA knockdown and lentiviral overexpression of PRDM16 in hiPSC-derived
    cardiomyocytes, directly probing the proliferation-maturation axis
    implicated in the PRDM16 loss-of-function mechanism curated above
    (reduced PRDM16 impairs metabolic/structural maturation and sarcomeric
    protein ratios; no linked PMID at time of curation).

references:
- reference: PMID:20301486
  title: Dilated Cardiomyopathy Overview.
  tags:
  - GeneReviews
📚

References & Deep Research

References

1
PMID:20301486
Dilated Cardiomyopathy Overview.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 23 citations 2026-08-17T21:36:01.118017

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

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

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

Disease Characteristics Research Template

Target Disease

  • Disease Name: Left Ventricular Noncompaction 8
  • MONDO ID: (if available)
  • Category: Genetic

Research Objectives

Please provide a comprehensive research report on Left Ventricular Noncompaction 8 covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

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

1. Disease Information

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

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

2. Etiology

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

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

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

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

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

4. Genetic/Molecular Information

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

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

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

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

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

5. Environmental Information

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

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

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

6. Mechanism / Pathophysiology

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

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

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

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

7. Anatomical Structures Affected

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

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

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

    Search first: OMIM, Orphanet, HPO, PubMed

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

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

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

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

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

10. Diagnostics

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

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

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

11. Outcome/Prognosis

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

12. Treatment

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

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

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

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

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

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

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

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

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

15. Model Organisms

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

Citation Requirements

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

Output Format

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

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

Left Ventricular Noncompaction 8 (LVNC8): comprehensive disease-characteristics report

Scope and evidence note. LVNC8 is an exceptionally rare, genetically defined subtype of left-ventricular noncompaction associated with PRDM16. Most clinical evidence consists of individual families and aggregated case series; accordingly, many epidemiologic and management statements below derive from broader LVNC/noncompaction-cardiomyopathy literature and are explicitly labeled as such. This is not an individual-patient/EHR summary.

Domain LVNC8-specific finding Broader LVNC context Key identifiers / evidence
Identity Left Ventricular Noncompaction 8 (LVNC8) is the PRDM16-associated monogenic LVNC subtype; disease-level evidence is aggregated from published case series/reviews rather than EHR-derived individual databases. Broad LVNC / left ventricular noncompaction is recognized as a phenotype/cardiomyopathy spectrum with controversy over whether it is a distinct cardiomyopathy or a morphologic trait shared across disorders. Broad LVNC MONDO:0018901; PRDM16-associated disease-target evidence in Open Targets (OpenTargets Search: left ventricular noncompaction-PRDM16, wu2022prdm16isa pages 13-14)
Causal gene PRDM16 (PR/SET domain 16) is the established causal gene for LVNC8; truncating variants are the main LVNC-associated class. Other LVNC genes exist, but they define other subtypes or broader nonspecific LVNC phenotypes. PRDM16 / ENSG00000142611; original human causal paper cited via review as Arndt et al. 2013, PMID 23768516 (wu2022prdm16isa pages 13-14)
Inheritance Predominantly autosomal dominant with de novo and familial cases reported; penetrance appears incomplete/variable but subtype-specific estimates are not established. Familial screening is recommended in LVNC more generally when cardiomyopathy is suspected. Multiple inherited and de novo truncating variants summarized in 2023 review (walsh2023thetroublewith pages 10-11)
Strongest human genetic statistic In a cohort enrichment analysis, PRDM16 variants were found in 1.35% (6/444) of LVNC cases versus 0.006% (7/120,147) in gnomAD, p = 4.0E-12. Supports pathogenic enrichment beyond background variation and strengthens subtype validity. Walsh 2023, DOI: 10.1007/s12265-023-10459-6 (walsh2023thetroublewith pages 10-11)
Core phenotype LVNC8 presents with excessive LV trabeculation/noncompaction, ventricular dysfunction, and can include dilation, heart failure, conduction disease, arrhythmia, or sudden death; severity ranges from fetal/childhood onset to adult disease. Broader LVNC may occur isolated or alongside DCM/HCM/RCM/ARVC phenotypes and congenital heart disease. Human variant summaries across countries/populations (walsh2023thetroublewith pages 10-11)
Imaging criteria No PRDM16-specific imaging criteria exist; LVNC8 uses standard LVNC imaging thresholds. Echo criterion commonly cited: end-systolic noncompacted/compacted ratio >2.0; CMR criterion commonly cited: ratio >2.3; diagnostic overcall is a known concern. Arbustini 2014 JACC DOI: 10.1016/j.jacc.2014.08.030 (arbustini2014leftventricularnoncompaction pages 7-8); Walsh 2023 (walsh2023thetroublewith pages 1-2)
Major complications Reported LVNC8 complications include severe biventricular heart failure, ventricular enlargement, conduction abnormalities, arrhythmias, and sudden cardiac death. In symptomatic broader LVNC cohorts, ventricular tachyarrhythmias up to 47% and sudden cardiac death 13–18% have been reported; thromboembolism risk motivates anticoagulation consideration in selected patients. PRDM16-specific case summaries (walsh2023thetroublewith pages 10-11); broader LVNC management review (arbustini2014leftventricularnoncompaction pages 8-9, arbustini2014leftventricularnoncompaction pages 9-10)
Key mechanism PRDM16 is a compact-myocardium-enriched transcription factor required to maintain left-ventricular compact cardiomyocyte identity; loss causes shift toward trabecular, neuronal-like, atrial, and conduction-system programs, with downstream dysfunction. LVNC pathogenesis broadly implicates disturbed trabeculation/compaction, developmental signaling, and myocardial maturation failure. Wu 2022 Circulation DOI: 10.1161/CIRCULATIONAHA.121.056666 (wu2022prdm16isa pages 1-3, wu2022prdm16isa pages 9-11); Van Wauwe 2024 DOI: 10.26508/lsa.202402719 (wauwe2024prdm16determinesspecification pages 1-2)
Latest 2023–2024 developments 2023 multi-omics mouse work showed early metabolic dysregulation, oxidative stress, sex-specific substrate-use defects, and novel regulators Pyroxd2/Pbxip1 in PRDM16-associated cardiomyopathy; 2024 single-cell RNA+ATAC work showed PRDM16 suppresses alternative atrial/conduction fates and prevents distal ventricular conduction system hyperplasia. 2024 cardiomyopathy guidance/commentary continues to frame LV trabeculation as dynamic and emphasizes genetics plus deep phenotyping for interpretation. Kühnisch 2023 DOI: 10.1093/cvr/cvad154 (kuhnisch2023prdm16mutationdetermines pages 1-2, kuhnisch2023prdm16mutationdetermines pages 4-7, kuhnisch2023prdm16mutationdetermines pages 10-11); Van Wauwe 2024 (wauwe2024prdm16determinesspecification pages 1-2); ESC commentary 2024 DOI: 10.1093/eurheartjsupp/suae002 (context from search, not directly cited here)
Management No PRDM16-targeted therapy exists; management is phenotype-directed: standard heart-failure therapy, arrhythmia surveillance, ICD when indicated by conventional risk factors, anticoagulation in selected patients, and family/genetic screening. Asymptomatic patients with normal LV size/function are generally monitored; symptomatic patients are treated per HF/arrhythmia guidelines; family echocardiographic screening is recommended in familial disease. Arbustini 2014 (arbustini2014leftventricularnoncompaction pages 8-9, arbustini2014leftventricularnoncompaction pages 9-10)
Trials / real-world studies No PRDM16-specific interventional trial was identified. Active LVNC observational studies include NCT06024759 (risk registry, recruiting, n=500), NCT04265040 (TORCH-Plus registry, recruiting, n=2040), NCT06607471 (multicenter registry, recruiting), plus prior imaging/risk studies NCT01470014, NCT03572569, NCT02568072. ClinicalTrials.gov records (NCT06024759 chunk 1, NCT04265040 chunk 1, NCT06607471 chunk 23, NCT01470014 chunk 1, NCT03572569 chunk 1, NCT02568072 chunk 1)
Major evidence gaps Exact LVNC8 OMIM/MONDO subtype identifier, prevalence/incidence, penetrance, carrier frequency, genotype-specific prognosis, pregnancy/exercise guidance, and prospective treatment-response data are not well established. Most evidence is from small families, case series, reviews, and model systems. Broader LVNC itself remains diagnostically controversial because hypertrabeculation can be physiologic (e.g., athletes, pregnancy) and may not correlate with prognosis in isolation. Evidence-gap summary supported by genetics review and broader LVNC controversy literature (walsh2023thetroublewith pages 10-11, walsh2023thetroublewith pages 1-2)

