Dilated Cardiomyopathy 2B

Mendelian MONDO:0013848 Pathograph 31 Show in embeddings browser familial isolated dilated cardiomyopathy Dilated Cardiomyopathy

Dilated cardiomyopathy 2B (CMD2B) is an autosomal recessive, adult-onset, nonsyndromic dilated cardiomyopathy attributed to a homozygous missense variant, c.304T>C p.(Ser102Pro), in GATAD1, which encodes GATA zinc finger domain-containing protein 1. The entity rests on a single consanguineous family of Norwegian ancestry: two sisters developed dilated cardiomyopathy with heart failure at 50 and 53 years of age and their brother had idiopathic left ventricular enlargement at 57, all three homozygous for the variant, while thirteen heterozygous relatives had normal hearts into old age. The clinical course in that family resembled ordinary adult dilated cardiomyopathy and was chronic rather than fulminant, with the two sisters still in NYHA class II more than two decades after diagnosis on standard heart failure therapy. GATAD1 is a ubiquitously expressed protein, found in the nucleus and cytoplasm of cardiomyocytes, that co-purifies with the EMSY/KDM5A/SIN3B chromatin-regulatory complex, which binds H3K4me3-marked promoters, and the discovery paper proposed epigenetic dysregulation as the disease mechanism. How the variant damages the heart is not known. The proband's myocardium showed a disturbed extranuclear GATAD1 staining pattern and abnormally globular cardiomyocyte nuclei; Ser102 is a phosphorylation site whose phosphorylated form binds 14-3-3 proteins, a binding the proline substitution abolishes in vitro; a gatad1 knockout zebrafish develops heart failure-like phenotypes only under added stress; and a cardiomyocyte-specific Gatad1 knockout mouse does not develop cardiomyopathy. ClinGen classifies the GATAD1-dilated cardiomyopathy relationship as Limited.

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1
Inheritance
8
Pathophys.
2
Histopath.
9
Phenotypes
4
Hypotheses
3
Gaps
31
Pathograph
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Genes
1
Variants
10
Medical Actions
2
Differentials
3
Models
9
References
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Deep Research
👪

Inheritance

1
Autosomal recessive HP:0000007
Consanguineous kindred (the parents of the affected sibship were first cousins). All three affected siblings were homozygous for GATAD1 S102P; the six unaffected siblings were heterozygous or homozygous for the reference allele, and all eight offspring of the affected siblings were obligate heterozygotes without dilated cardiomyopathy on echocardiography. Linkage modelled as dominant, at any of three penetrance settings, found no locus.
Autosomal recessive inheritance
Show evidence (3 references)
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"In summary, the family history and clinical evaluations indicated that nonsyndromic DCM was inherited as an autosomal recessive trait."
States the recessive mode of inheritance from the pedigree and screening echocardiography.
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"We have clearly shown that the GATAD1-S102P mutation is recessive, as 13 heterozygous carriers had normal cardiac phenotypes."
Heterozygous carriers were unaffected, which is the basis for calling the allele recessive.
CGGV:assertion_56933afb-863f-46f5-884d-17522adb31a8-2024-08-07T160000.000Z SUPPORT Other
"GATAD1 | HGNC:29941 | dilated cardiomyopathy | MONDO:0005021 | AR | Limited"
ClinGen records the GATAD1-dilated cardiomyopathy relationship with autosomal recessive inheritance.
◈