Table: This compact table summarizes subtype-specific facts for PRDM16-associated Left Ventricular Noncompaction 8 and separates them from broader LVNC evidence. It highlights what is established, what is extrapolated from general LVNC literature, and where important evidence gaps remain.

1. Disease information

Definition

LVNC8 is a genetic cardiomyopathy characterized by excessive ventricular trabeculation, deep intertrabecular recesses, and a relatively thin compact myocardial layer, caused principally by pathogenic heterozygous variants affecting PRDM16. The phenotype can coexist with ventricular dilation or systolic dysfunction and may manifest as heart failure, conduction disease, ventricular arrhythmia, thromboembolism, or sudden cardiac death.

A crucial current distinction is between pathologic noncompaction cardiomyopathy and isolated hypertrabeculation. Sensitive cardiac MRI may identify marked trabeculation in up to 15% of healthy people; reversible increases also occur during pregnancy and intensive athletic training. Trabeculation burden alone does not reliably correlate with ventricular dysfunction or prognosis. Diagnosis should therefore integrate morphology with ventricular function, ECG findings, fibrosis, symptoms, family history, and genotype (Walsh, published November 2023; DOI: https://doi.org/10.1007/s12265-023-10459-6). (walsh2023thetroublewith pages 1-2)

Identifiers and nomenclature

  • Preferred name: Left ventricular noncompaction 8; LVNC8.
  • Causal-gene name: PRDM16-associated cardiomyopathy/noncompaction cardiomyopathy.
  • Broad disease MONDO: MONDO:0018901, left ventricular noncompaction. Open Targets associates PRDM16/ENSG00000142611 with this entity. A confidently verified subtype-specific MONDO identifier was not recovered. (OpenTargets Search: left ventricular noncompaction-PRDM16)
  • OMIM: PRDM16 is MIM 605557. The original causal report is Arndt et al., 2013, PMID 23768516. A subtype-specific OMIM number should be verified directly in the current OMIM release before database deposition because it was not independently recovered in the retrieved evidence. (micolonghi2024unveilingthespectrum pages 18-19, wu2022prdm16isa pages 13-14)
  • HPO disease-phenotype concept: Left ventricular noncompaction cardiomyopathy, HP:0011664. (OpenTargets Search: left ventricular noncompaction-PRDM16)
  • ICD: No dedicated ICD-10-CM code uniquely identifies LVNC8; it is generally coded under cardiomyopathy (e.g., I42.8/I42.9 depending jurisdiction and documentation). ICD-11 likewise does not provide a PRDM16-specific code in the retrieved material.
  • Synonyms: noncompaction cardiomyopathy, left-ventricular hypertrabeculation/noncompaction, spongy myocardium, PRDM16-related cardiomyopathy. “Isolated LVNC” should be used cautiously because associated DCM, congenital, neuromuscular, and arrhythmic phenotypes are common.

2. Etiology, risk, and protective factors

Primary causal factor

The principal cause is a germline heterozygous pathogenic PRDM16 variant, particularly a nonsense or frameshift variant producing protein truncation or loss of function. Contemporary review evidence indicates that truncating variants are preferentially associated with LVNC, whereas missense variants have more often been reported with dilated cardiomyopathy. PRDM16 is predicted to be highly loss-of-function intolerant. (micolonghi2024unveilingthespectrum pages 18-19)

The strongest reported enrichment analysis found PRDM16 variants in 6/444 LVNC cases (1.35%), compared with 7/120,147 gnomAD individuals (0.006%), p=4.0×10⁻¹². Variants occurred in geographically diverse families and included de novo and inherited alleles, supporting a genuine but rare disease association rather than a founder effect. (walsh2023thetroublewith pages 10-11)

Risk factors and modifiers

  • Established: a pathogenic PRDM16 allele; a family history of cardiomyopathy, congenital heart disease, arrhythmia, or sudden death.
  • Possible genetic modifiers: broader cardiomyopathy-variant burden, and interaction with developmental regulators including TBX5, HAND1, TBX20, and SKI. Modifier effects are mechanistically plausible but not quantitatively validated for human LVNC8. PRDM16 and SKI reduction interacted to lower cardiac output in zebrafish. (theisen2024characterisationofthe pages 17-21)
  • Age/sex: onset ranges from fetal life through adulthood. Human sex-specific penetrance is unresolved. A 1p36-deletion cardiomyopathy series included 16 females among 18 individuals, while heterozygous mouse disease was more severe in females; neither observation establishes a human female risk ratio. (theisen2024characterisationofthe pages 17-21, kuhnisch2023prdm16mutationdetermines pages 1-2)
  • Environmental/lifestyle risks: no toxin, infection, diet, smoking, alcohol, or occupational exposure is established as a cause of LVNC8. Pregnancy and endurance training can increase trabeculation and thereby mimic or unmask the morphology, but are not demonstrated causes of PRDM16 disease. (walsh2023thetroublewith pages 1-2, NCT02568072 chunk 1)
  • Protective factors: no validated genetic or environmental protective factor is known. Early detection, guideline-directed therapy, and avoidance of individually unsafe exertion prevent complications rather than prevent the congenital genetic substrate.

3. Phenotypes

Frequencies specific to LVNC8 are unavailable because published patients are too few and ascertainment is nonuniform.

Phenotype Type, onset, course, impact Suggested HPO term
Left-ventricular noncompaction/hypertrabeculation Imaging sign; congenital substrate, detectable fetally or later; may remain stable or accompany progressive dysfunction HP:0011664
Dilated or hypoplastic LV; reduced ejection fraction Structural/functional sign; severity variable from asymptomatic to biventricular failure Dilated cardiomyopathy HP:0001644; decreased LV ejection fraction HP:0012664
Heart failure Symptom/sign; pediatric or adult onset; potentially progressive and transplant-requiring HP:0001635
Exercise intolerance, dyspnea, fatigue Symptoms secondary to low output/congestion; impair mobility, school/work, and quality of life HP:0002875; HP:0002094; HP:0012378
Ventricular arrhythmia/palpitations Episodic; may cause syncope, ICD therapy, or sudden death HP:0004308; HP:0001962
Conduction abnormality ECG sign; mechanistically consistent with altered ventricular-conduction-cell specification HP:0001678
Sudden cardiac death Severe outcome, reported in PRDM16 families HP:0001645
Intracardiac thrombosis/systemic embolism Complication, especially with dysfunction, atrial fibrillation, or prior thrombus HP:0031292; HP:0002204
Myocardial fibrosis CMR/pathologic sign; not universal HP:0031325

PRDM16 case summaries include fetal-to-adult presentation, severe biventricular failure in a 33-year-old man, onset at 12 years in a female, ventricular/atrial enlargement, fibrosis, and sudden death. (walsh2023thetroublewith pages 10-11) Broader historical symptomatic LVNC cohorts reported ventricular tachyarrhythmias in as many as 47% and sudden death in 13–18%, but these figures must not be treated as LVNC8-specific. (arbustini2014leftventricularnoncompaction pages 8-9)

4. Genetic and molecular information

Gene and variants

  • Gene: PRDM16, PR/SET domain 16; Ensembl ENSG00000142611; protein is a zinc-finger transcriptional/epigenetic regulator. (OpenTargets Search: left ventricular noncompaction-PRDM16, micolonghi2024unveilingthespectrum pages 18-19)
  • Variant spectrum: principally germline nonsense and frameshift/truncating alleles in LVNC; missense alleles are more frequently associated with DCM. The experimentally examined truncating allele c.2104A>T (p.Lys702Ter) impaired zebrafish cardiac function. (micolonghi2024unveilingthespectrum pages 18-19, theisen2024characterisationofthe pages 17-21)
  • Origin: germline; familial autosomal-dominant and de novo cases occur. No evidence supports a somatic origin.
  • Population frequency: causal alleles are individually very rare or absent from population databases. Aggregate comparison was 0.006% in gnomAD versus 1.35% in LVNC cases, but each variant requires transcript-aware gnomAD review and ACMG/AMP classification. (walsh2023thetroublewith pages 10-11)
  • Functional effect: haploinsufficiency/loss of transcriptional regulation is the leading model. Variant-specific dominant-negative or gain-of-function effects are not established universally.

Chromosomal and epigenetic context

The original mapping arose from 1p36 deletion syndrome: 18 deletion patients with cardiomyopathy shared a deleted interval containing PRDM16 exons 4–17. Large 1p36 deletions can remove additional genes, so their phenotype is not equivalent to isolated LVNC8. (theisen2024characterisationofthe pages 17-21)

PRDM16 has histone-methyltransferase/chromatin-regulatory activity, but no reproducible disease-specific DNA-methylation signature has been defined. Variant interpretation should not infer LVNC8 from a 1p36 deletion without considering deletion extent and other dosage-sensitive genes.

Testing interpretation

Apply ACMG/AMP criteria with ClinVar/ClinGen curation, segregation, de novo status, phenotype specificity, functional evidence, and population frequency. A rare PRDM16 missense VUS should not by itself establish LVNC8, especially when trabeculation is isolated.

5. Environmental, lifestyle, and infectious information

No infectious agent, toxin, radiation exposure, dietary factor, or occupational exposure is known to cause LVNC8. Physiologic remodeling during pregnancy or high-intensity training can meet morphology-based thresholds, creating a gene–environment diagnostic interaction rather than proven PRDM16 penetrance modification. The MARATHON study, NCT02568072, specifically examined exercise-induced trabeculation and reversibility after detraining. (NCT02568072 chunk 1)

For affected individuals, exercise recommendations should be individualized according to ejection fraction, arrhythmia burden, fibrosis, symptoms, and genotype rather than trabeculation alone. Standard cardiovascular risk reduction—no smoking, moderate alcohol, blood-pressure control, and appropriate activity—supports general cardiac health but is not primary prevention of LVNC8.