Mechanistic Hypotheses

4
S102P disturbs GATAD1-dependent chromatin regulation in the heart
gatad1_epigenetic_dysregulation EMERGING
Evidence balance 1 support
The model proposed with the gene discovery: GATAD1 works in an H3K4me3-associated chromatin-regulatory complex, and the variant perturbs cardiac gene expression, as combined loss of the complex partners Hdac1 and Hdac2 does in mouse heart. It is an inference from GATAD1's interaction partners. No GATAD1-dependent cardiac gene set has been measured, and the S102P protein keeps its complex partners in HEK293 cells.
Pathograph links
Homozygous GATAD1 p.Ser102Pro Variant -> Perturbed GATAD1-Associated Chromatin Regulation UNKNOWN Proposed by the discovery paper from GATAD1's known chromatin associations; not measured for the S102P protein in heart tissue.
Perturbed GATAD1-Associated Chromatin Regulation -> Left Ventricular Dilation and Remodeling INDIRECT UNKNOWN INTERMEDIATES Hypothesized, by analogy with Hdac1/Hdac2 cardiac double-knockout mice; no GATAD1 target genes in heart have been identified.
Show evidence (1 reference)
PMID:21965549 SUPPORT INDIRECT PRIMARY RESULT Human Clinical
"While the specific effects of GATAD1-S102P on nucleosome protein interactions and downstream gene expression are unknown, the mutation leads to a heart-specific phenotype and implicates epigenetic dysregulation as a novel basis for human DCM."
States the hypothesis and that its molecular basis is unmeasured.
Loss of phospho-Ser102/14-3-3 binding alters GATAD1 nucleocytoplasmic distribution
gatad1_14_3_3_nucleocytoplasmic EMERGING
Evidence balance 1 support
Ser102, the residue the variant replaces, is a phosphorylation site whose phosphorylated form binds 14-3-3 proteins, possibly masking a nuclear localization signal. Losing it could explain the disturbed GATAD1 distribution seen in the proband's myocardium. The binding is shown only with peptides and recombinant protein, and in HEK293 cells the tagged S102P protein still reached the nucleus.
Pathograph links
Loss of Phospho-Ser102-Dependent 14-3-3 Binding -> Aberrant GATAD1 Subcellular Distribution in Cardiomyocytes INDIRECT UNKNOWN INTERMEDIATES Proposed link: 14-3-3 binding may mask a nuclear localization signal and so regulate GATAD1 nucleocytoplasmic transport. Not tested in cardiomyocytes, and tagged S102P GATAD1 localized normally to the nucleus in HEK293 cells, where Ser102 is probably not phosphorylated.
Show evidence (1 reference)
PMID:38605029 SUPPORT INDIRECT PRIMARY RESULT In Vitro
"Follow-up experiments reveal the structural basis of this interaction and suggest that 14-3-3 binding affects GATAD1 nucleocytoplasmic transport by masking a nuclear localisation signal."
The hypothesis as proposed by the authors of the interaction study.
S102P acts through a mutation-specific effect rather than simple loss of GATAD1
gatad1_s102p_mutation_specific EMERGING
Evidence balance 2 support
The mutant protein is present in patient heart, the patient nuclear and localization abnormalities are absent from the Gatad1 cardiomyocyte knockout mouse, and that mouse has no cardiomyopathy. These observations favour an effect specific to the S102P protein over simple deficiency. Heterozygous carriers are unaffected, so any such effect would have to be dose-dependent. The authors of the mouse study propose testing it in an S102P knock-in.
Show evidence (2 references)
PMID:39641830 SUPPORT INDIRECT PRIMARY RESULT Model Organism
"While the recessive mutation is often considered a loss-of-function mutation, it remains possible that the S102P mutation could be a gain-of-function mutation with dose-dependent effects that impair cellular functions."
The mouse study's reading of its negative result.
PMID:21965549 SUPPORT INDIRECT PRIMARY RESULT Human Clinical
"The similarity of GATAD1 staining patterns and nuclear morphology in TPM1-DCM and normal control tissues, distinct from the proband, indicates that GATAD1-S102P has a mutation-specific effect."
The discovery paper's reading of the patient histology.
S102P is a recessive loss-of-function allele
gatad1_loss_of_function EMERGING
Evidence balance 2 support 1 refute
Recessive inheritance with healthy heterozygotes is the usual signature of loss of function, and gatad1 knockout zebrafish develop heart failure-like phenotypes when stressed. Against it, the mutant protein is present in patient myocardium, and deleting Gatad1 in mouse cardiomyocytes causes no cardiomyopathy up to 18 months or after pressure overload. The mouse result does not exclude a requirement for GATAD1 in other cardiac cell types or in cardiomyocyte progenitors before the Cre driver acts. A separate myocardium-specific Gatad1 knockout fared worse after ischemia-reperfusion, with GATAD1 acting as a transcriptional regulator of fatty acid and glucose oxidation genes; like the zebrafish result, the requirement shows only under an added stress, and ischemic injury is not the disease modelled here.
Show evidence (3 references)
PMID:39626862 SUPPORT INDIRECT PRIMARY RESULT Model Organism