6. Mechanism and pathophysiology

Causal chain

  1. Upstream trigger: heterozygous PRDM16 loss of function or deletion reduces effective PRDM16 activity in developing ventricular cardiomyocytes.
  2. Cell-identity defect: PRDM16 normally activates compact-myocardial genes and represses trabecular, neuronal, atrial, and conduction-system programs, partly with TBX5 and HAND1.
  3. Developmental consequence: compact-layer cardiomyocytes adopt trabecular/alternative identities; proliferation and ventricular-wall maturation are disturbed, producing excessive trabeculation and a thin compact layer.
  4. Metabolic consequence: altered mitochondrial substrate use, redox stress, and reduced glycolytic/TCA intermediates impair energy reserve.
  5. Tissue/organ consequence: ventricular dilation or hypoplasia, systolic/diastolic dysfunction, conduction-system abnormalities, fibrosis in some models/patients, arrhythmia, heart failure, and sudden death.

Multi-omics and advanced technologies

Cardiomyocyte-specific Prdm16 knockout mice developed LV-specific dilation/dysfunction and biventricular noncompaction. RNA-seq, ChIP-seq, single-cell RNA-seq, and spatial transcriptomics showed that LV compact cardiomyocytes ectopically expressed trabecular genes (Nppa, Nppb, Cited1, Mest) and neural genes (Cttnbp2, Spon1), while compact-myocardial genes (Hey2, Mb) fell. In 7,783 single cardiomyocytes, the dominant changes occurred in LV compact myocardium, whereas right-ventricular compact cells were comparatively preserved. (wu2022prdm16isa pages 9-11, wu2022prdm16isa pages 1-3)

A 2024 combined single-cell RNA+ATAC study found that developmental PRDM16 loss shifted ventricular working cardiomyocytes toward atrial and conduction fates, caused distal ventricular conduction-system hyperplasia, abnormal electrophysiology, contractile dysfunction, and premature death. Direct abstract statement: “PRDM16 favors ventricular working cardiomyocyte identity, by opposing the activity of master regulators of ventricular conduction and atrial fate.” (Van Wauwe et al., published September 2024; DOI: https://doi.org/10.26508/lsa.202402719). (wauwe2024prdm16determinesspecification pages 1-2)

The 2023 heterozygous-mouse multi-omics study found hypoplastic hearts and reduced stroke volume, output, and ejection fraction with normal survival through eight months. Cardiac metabolites involved in amino-acid/glycerol metabolism, glycolysis, pentose-phosphate metabolism, and the TCA cycle were reduced; glutathione fell and IMP rose, indicating oxidative and energetic stress. Males accumulated triacylglycerides and showed reduced fatty-acid use; females had a more severe phenotype and prominent glucose/mitochondrial abnormalities. PYROXD2 and PBXIP1 emerged as candidate downstream metabolic regulators. (Kühnisch et al., published October 2023; DOI: https://doi.org/10.1093/cvr/cvad154). (kuhnisch2023prdm16mutationdetermines pages 1-2, kuhnisch2023prdm16mutationdetermines pages 4-7, kuhnisch2023prdm16mutationdetermines pages 10-11, kuhnisch2023prdm16mutationdetermines pages 8-10)

In zebrafish, PRDM16 knockdown or p.Lys702Ter expression caused bradycardia, reduced output, diminished cardiomyocyte proliferation, increased apoptosis, and electrical uncoupling. (theisen2024characterisationofthe pages 17-21)

Suggested ontology annotations: GO:0007507 heart development; GO:0003208 cardiac ventricle morphogenesis; GO:0060415 muscle-tissue morphogenesis; GO:0006355 regulation of DNA-templated transcription; GO:0007005 mitochondrion organization; GO:0006091 generation of precursor metabolites and energy; GO:0006979 response to oxidative stress. Cell types: ventricular cardiomyocyte (CL:0000746, verify current release), cardiac conduction cell, endothelial cell, and cardiac fibroblast.

7. Anatomical structures affected

  • Primary organ/system: heart/cardiovascular system; primarily left ventricle, sometimes biventricular myocardium.
  • Localization: apical and mid-ventricular segments are commonly emphasized in LVNC imaging; the process is not a lateralized paired-organ disorder.
  • Tissues: compact and trabecular myocardium, ventricular conduction system, and secondarily interstitium/fibrosis.
  • Cells: ventricular working cardiomyocytes are primary; conduction cardiomyocytes are secondarily expanded/mis-specified in models. Endocardial/endothelial signaling contributes to normal trabeculation generally, but direct endothelial causality in LVNC8 remains insufficiently established.
  • Subcellular compartments: nucleus/chromatin—PRDM16 transcriptional regulation; mitochondria—energy/redox abnormalities; sarcomere and intercalated/electrical-coupling structures as downstream functional compartments.

Suggested anatomy terms include UBERON:0000948 heart, UBERON:0002084 heart left ventricle, ventricular myocardium, and interventricular septum; exact accession numbers beyond these should be validated against the production ontology release.

8. Temporal development and natural history

The structural susceptibility is developmental, but clinical recognition can be fetal, neonatal, childhood, or adult. PRDM16 expression is ventricular and developmentally prominent, declining postnatally. (wauwe2024prdm16determinesspecification pages 1-2)

Disease course is highly variable: lifelong asymptomatic morphology; stable mild dysfunction; or progressive dilation, heart failure, arrhythmia, and transplantation/death. No validated LVNC8 staging system exists. Practical stages are: genotype-positive/phenotype-negative; hypertrabeculation with preserved function; cardiomyopathy with dysfunction or arrhythmia; and advanced heart failure. Apparent “remission” can reflect reverse remodeling with heart-failure therapy or resolution of physiologic pregnancy/exercise trabeculation, not correction of the germline defect.

9. Inheritance and population

  • Inheritance: predominantly autosomal dominant; de novo cases occur. Expressivity is markedly variable and penetrance is likely incomplete/age-dependent, but no reliable percentage exists. (walsh2023thetroublewith pages 10-11)
  • Anticipation: not established.
  • Germline mosaicism: theoretically possible after an apparently de novo event, but no LVNC8-specific frequency is known.
  • Founder effect/consanguinity: none established; variants have been reported across European, Asian, and Australian populations. (walsh2023thetroublewith pages 10-11)
  • Prevalence/incidence/carrier frequency: unknown for LVNC8. The 1.35% statistic is the proportion of an ascertained LVNC cohort carrying qualifying PRDM16 variants, not population prevalence. (walsh2023thetroublewith pages 10-11)
  • Sex ratio: unknown. Mouse sexual dimorphism cannot be directly converted into human epidemiology. (kuhnisch2023prdm16mutationdetermines pages 1-2)

10. Diagnostics

Clinical and imaging work-up

  1. History, three-generation pedigree, physical examination, ECG, ambulatory rhythm monitoring, and transthoracic echocardiography.
  2. Common echocardiographic criterion: end-systolic noncompacted-to-compacted myocardial ratio >2.0 with characteristic two-layer morphology and perfused recesses.
  3. CMR: commonly cited end-diastolic NC/C ratio >2.3; also assesses ventricular volumes/function, regional morphology, thrombus, and late-gadolinium-enhancement fibrosis. Neither threshold is sufficiently specific in isolation. (arbustini2014leftventricularnoncompaction pages 7-8)
  4. Biomarkers such as BNP/NT-proBNP and troponin assess heart failure/injury but are not diagnostic of LVNC8. Heterozygous Prdm16 mice showed elevated BNP, supporting stretch/dysfunction rather than a specific biomarker. (kuhnisch2023prdm16mutationdetermines pages 2-3)
  5. CT can assess trabeculation when MRI is unavailable or contraindicated; NCT01470014 enrolled 39 patients to investigate CT discrimination of isolated LVNC. (NCT01470014 chunk 1)

Genetic testing

Use a validated cardiomyopathy panel including PRDM16 plus established sarcomeric, cytoskeletal, nuclear-envelope, ion-channel, mitochondrial, and syndromic LVNC genes. Exome/genome sequencing is appropriate when panel testing is negative, phenotype is syndromic, or structural variants are suspected. Copy-number analysis/CMA is important for developmental abnormalities suggestive of 1p36 deletion. Karyotype/FISH is not routine unless a chromosomal rearrangement is suspected. Mitochondrial-DNA testing is phenotype-driven; repeat-expansion testing has no specific role.

RNA sequencing may clarify splice variants but remains an adjunct. No validated diagnostic proteomic, metabolomic, epigenomic, or liquid-biopsy assay exists.

Differential diagnosis

Physiologic athletic/pregnancy remodeling; normal prominent trabeculation; DCM/HCM with secondary trabeculation; apical HCM; endocardial fibroelastosis; arrhythmogenic cardiomyopathy; myocarditis; congenital heart disease; endomyocardial fibrosis; cardiac thrombus or tumor; neuromuscular/mitochondrial disorders. Dysfunction, fibrosis, arrhythmia, pathogenic genotype, and familial segregation favor cardiomyopathy over a benign trait.

Screening

Offer genetic counseling and cascade testing for a pathogenic/likely pathogenic familial PRDM16 variant. First-degree relatives should have baseline ECG and imaging; variant-positive relatives require longitudinal surveillance. Echocardiographic family screening is recommended in familial LVNC. (arbustini2014leftventricularnoncompaction pages 9-10)

11. Outcome and prognosis

No LVNC8-specific 5- or 10-year survival estimate exists. Prognosis is driven less by trabeculation extent than by ventricular dysfunction, dilation, fibrosis, sustained ventricular arrhythmia, syncope, conduction disease, thrombus/embolism, and heart-failure severity. (walsh2023thetroublewith pages 1-2)

Broader LVNC morbidity includes heart-failure hospitalization, ICD implantation, stroke/systemic embolism, mechanical circulatory support, transplant, and sudden death. In one small historical ICD series, 37% of 30 patients received appropriate ICD therapy during 40±34 months, but this is neither a randomized estimate nor LVNC8-specific. (arbustini2014leftventricularnoncompaction pages 9-10)

Quality-of-life instruments specific to LVNC8 have not been validated. EQ-5D, SF-36, Kansas City Cardiomyopathy Questionnaire, pediatric quality-of-life tools, and PROMIS measures can quantify the impact of dyspnea, fatigue, arrhythmia anxiety, activity restriction, repeated imaging, and familial genetic risk.

12. Treatment and current applications

There is no approved PRDM16-directed, gene, cell, RNA, or epigenetic therapy. Treatment is phenotype-directed:

  • Heart failure: guideline-directed therapy appropriate to age and ejection fraction—typically renin–angiotensin-system inhibition/ARNI, evidence-based beta-blocker, mineralocorticoid-receptor antagonist, SGLT2 inhibitor, and diuretic for congestion. Pediatric regimens require specialist dosing.
  • Arrhythmia: ambulatory monitoring; antiarrhythmic therapy or ablation as clinically indicated. ICD placement follows conventional secondary-prevention or cardiomyopathy primary-prevention criteria rather than trabeculation alone. CRT may be considered with EF ≤35% and qualifying electrical dyssynchrony. (arbustini2014leftventricularnoncompaction pages 8-9)
  • Anticoagulation: indicated for atrial fibrillation, documented ventricular thrombus, prior systemic embolism, or another standard indication; often considered when substantial LV dysfunction is present. Routine anticoagulation for isolated trabeculation with normal function remains debated. (arbustini2014leftventricularnoncompaction pages 9-10, arbustini2014leftventricularnoncompaction pages 8-9)
  • Advanced disease: mechanical circulatory support and heart transplantation according to standard advanced-heart-failure criteria.
  • Rehabilitation/support: individualized cardiac rehabilitation, exercise prescription, vaccination and infection prevention appropriate to heart-failure care, pregnancy counseling, psychosocial support, and genetic counseling.
  • Pharmacogenomics: no PRDM16-specific drug-response guidance exists.