"myocardium-specific Gatad1 knockout (Gatad1 CKO) significantly increased the myocardial infarct size, impaired cardiac function in I/R mice"
Loss of Gatad1 in mouse myocardium reduces tolerance of an acute ischemic stress; indirect for dilated cardiomyopathy, which this model does not test.
PMID:28955713 SUPPORT INDIRECT PRIMARY RESULT Model Organism
"Under stress conditions, longitudinal studies uncovered heart failure (HF)-like phenotypes in stable KO mutants and a tendency toward HF phenotypes in transgenic lines."
Loss of gatad1 in zebrafish produces heart failure-like phenotypes under stress.
PMID:39641830 REFUTE PRIMARY RESULT Model Organism
"Together, these observations suggest that deletion of Gatad1 in cardiomyocytes does not induce cardiomyopathy during aging or affect the response to pressure overload stress in mice."
Cardiomyocyte loss of Gatad1 is not sufficient for cardiomyopathy in mice.
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Discussions and Knowledge Gaps

3
By what mechanism does homozygous GATAD1 S102P cause dilated cardiomyopathy, and in which cell type does it act?
KNOWLEDGE GAP OPEN gatad1_mechanism_unknown
Attached to
pathophysiology#Homozygous GATAD1 p.Ser102Pro Variant pathophysiology#Perturbed GATAD1-Associated Chromatin Regulation pathophysiology#Loss of Phospho-Ser102-Dependent 14-3-3 Binding
Every step between the variant and the ventricle is unmeasured in human heart. The chromatin hypothesis is an inference from GATAD1's interaction partners, which the variant does not disrupt in HEK293 cells; the 14-3-3 hypothesis rests on peptide binding and a crystal structure; and the abnormal GATAD1 distribution and globular nuclei come from one biopsy. The source papers name the experiments that would resolve it: an S102P knock-in and human iPSC-derived cardiomyocytes carrying the variant.
Proposed experiments
Human iPSC-derived cardiomyocytes carrying GATAD1 S102P
gatad1_s102p_ipsc_cardiomyocytes
Compare homozygous S102P, knockout and isogenic control iPSC-derived cardiomyocytes for GATAD1 localization, nuclear shape, 14-3-3 binding, chromatin occupancy, transcriptome and contractility.
Would support
mechanistic_hypotheses#gatad1_s102p_mutation_specific
Show evidence (2 references)
PMID:39641830 SUPPORT PRIMARY RESULT Model Organism
"Utilizing human iPSC-derived cardiomyocytes with GATAD1 knockout or mutation could be an excellent approach to assess the function of human GATAD1 in cardiomyocyte differentiation."
The mouse study names human iPSC-cardiomyocyte models as the next step.
PMID:38605029 SUPPORT BACKGROUND In Vitro
"However, neither the pathogenic mechanism nor the function of this GATAD1 phosphorylation site are currently known."
States that the mechanism is unknown.
Why does loss of Gatad1 in mouse cardiomyocytes cause no cardiomyopathy when homozygous S102P causes dilated cardiomyopathy in humans?
HUMAN MODEL MISMATCH OPEN gatad1_mouse_model_mismatch
Attached to
animal_models#Mouse pathophysiology#Left Ventricular Dilation and Remodeling mechanistic_hypotheses#gatad1_loss_of_function
The mouse result can mean that S102P acts through a mutation-specific effect a null allele cannot model, that GATAD1 is required in cells other than cardiomyocytes or before the Cre driver switches on, that onset in mouse lies beyond 18 months, that strain background hides the phenotype, or that human and mouse GATAD1 differ in function. The zebrafish data do not settle it: the knockout needs stressors to show a phenotype, and fish Gatad1 lacks the Ser102 residue.
Proposed experiments
Gatad1 S102P knock-in mouse
gatad1_s102p_knockin_mouse
Homozygous S102P knock-in, aged beyond 18 months and on more than one inbred background, with echocardiography and nuclear morphology.
Would support
mechanistic_hypotheses#gatad1_s102p_mutation_specific
Would refute
mechanistic_hypotheses#gatad1_loss_of_function
Show evidence (2 references)
PMID:39641830 SUPPORT PRIMARY RESULT Model Organism
"it is important to recognize that the function of GATAD1 in humans and mice may not be directly comparable. There could be unknown genetic modifiers necessary to manifest a cardiomyopathy phenotype."
The authors' own statement of the species and modifier caveats.
PMID:39641830 SUPPORT PRIMARY RESULT Model Organism
"This possibility could be tested using an S102P knock-in mutant in future studies."
Names the knock-in experiment.
Do other families with biallelic GATAD1 variants and dilated cardiomyopathy exist?
KNOWLEDGE GAP OPEN gatad1_single_family_evidence
Attached to
disease#Dilated Cardiomyopathy 2B genetic#GATAD1
The entity is defined by one family with one allele, and ClinGen classifies the gene-disease relationship as Limited. A second unrelated family, or a different biallelic allele, is what would move the classification and show the phenotypic range.
Show evidence (1 reference)
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"GATAD1 mutations appear to be a rare cause for DCM, yet defects within other nucleosome interacting proteins may prove to be important in disease pathogenesis."
The discovery paper itself notes the rarity of GATAD1 disease.
⚙

Pathophysiology

8
Homozygous GATAD1 p.Ser102Pro Variant
The only reported CMD2B allele is c.304T>C in exon 2 of GATAD1, replacing serine 102 with proline. It was the single rare variant shared by the two exome-sequenced sisters inside the 7q21 homozygous interval, and it was absent from 1,558 control and proband chromosomes. The mutant protein is present in patient myocardium, so the allele does not act by abolishing GATAD1 protein. Whether it is a loss-of-function allele or has a mutation-specific effect is unresolved; both models are recorded under mechanistic_hypotheses.
S102P disturbs GATAD1-dependent chromatin regulation in the heart
GATAD1 hgnc:29941 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves GATAD1 (hgnc:29941). hgnc:29941 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context allele_type: missense variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: UNKNOWN
NM_021167 c.304T>C p.(Ser102Pro), homozygous in all three affected siblings of a consanguineous family.
Downstream
Loss of Phospho-Ser102-Dependent 14-3-3 Binding Proline at position 102 removes the phosphorylatable serine, and a peptide carrying the substitution does not bind 14-3-3 epsilon.
Aberrant GATAD1 Subcellular Distribution in Cardiomyocytes Observed in the homozygous proband's myocardium by immunohistochemistry and not in control or TPM1-related dilated cardiomyopathy myocardium. How the substitution disturbs localization is not established.
Globular Cardiomyocyte Nuclei Observed in the proband's biopsy and not in control or TPM1-related dilated cardiomyopathy myocardium, which the authors read as a mutation-specific effect.
Perturbed GATAD1-Associated Chromatin Regulation Proposed by the discovery paper from GATAD1's known chromatin associations; not measured for the S102P protein in heart tissue. S102P disturbs GATAD1-dependent chromatin regulation in the heart
Left Ventricular Dilation and Remodeling The genetic evidence (linkage, homozygosity mapping, exome filtering and co-segregation in one family) links the genotype to the cardiomyopathy without establishing any intermediate step.
Show evidence (3 references)
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"A solitary mutation in GATAD1 remained, for which the three affected siblings were homozygous and which mapped to the 7q21 critical region."
Identifies the homozygous GATAD1 variant as the only candidate segregating with disease.
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"The resultant S102P substitution replaces a polar hydroxyl serine with a nonpolar cyclic proline."
Describes the amino acid change.
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"the GATAD1-S102P mutant protein was detected in the proband's myocardium, ruling out deficiency of GATAD1 as a consequence of the underlying homozygous mutation"
The mutant protein is present in patient heart, so the allele does not simply abolish GATAD1.
Loss of Phospho-Ser102-Dependent 14-3-3 Binding
Phosphorylated Ser102 of GATAD1 binds 14-3-3 proteins with low-micromolar affinity, and a crystal structure of 14-3-3 epsilon with the phosphopeptide has been solved. Binding requires the phosphate: neither the unphosphorylated peptide, the S102P peptide nor phosphomimetic aspartate or glutamate peptides bind. Ser102 phosphorylation has been detected only in murine heart tissue, which the authors take as a hint of a heart-specific function. Full-length S102P GATAD1 in HEK293 cells kept the same interaction partners as wild type, so the known complexes are not disrupted; the effect of losing the 14-3-3 interaction in cardiomyocytes has not been tested.
Loss of phospho-Ser102/14-3-3 binding alters GATAD1 nucleocytoplasmic distribution
GATAD1 hgnc:29941 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves GATAD1 (hgnc:29941). hgnc:29941 is a gene from the HUGO Gene Nomenclature Committee.
14-3-3 protein binding (phospho-Ser102) GO:0071889 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves absent 14-3-3 protein binding (phospho-Ser102), annotated with 14-3-3 protein binding (GO:0071889). GO:0071889 is a molecular function from the Gene Ontology. ∅ ABSENT
Downstream
Aberrant GATAD1 Subcellular Distribution in Cardiomyocytes Proposed link: 14-3-3 binding may mask a nuclear localization signal and so regulate GATAD1 nucleocytoplasmic transport. Not tested in cardiomyocytes, and tagged S102P GATAD1 localized normally to the nucleus in HEK293 cells, where Ser102 is probably not phosphorylated. Loss of phospho-Ser102/14-3-3 binding alters GATAD1 nucleocytoplasmic distribution
Show evidence (3 references)
PMID:38605029 SUPPORT PRIMARY RESULT In Vitro
"We find that this phosphorylation site mediates interaction with 14-3-3 family proteins."
Identifies the phosphorylation-dependent 14-3-3 interaction at Ser102.
PMID:38605029 SUPPORT PRIMARY RESULT In Vitro
"Overall, the AP-MS data for all the GATAD1 mutant variants was very similar to the wild-type with the same interaction partners identified in all"
The S102P substitution does not disrupt the other known GATAD1 interactions in HEK293 cells, which narrows its measurable molecular effect to the phospho-dependent 14-3-3 binding.
PMID:38605029 SUPPORT BACKGROUND In Vitro
"Intriguingly, although GATAD1 is expressed in many tissues, the only evidence for phosphorylation of this site comes from murine heart tissue, indicative of a heart-specific function"
The phosphorylation site has so far been observed only in heart, restating published phosphoproteomic data.
Aberrant GATAD1 Subcellular Distribution in Cardiomyocytes
In normal left ventricle GATAD1 stains the nucleus and cytoplasm in a homogeneous, striated pattern; in zebrafish cardiomyocytes tagged Gatad1 localizes to the nucleus and the sarcomeric I-band. In the homozygous proband the extranuclear distribution was markedly disturbed, while actin staining was normal. This is a single-biopsy observation.
cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
nucleus GO:0005634 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves nucleus (GO:0005634). GO:0005634 is a cellular component from the Gene Ontology. I band GO:0031674 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves I band (GO:0031674). GO:0031674 is a cellular component from the Gene Ontology.
Show evidence (3 references)
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"Within healthy left ventricular tissue, GATAD1 localized to the nucleus and cytoplasm with a homogenous, striated staining pattern"
Normal cardiac localization of GATAD1, the reference against which the patient pattern is abnormal.
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"In contrast, homozygosity for the S102P in GATD1 resulted in a marked disturbance in its extranuclear distribution in the proband"
The abnormal GATAD1 distribution in patient myocardium.
PMID:28955713 SUPPORT PRIMARY RESULT Model Organism
"Together, these data indicate that Gatad1-GFP is localized to both the nucleus and the I-band region of myofibrils."
Nuclear and sarcomeric localization of Gatad1 in zebrafish cardiomyocytes.
Globular Cardiomyocyte Nuclei
Cardiomyocyte nuclei in the proband's endomyocardial biopsy were globular rather than the normal elongated spindle shape. The authors compare this with the abnormal nuclear morphology of Lmna-knockout dilated cardiomyopathy, but GATAD1 is not a nuclear envelope protein and the finding has not been reproduced: cardiomyocytes from the Gatad1 cardiomyocyte knockout mouse had normal nuclei.
cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology.
nucleus organization GO:0006997 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal nucleus organization (GO:0006997). GO:0006997 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Animal models
Gatad1 cardiomyocyte-specific knockout mouse Mouse fails to recapitulate Isolated knockout cardiomyocytes have normal nuclear shape.
Show evidence (2 references)