Suggested NCIt intervention concepts include genetic counseling, echocardiography, cardiac MRI, electrocardiography, Holter monitoring, anticoagulant therapy, beta-blocker therapy, implantable cardioverter-defibrillator, cardiac resynchronization therapy, ventricular assist device, and heart transplantation; exact NCIt accessions should be resolved against the implementation release.

Trials and real-world implementation

No PRDM16-specific interventional trial was identified. Current implementation is through registries and risk-stratification studies:

  • NCT06024759, recruiting, observational, target 500, 10-year LVNC risk registry examining genetics, ventricular dysfunction, arrhythmia, strain, and ICD predictors. https://clinicaltrials.gov/study/NCT06024759 (NCT06024759 chunk 1)
  • NCT04265040, recruiting, TORCH-Plus cardiomyopathy registry, target 2,040, with phenotyping, biosampling, genomics, inflammation, and four-year mortality. https://clinicaltrials.gov/study/NCT04265040 (NCT04265040 chunk 1)
  • NCT03572569, prospective family-based pediatric cardiomyopathy study, target 200, evaluating death, mechanical support, and transplant over up to eight years. https://clinicaltrials.gov/study/NCT03572569 (NCT03572569 chunk 1)
  • NCT01470014, completed CT diagnostic study, 39 participants. https://clinicaltrials.gov/study/NCT01470014 (NCT01470014 chunk 1)

13. Prevention

Primary prevention: the germline disorder cannot currently be prevented by lifestyle or vaccination. Reproductive options after counseling include prenatal diagnosis and preimplantation genetic testing when a familial pathogenic variant is known.

Secondary prevention: cascade genetic testing, periodic ECG/imaging, ambulatory rhythm monitoring, and early treatment of dysfunction or arrhythmia. Population or newborn screening is not recommended because prevalence, penetrance, and test performance are insufficiently defined.

Tertiary prevention: guideline-directed heart-failure therapy; thrombosis prevention when indicated; ICD/CRT in selected patients; exercise and pregnancy risk assessment; prompt treatment of decompensation; and family education regarding syncope, sustained palpitations, chest pain, and heart-failure warning signs.

14. Other species and natural disease

  • Human: Homo sapiens, NCBI Taxon 9606.
  • Mouse: Mus musculus, Taxon 10090; ortholog Prdm16.
  • Zebrafish: Danio rerio, Taxon 7955; prdm16 perturbation produces developmental cardiac dysfunction.

Naturally occurring LVNC-like disease has been described in veterinary species and Japanese macaques, but no retrieved evidence established a naturally occurring PRDM16-defined LVNC8 orthologous disease, breed predisposition, or VBO term. The condition is noninfectious and has no zoonotic or cross-species transmission.

15. Model organisms and experimental systems

Zebrafish

Morpholino/antisense knockdown and expression of human p.Lys702Ter produced reduced output, bradycardia, diminished proliferation, apoptosis, and electrical uncoupling. Advantages include rapid developmental and cardiac-function assays; limitations include two-chamber anatomy, gene-duplication differences, and imperfect modeling of human ventricular compaction. (theisen2024characterisationofthe pages 17-21)

Mouse

  • Cardiomyocyte-specific biallelic Prdm16 knockout: LV dilation/dysfunction and biventricular noncompaction; strong model for developmental cell-identity mechanisms, but more severe than many heterozygous human cases. (wu2022prdm16isa pages 1-3)
  • Prdm16csp1/wt heterozygote: viable with mild hypoplastic cardiomyopathy, reduced systolic performance, early metabolic stress, and female-predominant severity. It better models haploinsufficiency but lacks the full human structural/arrhythmic spectrum and showed no fibrosis in one characterization. (kuhnisch2023prdm16mutationdetermines pages 1-2, theisen2024characterisationofthe pages 76-81)
  • Developmental cardiomyocyte knockout with single-cell RNA+ATAC: demonstrates atrial/conduction fate shift and conduction-system hyperplasia; useful for chromatin and lineage studies, though premature death limits chronic-treatment experiments. (wauwe2024prdm16determinesspecification pages 1-2)

Human cellular systems

Patient-specific iPSC cardiomyocytes have established the broader LVNC paradigm that abnormal developmental signaling and impaired cardiomyocyte proliferation can be modeled and rescued experimentally. In TBX20-associated LVNC, TGF-β activation reduced proliferation; PRDM16 was identified as a downstream target, and PRDM16 editing itself caused proliferation defects. This supports pathway convergence but is not a direct PRDM16-patient LVNC8 model. Relevant abstract language states that “inhibition of TGF-β signalling and genome correction of the TBX20 mutation were sufficient to reverse the disease phenotype” (Kodo et al., 2016; DOI: https://doi.org/10.1038/ncb3411).

Evidence appraisal and critical gaps

The strongest LVNC8 evidence combines rare-variant enrichment, de novo/familial truncating alleles, 1p36 deletion mapping, and concordant zebrafish/mouse functional studies. Recent 2023–2024 work substantially advances mechanism through multi-omics and single-cell chromatin/transcriptome analysis. However, exact prevalence, penetrance, variant-specific prognosis, human sex effects, environmental modifiers, quality-of-life data, and treatment-response rates remain unknown. Morphology-only diagnosis risks substantial overcalling; expert interpretation should prioritize the integrated genotype–phenotype–function–family context rather than the NC/C ratio alone. (walsh2023thetroublewith pages 10-11, wauwe2024prdm16determinesspecification pages 1-2, walsh2023thetroublewith pages 1-2, kuhnisch2023prdm16mutationdetermines pages 1-2)

References

  1. (OpenTargets Search: left ventricular noncompaction-PRDM16): Open Targets Query (left ventricular noncompaction-PRDM16, 2 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  2. (wu2022prdm16isa pages 13-14): Tongbin Wu, Zhengyu Liang, Zengming Zhang, Canzhao Liu, Lunfeng Zhang, Yusu Gu, Kirk L. Peterson, Sylvia M. Evans, Xiang-Dong Fu, and Ju Chen. Prdm16 is a compact myocardium-enriched transcription factor required to maintain compact myocardial cardiomyocyte identity in left ventricle. Circulation, 145:586-602, Feb 2022. URL: https://doi.org/10.1161/circulationaha.121.056666, doi:10.1161/circulationaha.121.056666. This article has 106 citations and is from a highest quality peer-reviewed journal.