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"Additionally, myocyte nuclei in the proband had a unique globular morphology, contrasting with the elongated spindle shape observed in the controls."
Documents the nuclear shape abnormality in patient myocardium.
PMID:39641830 REFUTE PRIMARY RESULT Model Organism
"Unlike the abnormal nuclei shape observed in patients carrying GATAD1 mutations, the nuclei shape of cardiomyocytes remained unaffected by the loss of Gatad1."
Loss of Gatad1 in mouse cardiomyocytes does not reproduce the nuclear phenotype, so the finding is either specific to S102P, specific to human, or secondary.
Perturbed GATAD1-Associated Chromatin Regulation
Hypothesized node. GATAD1 co-purifies with the EMSY/KDM5A/SIN3B complex (with PHF12 and RBBP4/7), which binds H3K4me3-marked active promoters, and it was first identified as an H3K4me3-associated protein; HDAC1 and HDAC2 are also reported binding partners. The discovery paper inferred that GATAD1 S102P causes dilated cardiomyopathy through epigenetic dysregulation, by analogy with the dilated cardiomyopathy of combined Hdac1/Hdac2 cardiac knockout mice. No study has measured chromatin occupancy or gene expression driven by the S102P protein, and the variant does not change GATAD1's complex partners in HEK293 cells.
S102P disturbs GATAD1-dependent chromatin regulation in the heart
GATAD1 hgnc:29941 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves GATAD1 (hgnc:29941). hgnc:29941 is a gene from the HUGO Gene Nomenclature Committee.
regulation of DNA-templated transcription GO:0006355 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated regulation of DNA-templated transcription (GO:0006355). GO:0006355 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Sin3-type complex (EMSY/KDM5A/SIN3B) GO:0070822 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves Sin3-type complex (EMSY/KDM5A/SIN3B), annotated with Sin3-type complex (GO:0070822). GO:0070822 is a cellular component from the Gene Ontology.
Downstream
Left Ventricular Dilation and Remodeling Hypothesized, by analogy with Hdac1/Hdac2 cardiac double-knockout mice; no GATAD1 target genes in heart have been identified. S102P disturbs GATAD1-dependent chromatin regulation in the heart
Show evidence (4 references)
PMID:21965549 SUPPORT INDIRECT PRIMARY RESULT Human Clinical
"GATAD1 binds to a histone modification site that regulates gene expression. Consistent with murine DCM caused by genetic disruption of histone deacetylases, the data implicate an inherited basis for epigenetic dysregulation in human heart failure."
The discovery paper's mechanistic inference; it rests on GATAD1's known chromatin association, not on a measurement in patients.
PMID:38605029 SUPPORT PRIMARY RESULT In Vitro
"This included several well-known GATAD1 binders such as the transcriptional regulators KDM5A, RBBP7/4 PHF12, and SIN3B. Together, these proteins form the EMSY complex, which binds to H3K4me3-marked, active promoters"
Affinity purification places GATAD1 in the EMSY chromatin-regulatory complex.
PMID:26841866 SUPPORT BACKGROUND In Vitro
"Recent work from others and us revealed interactions between the Sin3/HDAC complex, the H3K4me3 demethylase KDM5A, GATAD1, and EMSY."
Independent proteomic group placing GATAD1 with the Sin3/HDAC complex and KDM5A.
+ 1 more reference
Left Ventricular Dilation and Remodeling
Left ventricular enlargement was present in all three homozygous siblings, with a dilated, poorly contracting ventricle in the two sisters and enlargement with a borderline ejection fraction in the brother, which the authors describe as an intermediate phenotype of dilated cardiomyopathy. The proband's endomyocardial biopsy showed moderate myocyte hypertrophy, mild focal interstitial fibrosis and mild diffuse endocardial fibrosis, the non-specific remodeling of a chronic cardiomyopathy.
cardiomyocyte CL:0000746 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiomyocyte, annotated with cardiac muscle cell (CL:0000746). CL:0000746 is a cell type from the Cell Ontology. cardiac fibroblast CL:0002548 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cardiac fibroblast, annotated with fibroblast of cardiac tissue (CL:0002548). CL:0002548 is a cell type from the Cell Ontology.
cardiac muscle hypertrophy GO:0003300 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased cardiac muscle hypertrophy (GO:0003300). GO:0003300 is a biological process from the Gene Ontology. ↑ INCREASED extracellular matrix organization GO:0030198 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased extracellular matrix organization (GO:0030198). GO:0030198 is a biological process from the Gene Ontology. ↑ INCREASED
left ventricle UBERON:0002084 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in left ventricle, annotated with heart left ventricle (UBERON:0002084). UBERON:0002084 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Gatad1 cardiomyocyte-specific knockout mouse Mouse fails to recapitulate Loss of Gatad1 in cardiomyocytes does not produce ventricular dilation or dysfunction at baseline or under pressure overload.
Downstream
Left Ventricular Systolic Dysfunction The dilated, remodeled ventricle contracts poorly; ejection fraction was 21% in the proband and 43% in her sister at diagnosis.
Dilated cardiomyopathy
Left ventricular dilatation
Cardiomyocyte hypertrophy
Interstitial cardiac fibrosis
Show evidence (2 references)
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"Left ventricular endomyocardial biopsy revealed moderate myocyte hypertrophy, mild focal interstitial fibrosis, and mild diffuse endocardial fibrosis, consistent with a chronic cardiomyopathy."
Histological remodeling in the proband's left ventricle.
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"Echocardiography in 17 adult descendants of first cousins revealed DCM in 2 female siblings and idiopathic left ventricular enlargement in their brother."
Ventricular enlargement in every homozygous sibling.
Left Ventricular Systolic Dysfunction
Reduced left ventricular ejection fraction in the two affected sisters (21% and 43% at diagnosis; 25% and 40% more than twenty years later) and a borderline 50% on angiography in the brother at 68.
heart contraction GO:0060047 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased heart contraction (GO:0060047). GO:0060047 is a biological process from the Gene Ontology. ↓ DECREASED
left ventricle UBERON:0002084 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in left ventricle, annotated with heart left ventricle (UBERON:0002084). UBERON:0002084 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Chronic Systolic Heart Failure
Reduced left ventricular ejection fraction
Show evidence (1 reference)
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"is in NYHA class II heart failure with moderate-severe left ventricular enlargement and ejection fraction of 25%"
Persistent severe systolic dysfunction in the proband.
Chronic Systolic Heart Failure
Both affected sisters developed clinical heart failure (the proband presented with it at 50), which was controlled in NYHA class II on standard therapy for more than two decades. No sudden death, ventricular arrhythmia or heart transplantation was reported in the family.
heart contraction GO:0060047 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased heart contraction (GO:0060047). GO:0060047 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
gatad1 knockout zebrafish Zebrafish partially recapitulates Heart failure-like phenotypes appear only under combined stress and without significant chamber enlargement.
Tg(myl7:GATAD1-S102P) zebrafish Zebrafish partially recapitulates Reduced survival and a single enlarged heart in fish overexpressing the patient allele, suggesting a possible effect of the mutant protein itself.
Downstream
Congestive heart failure
Cardiomegaly
Show evidence (1 reference)
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"presented at age 50 years with heart failure and cardiomegaly"
Clinical heart failure at presentation in the proband.
✶

Histopathology

2
Globular cardiomyocyte nuclei
Cardiomyocyte nuclei in the proband's biopsy were globular instead of spindle-shaped; not seen in control or TPM1-related dilated cardiomyopathy myocardium.
Show evidence (1 reference)
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"Additionally, myocyte nuclei in the proband had a unique globular morphology, contrasting with the elongated spindle shape observed in the controls."
The nuclear finding on the proband's biopsy.
Disturbed extranuclear GATAD1 immunostaining
On GATAD1 immunohistochemistry of the proband's biopsy the extranuclear staining was markedly disturbed, whereas normal and TPM1-related dilated cardiomyopathy myocardium showed a homogeneous striated pattern. Actin staining was normal.
Show evidence (1 reference)
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"In contrast, homozygosity for the S102P in GATD1 resulted in a marked disturbance in its extranuclear distribution in the proband"
The GATAD1 staining abnormality on the proband's biopsy.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Dilated Cardiomyopathy 2B Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

9
Blood 1
Left ventricular thrombus HP:0040412 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Left ventricular apical thrombus, annotated with Left ventricular thrombus (HP:0040412). HP:0040412 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"Her medical therapy included digoxin, furosemide, carvedilol, enalapril, spironolactone, and warfarin (for apical thrombus)."
Records the apical thrombus in the proband.
Cardiovascular 8
Dilated cardiomyopathy HP:0001644 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dilated cardiomyopathy (HP:0001644), qualified as adult onset, range 50-57y. HP:0001644 is a phenotype from the Human Phenotype Ontology.
Onset: ADULT; 50-57y
Show evidence (2 references)
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"Echocardiography was diagnostic for DCM and angiography ruled out coronary artery disease."
Diagnosis of dilated cardiomyopathy in the proband with ischemic disease excluded.
PMID:39641830 SUPPORT BACKGROUND Human Clinical
"presented with full penetrance adult-onset DCM and heart failure in their fifties, being 50, 53 and 57 years of age"
Restates the ages at diagnosis of the three homozygotes from the discovery paper; "full penetrance" here describes three of three homozygous siblings.
Left ventricular dilatation HP:4000141 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Left ventricular dilatation (HP:4000141). HP:4000141 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"was diagnosed with idiopathic left ventricular enlargement, a known intermediate phenotype of DCM"
Left ventricular enlargement as the phenotype of the affected brother.
Reduced left ventricular ejection fraction HP:0012664 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced left ventricular ejection fraction (HP:0012664). HP:0012664 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"She has remained in NYHA class II heart failure 23 years after diagnosis with mild left ventricular enlargement and ejection fraction of 40%."
Reduced ejection fraction in the affected sister.
Congestive heart failure HP:0001635 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Heart failure, annotated with Congestive heart failure (HP:0001635), qualified as temporality chronic. HP:0001635 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC
Show evidence (2 references)
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"presented at age 50 years with heart failure and cardiomegaly"
Heart failure at presentation in the proband.
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"She has remained in NYHA class II heart failure 23 years after diagnosis with mild left ventricular enlargement and ejection fraction of 40%."
Chronic heart failure in the affected sister.
Cardiomegaly HP:0001640 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cardiomegaly (HP:0001640). HP:0001640 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"At age 68 years, he had cardiomegaly on chest radiography and a borderline ejection fraction of 50% on left ventricular angiography."
Cardiomegaly in the affected brother.
Atrial fibrillation HP:0005110 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Atrial fibrillation (HP:0005110), qualified as temporality chronic. HP:0005110 is a phenotype from the Human Phenotype Ontology.
Temporal: CHRONIC
Show evidence (1 reference)
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"Her treatment included furosemide, metoprolol, losartan, spironolactone, warfarin, and AV node ablation with pacemaker implantation for persistent atrial fibrillation."
Persistent atrial fibrillation in the affected sister.
Cardiomyocyte hypertrophy HP:0031319 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cardiomyocyte hypertrophy (HP:0031319). HP:0031319 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"Left ventricular endomyocardial biopsy revealed moderate myocyte hypertrophy, mild focal interstitial fibrosis, and mild diffuse endocardial fibrosis, consistent with a chronic cardiomyopathy."
Biopsy finding in the proband.
Interstitial cardiac fibrosis HP:0031329 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Interstitial cardiac fibrosis (HP:0031329). HP:0031329 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"Left ventricular endomyocardial biopsy revealed moderate myocyte hypertrophy, mild focal interstitial fibrosis, and mild diffuse endocardial fibrosis, consistent with a chronic cardiomyopathy."
Biopsy finding in the proband.
🧬

Genetic Associations

1
GATAD1 (Pathogenic Variants)
Gene: GATAD1 hgnc:29941 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GATAD1 (hgnc:29941). hgnc:29941 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
CGGV:assertion_56933afb-863f-46f5-884d-17522adb31a8-2024-08-07T160000.000Z SUPPORT Other
"GATAD1 | HGNC:29941 | dilated cardiomyopathy | MONDO:0005021 | AR | Limited"
ClinGen classifies the GATAD1-dilated cardiomyopathy relationship as Limited with autosomal recessive inheritance.
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"The mutation, absent in HapMap, 1000 Genomes, and 474 ethnically matched controls, altered a conserved residue of GATAD1, encoding GATA zinc finger domain-containing protein 1. Thirteen relatives were heterozygous mutation carriers with no evidence of myocardial disease, even at advanced ages."
Variant rarity, residue conservation and unaffected heterozygous carriers.
🔬

Variants

1
GATAD1 p.Ser102Pro
Gene: GATAD1 hgnc:29941 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in GATAD1 (hgnc:29941). hgnc:29941 is a gene from the HUGO Gene Nomenclature Committee. single nucleotide variant
The only CMD2B allele reported (NM_021167.5:c.304T>C), homozygous in three affected siblings. The residue lies in a stretch (Gly79 to Ile136) that is fully conserved across mammals; fish carry serines at the neighbouring positions instead. ClinVar (VCV000031656, retrieved 2026-09-25) lists it as Pathogenic for dilated cardiomyopathy 2B with the review status "no assertion criteria provided" on a single submission (SCV000045643); no clinical_significance is set here because that record is not an independent classification and ClinGen rates the gene-disease relationship Limited.
Identifiers: c.304T>C clinvar:VCV000031656 dbSNP:rs387907188
Show evidence (2 references)
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"The identified missense mutation was a c.304 T>C nucleotide transition in exon 2 of GATAD1"
Gives the nucleotide change and exon.
PMID:28955713 SUPPORT PRIMARY RESULT Computational
"In mammals, the peptide sequence surrounding the human GATAD1-S102P mutation, ranging from G79 to I136, is 100% conserved"
Sequence conservation around the variant from the zebrafish study's alignment.
💊