  3. (walsh2023thetroublewith pages 10-11): Roddy Walsh. The trouble with trabeculation: how genetics can help to unravel a complex and controversial phenotype. Journal of cardiovascular translational research, 16:1310-1324, Nov 2023. URL: https://doi.org/10.1007/s12265-023-10459-6, doi:10.1007/s12265-023-10459-6. This article has 11 citations and is from a peer-reviewed journal.

  4. (arbustini2014leftventricularnoncompaction pages 7-8): Eloisa Arbustini, Frank Weidemann, and Jennifer L. Hall. Left ventricular noncompaction: a distinct cardiomyopathy or a trait shared by different cardiac diseases? Journal of the American College of Cardiology, 64 17:1840-50, Oct 2014. URL: https://doi.org/10.1016/j.jacc.2014.08.030, doi:10.1016/j.jacc.2014.08.030. This article has 324 citations and is from a highest quality peer-reviewed journal.

  5. (walsh2023thetroublewith pages 1-2): Roddy Walsh. The trouble with trabeculation: how genetics can help to unravel a complex and controversial phenotype. Journal of cardiovascular translational research, 16:1310-1324, Nov 2023. URL: https://doi.org/10.1007/s12265-023-10459-6, doi:10.1007/s12265-023-10459-6. This article has 11 citations and is from a peer-reviewed journal.

  6. (arbustini2014leftventricularnoncompaction pages 8-9): Eloisa Arbustini, Frank Weidemann, and Jennifer L. Hall. Left ventricular noncompaction: a distinct cardiomyopathy or a trait shared by different cardiac diseases? Journal of the American College of Cardiology, 64 17:1840-50, Oct 2014. URL: https://doi.org/10.1016/j.jacc.2014.08.030, doi:10.1016/j.jacc.2014.08.030. This article has 324 citations and is from a highest quality peer-reviewed journal.

  7. (arbustini2014leftventricularnoncompaction pages 9-10): Eloisa Arbustini, Frank Weidemann, and Jennifer L. Hall. Left ventricular noncompaction: a distinct cardiomyopathy or a trait shared by different cardiac diseases? Journal of the American College of Cardiology, 64 17:1840-50, Oct 2014. URL: https://doi.org/10.1016/j.jacc.2014.08.030, doi:10.1016/j.jacc.2014.08.030. This article has 324 citations and is from a highest quality peer-reviewed journal.

  8. (wu2022prdm16isa pages 1-3): Tongbin Wu, Zhengyu Liang, Zengming Zhang, Canzhao Liu, Lunfeng Zhang, Yusu Gu, Kirk L. Peterson, Sylvia M. Evans, Xiang-Dong Fu, and Ju Chen. Prdm16 is a compact myocardium-enriched transcription factor required to maintain compact myocardial cardiomyocyte identity in left ventricle. Circulation, 145:586-602, Feb 2022. URL: https://doi.org/10.1161/circulationaha.121.056666, doi:10.1161/circulationaha.121.056666. This article has 106 citations and is from a highest quality peer-reviewed journal.

  9. (wu2022prdm16isa pages 9-11): Tongbin Wu, Zhengyu Liang, Zengming Zhang, Canzhao Liu, Lunfeng Zhang, Yusu Gu, Kirk L. Peterson, Sylvia M. Evans, Xiang-Dong Fu, and Ju Chen. Prdm16 is a compact myocardium-enriched transcription factor required to maintain compact myocardial cardiomyocyte identity in left ventricle. Circulation, 145:586-602, Feb 2022. URL: https://doi.org/10.1161/circulationaha.121.056666, doi:10.1161/circulationaha.121.056666. This article has 106 citations and is from a highest quality peer-reviewed journal.

  10. (wauwe2024prdm16determinesspecification pages 1-2): Jore Van Wauwe, Alexia Mahy, Sander Craps, Samaneh Ekhteraei-Tousi, Pieter Vrancaert, Hannelore Kemps, Wouter Dheedene, Rosa Doñate Puertas, Sander Trenson, H. Llewelyn Roderick, Manu Beerens, and Aernout Luttun. Prdm16 determines specification of ventricular cardiomyocytes by suppressing alternative cell fates. Life Science Alliance, 7:e202402719, Sep 2024. URL: https://doi.org/10.26508/lsa.202402719, doi:10.26508/lsa.202402719. This article has 8 citations and is from a peer-reviewed journal.

  11. (kuhnisch2023prdm16mutationdetermines pages 1-2): Jirko Kühnisch, Simon Theisen, Josephine Dartsch, Raphaela Fritsche-Guenther, Marieluise Kirchner, Benedikt Obermayer, Anna Bauer, Anne-Karin Kahlert, Michael Rothe, Dieter Beule, Arnd Heuser, Philipp Mertins, Jennifer A Kirwan, Nikolaus Berndt, Calum A MacRae, Norbert Hubner, and Sabine Klaassen. prdm16 mutation determines sex-specific cardiac metabolism and identifies two novel cardiac metabolic regulators. Cardiovascular Research, 119:2902-2916, Oct 2023. URL: https://doi.org/10.1093/cvr/cvad154, doi:10.1093/cvr/cvad154. This article has 16 citations and is from a domain leading peer-reviewed journal.