Medical Actions

10
Beta-Blocker Therapy
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: carvedilol CHEBI:3441 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses carvedilol (CHEBI:3441). CHEBI:3441 is a therapeutic agent from Chemical Entities of Biological Interest. metoprolol CHEBI:6904 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses metoprolol (CHEBI:6904). CHEBI:6904 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Carvedilol in the proband and metoprolol in the sister and brother, as part of standard heart failure therapy. No CMD2B-specific trial exists; use follows general dilated cardiomyopathy management.
Mechanism Target:
Left Ventricular Dilation and Remodeling — Neurohormonal blockade of adverse remodeling in the dilated ventricle.
Show evidence (1 reference)
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"Her medical therapy included digoxin, furosemide, carvedilol, enalapril, spironolactone, and warfarin (for apical thrombus)."
Carvedilol was part of the proband's long-term therapy.
ACE Inhibitor or Angiotensin Receptor Blocker Therapy
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: enalapril CHEBI:4784 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses enalapril (CHEBI:4784). CHEBI:4784 is a therapeutic agent from Chemical Entities of Biological Interest. losartan CHEBI:6541 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses losartan (CHEBI:6541). CHEBI:6541 is a therapeutic agent from Chemical Entities of Biological Interest. captopril CHEBI:3380 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses captopril (CHEBI:3380). CHEBI:3380 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Enalapril in the proband, losartan in the sister and captopril in the brother. General dilated cardiomyopathy management; no CMD2B-specific evidence of efficacy.
Mechanism Target:
Left Ventricular Dilation and Remodeling — Renin-angiotensin blockade of adverse remodeling.
Show evidence (1 reference)
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"He was treated with furosemide, metoprolol, and captopril."
ACE inhibitor therapy in the affected brother.
Mineralocorticoid Receptor Antagonist Therapy
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: spironolactone CHEBI:9241 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses spironolactone (CHEBI:9241). CHEBI:9241 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Spironolactone in both affected sisters, as part of standard heart failure therapy.
Mechanism Target:
Left Ventricular Dilation and Remodeling — Aldosterone blockade of adverse remodeling.
Show evidence (1 reference)
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"Her treatment included furosemide, metoprolol, losartan, spironolactone, warfarin, and AV node ablation with pacemaker implantation for persistent atrial fibrillation."
Spironolactone in the affected sister.
Loop Diuretic and Digoxin
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: furosemide CHEBI:47426 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses furosemide (CHEBI:47426). CHEBI:47426 is a therapeutic agent from Chemical Entities of Biological Interest. digoxin CHEBI:4551 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses digoxin (CHEBI:4551). CHEBI:4551 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Furosemide in all three affected siblings and digoxin in the proband, for congestion and symptom control.
Mechanism Target:
Congestive heart failure — Relief of congestion; digoxin adds inotropic and rate-control effects.
Target Phenotypes: Heart failure HP:0001635 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Heart failure, annotated with Congestive heart failure (HP:0001635). HP:0001635 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"Her medical therapy included digoxin, furosemide, carvedilol, enalapril, spironolactone, and warfarin (for apical thrombus)."
Furosemide and digoxin in the proband.
Anticoagulation
Action: anticoagulation therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is anticoagulation therapy (NCIT:C63341). NCIT:C63341 is a clinical intervention from the NCI Thesaurus. Ontology label: Anticoagulation Therapy NCIT:C63341
Agent: warfarin CHEBI:10033 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses warfarin (CHEBI:10033). CHEBI:10033 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Warfarin for the proband's apical left ventricular thrombus and for the sister's persistent atrial fibrillation.
Mechanism Target:
Left ventricular thrombus — Treatment of the intracardiac thrombus and prevention of embolism.
Target Phenotypes: Left ventricular thrombus HP:0040412 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Left ventricular thrombus (HP:0040412). HP:0040412 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"Her medical therapy included digoxin, furosemide, carvedilol, enalapril, spironolactone, and warfarin (for apical thrombus)."
Warfarin for the apical thrombus in the proband.
Atrioventricular Node Ablation With Pacemaker Implantation
Action: atrioventricular node ablationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is atrioventricular node ablation, annotated with Cardiac Ablation (NCIT:C100068). NCIT:C100068 is a clinical intervention from the NCI Thesaurus. Ontology label: Cardiac Ablation NCIT:C100068
Platform: Other
Used for rate control of persistent atrial fibrillation in the affected sister: ablation of the atrioventricular node followed by permanent pacing.
Mechanism Target:
Atrial fibrillation — Ventricular rate control for persistent atrial fibrillation.
Show evidence (1 reference)
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"Her treatment included furosemide, metoprolol, losartan, spironolactone, warfarin, and AV node ablation with pacemaker implantation for persistent atrial fibrillation."
AV node ablation and pacing for atrial fibrillation in the affected sister.
Permanent Pacemaker Placement
Action: pacemaker placementNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is pacemaker placement (NCIT:C80434). NCIT:C80434 is a clinical intervention from the NCI Thesaurus. Ontology label: Pacemaker Placement NCIT:C80434
Platform: Device
Implanted in the affected sister after atrioventricular node ablation for persistent atrial fibrillation.
Mechanism Target:
Atrial fibrillation — Provides ventricular pacing after the atrioventricular node is ablated.
Show evidence (1 reference)
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"Her treatment included furosemide, metoprolol, losartan, spironolactone, warfarin, and AV node ablation with pacemaker implantation for persistent atrial fibrillation."
Pacemaker implantation in the affected sister.
Implantable Cardioverter-Defibrillator
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. Ontology label: Implantable Cardioverter-Defibrillator Placement NCIT:C80435
Platform: Device
Not reported in the CMD2B family, in which no ventricular arrhythmia or sudden death was described. Listed because ICD placement is part of general dilated cardiomyopathy management; the evidence is general and not specific to GATAD1 disease.
Mechanism Target:
Chronic Systolic Heart Failure — Prevention of sudden arrhythmic death in systolic heart failure.
Show evidence (1 reference)
PMID:39519012 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical
"which may be in part attributed to increased utilization in guideline-directed medical therapy (GDMT), device therapies such as implantable cardioverter-defibrillators (ICD), and earlier patient identification"
General dilated cardiomyopathy evidence for ICD therapy; not specific to CMD2B.
Heart Transplantation
Action: heart transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is heart transplantation (NCIT:C15246). NCIT:C15246 is a clinical intervention from the NCI Thesaurus. Ontology label: Heart Transplantation NCIT:C15246
Platform: Surgery
Not reported in the CMD2B family. The option for end-stage dilated cardiomyopathy in general; the evidence is not specific to GATAD1 disease.
Mechanism Target:
Chronic Systolic Heart Failure — Replaces the failing myocardium in end-stage disease.
Show evidence (1 reference)
PMID:39519012 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical
"Individuals with DCM typically develop heart failure (HF), and DCM is the most frequent underlying reason for heart transplantation."
General dilated cardiomyopathy evidence; not specific to CMD2B.
Genetic Counseling and Cascade Screening
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
Platform: Other
Siblings of an affected person have a one in four risk of being homozygous. In the discovery family, disease appeared only in homozygotes and none of the eight obligate-heterozygous offspring of affected siblings developed dilated cardiomyopathy over 20 years, so carrier status alone has not been associated with disease. Echocardiographic screening of relatives detected the two asymptomatic affected siblings.
Show evidence (3 references)
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"DCM was also excluded in all 8 offspring of the 3 affected siblings, and none have developed heart failure over 20 years of follow up."
Obligate heterozygous offspring remained unaffected, informing counselling of carriers.
PMID:20301486 SUPPORT REVIEW SYNTHESIS Other
"relatives of a proband with DCM to inform cardiac surveillance and allow early detection and treatment of DCM to improve long-term outcome"
GeneReviews purpose statement on risk assessment and surveillance of at-risk relatives in dilated cardiomyopathy generally.
PMID:39833651 SUPPORT INDIRECT PRIMARY RESULT Human Clinical
"The yield of DCM family screening was ~10% at baseline and another ~10% during 5-year follow-up. Relatives without the familial LP/P variant could be safely discharged."
General dilated cardiomyopathy cohort supporting genotype-guided cascade screening of relatives; not specific to GATAD1, where only homozygous relatives would be at risk.
🔬