  12. (kuhnisch2023prdm16mutationdetermines pages 4-7): Jirko Kühnisch, Simon Theisen, Josephine Dartsch, Raphaela Fritsche-Guenther, Marieluise Kirchner, Benedikt Obermayer, Anna Bauer, Anne-Karin Kahlert, Michael Rothe, Dieter Beule, Arnd Heuser, Philipp Mertins, Jennifer A Kirwan, Nikolaus Berndt, Calum A MacRae, Norbert Hubner, and Sabine Klaassen. prdm16 mutation determines sex-specific cardiac metabolism and identifies two novel cardiac metabolic regulators. Cardiovascular Research, 119:2902-2916, Oct 2023. URL: https://doi.org/10.1093/cvr/cvad154, doi:10.1093/cvr/cvad154. This article has 16 citations and is from a domain leading peer-reviewed journal.

  13. (kuhnisch2023prdm16mutationdetermines pages 10-11): Jirko Kühnisch, Simon Theisen, Josephine Dartsch, Raphaela Fritsche-Guenther, Marieluise Kirchner, Benedikt Obermayer, Anna Bauer, Anne-Karin Kahlert, Michael Rothe, Dieter Beule, Arnd Heuser, Philipp Mertins, Jennifer A Kirwan, Nikolaus Berndt, Calum A MacRae, Norbert Hubner, and Sabine Klaassen. prdm16 mutation determines sex-specific cardiac metabolism and identifies two novel cardiac metabolic regulators. Cardiovascular Research, 119:2902-2916, Oct 2023. URL: https://doi.org/10.1093/cvr/cvad154, doi:10.1093/cvr/cvad154. This article has 16 citations and is from a domain leading peer-reviewed journal.

  14. (NCT06024759 chunk 1): Predictors of Risk in Left Ventricular Non-Compaction. London Health Sciences Centre Research Institute OR Lawson Research Institute of St. Joseph's. 2023. ClinicalTrials.gov Identifier: NCT06024759

  15. (NCT04265040 chunk 1): Benjamin Meder. DZHK TORCH-Plus is a Registry for Patients With Cardiomyopathies and Serves as Source for Cardiovascular Research Studies. University Hospital Heidelberg. 2020. ClinicalTrials.gov Identifier: NCT04265040

  16. (NCT06607471 chunk 23): Giovanni Peretto. Multimodal and Multidisciplinary Approach to Optimize Diagnostic, Prognostic, and Therapeutic Management of Patients with Non-ischemic Cardiomyopathies and Arrhythmogenic-inflammatory Phenotypes: a Multicenter, Observational, Retrospective and Prospective Registry Study.. Scientific Institute San Raffaele. 2018. ClinicalTrials.gov Identifier: NCT06607471

  17. (NCT01470014 chunk 1): Cardiac Computed Tomography: Characteristics of Isolated Left Ventricular Non-compaction. University of Zurich. 2011. ClinicalTrials.gov Identifier: NCT01470014

  18. (NCT03572569 chunk 1): Risk Stratification in Children and Adolescents With Primary Cardiomyopathy. German Heart Institute. 2013. ClinicalTrials.gov Identifier: NCT03572569

  19. (NCT02568072 chunk 1): Training-induced Increased Left Ventricular Trabeculation. St George's, University of London. 2015. ClinicalTrials.gov Identifier: NCT02568072

  20. (micolonghi2024unveilingthespectrum pages 18-19): Caterina Micolonghi, Federica Perrone, Marco Fabiani, Silvia Caroselli, Camilla Savio, Antonio Pizzuti, Aldo Germani, Vincenzo Visco, Simona Petrucci, Speranza Rubattu, and Maria Piane. Unveiling the spectrum of minor genes in cardiomyopathies: a narrative review. International Journal of Molecular Sciences, 25:9787, Sep 2024. URL: https://doi.org/10.3390/ijms25189787, doi:10.3390/ijms25189787. This article has 11 citations.

  21. (theisen2024characterisationofthe pages 17-21): Simon Theisen. Characterisation of the prdm16csp1/wt mouse as a model for the prdm16 associated cardiomyopathy. Text, Jan 2024. URL: https://doi.org/10.17169/refubium-41680, doi:10.17169/refubium-41680. This article has 0 citations and is from a peer-reviewed journal.

  22. (kuhnisch2023prdm16mutationdetermines pages 8-10): Jirko Kühnisch, Simon Theisen, Josephine Dartsch, Raphaela Fritsche-Guenther, Marieluise Kirchner, Benedikt Obermayer, Anna Bauer, Anne-Karin Kahlert, Michael Rothe, Dieter Beule, Arnd Heuser, Philipp Mertins, Jennifer A Kirwan, Nikolaus Berndt, Calum A MacRae, Norbert Hubner, and Sabine Klaassen. prdm16 mutation determines sex-specific cardiac metabolism and identifies two novel cardiac metabolic regulators. Cardiovascular Research, 119:2902-2916, Oct 2023. URL: https://doi.org/10.1093/cvr/cvad154, doi:10.1093/cvr/cvad154. This article has 16 citations and is from a domain leading peer-reviewed journal.

  23. (kuhnisch2023prdm16mutationdetermines pages 2-3): Jirko Kühnisch, Simon Theisen, Josephine Dartsch, Raphaela Fritsche-Guenther, Marieluise Kirchner, Benedikt Obermayer, Anna Bauer, Anne-Karin Kahlert, Michael Rothe, Dieter Beule, Arnd Heuser, Philipp Mertins, Jennifer A Kirwan, Nikolaus Berndt, Calum A MacRae, Norbert Hubner, and Sabine Klaassen. prdm16 mutation determines sex-specific cardiac metabolism and identifies two novel cardiac metabolic regulators. Cardiovascular Research, 119:2902-2916, Oct 2023. URL: https://doi.org/10.1093/cvr/cvad154, doi:10.1093/cvr/cvad154. This article has 16 citations and is from a domain leading peer-reviewed journal.

  24. (theisen2024characterisationofthe pages 76-81): Simon Theisen. Characterisation of the prdm16csp1/wt mouse as a model for the prdm16 associated cardiomyopathy. Text, Jan 2024. URL: https://doi.org/10.17169/refubium-41680, doi:10.17169/refubium-41680. This article has 0 citations and is from a peer-reviewed journal.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 11
Resolved 11
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 11
On topic 8
Off topic 0

All extracted references resolved successfully.