Diagnosis

4
Echocardiography
Echocardiography established the diagnosis in the proband and identified the two further affected siblings among sixteen screened relatives; screening of the eight offspring of affected siblings was normal.
echocardiography NCIT:C16525 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"Echocardiography was diagnostic for DCM and angiography ruled out coronary artery disease."
Echocardiographic diagnosis in the proband.
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"Two of eight asymptomatic siblings of the proband were found to have cardiomyopathy in the absence of established risk factors for coronary and myopathic heart disease."
Screening echocardiography detected disease in asymptomatic siblings.
Coronary Angiography
Used to exclude coronary artery disease as the cause of left ventricular dysfunction before the diagnosis of idiopathic dilated cardiomyopathy.
coronary angiography NCIT:C100085 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"Echocardiography was diagnostic for DCM and angiography ruled out coronary artery disease."
Angiographic exclusion of ischemic heart disease in the proband.
Endomyocardial Biopsy
Performed in the proband. It showed non-specific chronic cardiomyopathy changes and, on GATAD1 immunostaining, the abnormal GATAD1 distribution and globular nuclei; it is not a diagnostic test for CMD2B.
endomyocardial biopsy NCIT:C51674 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"Left ventricular endomyocardial biopsy revealed moderate myocyte hypertrophy, mild focal interstitial fibrosis, and mild diffuse endocardial fibrosis, consistent with a chronic cardiomyopathy."
Biopsy findings in the proband.
Exome Sequencing
The variant was found by exome sequencing of two affected sisters after linkage and homozygosity mapping. Confirming the diagnosis in a new patient requires biallelic GATAD1 variants; with a single reported allele and a ClinGen Limited classification, a GATAD1 result should be interpreted with caution.
whole exome sequencing NCIT:C101295 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"Exome sequencing of the affected sisters was then used as a complementary strategy for mutation discovery."
Exome sequencing identified the variant.
📈

Progression

1
Adult onset and chronic course
Age: diagnosis at 50 to 57 years; followed for more than 20 years
The proband presented with heart failure at 50 and her sister was diagnosed at 53; both remained in NYHA class II more than two decades later on heart failure therapy. The brother had left ventricular enlargement at 57 and a borderline ejection fraction at 68, and died of cancer at 73. This is a single family, so the course is not a generalisable natural history.
Show evidence (2 references)
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"She has had no history of arrhythmia and, 24 years after her initial presentation, is in NYHA class II heart failure with moderate-severe left ventricular enlargement and ejection fraction of 25%."
Long-term outcome of the proband.
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"She has remained in NYHA class II heart failure 23 years after diagnosis with mild left ventricular enlargement and ejection fraction of 40%."
Long-term outcome of the affected sister.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Three affected siblings in one consanguineous family. The discovery study also screened 273 unrelated dilated cardiomyopathy probands and found no previously unreported nonsynonymous GATAD1 variant.
Show evidence (2 references)
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"Echocardiography in 17 adult descendants of first cousins revealed DCM in 2 female siblings and idiopathic left ventricular enlargement in their brother."
The complete affected series for this entity.
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"there were no instances of unreported nonsynonymous variants within GATAD1, indicating highly conserved nucleotide and protein sequences"
Negative result of screening 273 unrelated probands, supporting that GATAD1 disease is rare.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Dilated Cardiomyopathy 2B:

Dilated cardiomyopathy caused by coronary artery disease Not Yet Curated MONDO:0005010
Overlapping Features Ischemic left ventricular dysfunction must be excluded before a diagnosis of idiopathic or familial dilated cardiomyopathy; in this family coronary angiography showed no coronary disease in the proband.
Show evidence (1 reference)
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"Echocardiography was diagnostic for DCM and angiography ruled out coronary artery disease."
Coronary artery disease was specifically excluded in the proband.
Autosomal dominant familial dilated cardiomyopathy Not Yet Curated MONDO:0700335
Overlapping Features Clinically the GATAD1 family resembled ordinary autosomal dominant or sporadic dilated cardiomyopathy; only the consanguinity, the absence of disease in parents and offspring and the linkage analysis pointed to recessive inheritance. Exome data excluded homozygous variants in known dilated cardiomyopathy genes. LMNA-related disease (CMD1A) is a specific consideration because abnormal cardiomyocyte nuclear shape is a hallmark of Lmna-deficient cardiomyopathy.
Show evidence (2 references)
PMID:21965549 SUPPORT PRIMARY RESULT Human Clinical
"In fact, the only clues for recessive inheritance were consanguinity, lack of heart failure in the ancestors of affected family members by history, and lack of DCM in offspring of affected family members by echocardiographic screening."
The GATAD1 phenotype does not distinguish it clinically from dominant disease.
PMID:21965549 SUPPORT BACKGROUND Human Clinical
"abnormal nuclear morphology is a hallmark of DCM caused by knockout of Lmna, a gene that encodes a structural protein of the nuclear membrane"
The overlap in nuclear morphology with LMNA-related disease, restated from earlier mouse work.
🐁

Animal Models

3
Gatad1 cardiomyocyte-specific knockout mouse
Cardiomyocyte deletion from embryonic day 7.5. Mice survived normally to 18 months with normal echocardiographic function, heart weight, histology and cardiomyocyte nuclear shape, and responded normally to transverse aortic constriction, although Nppa and Nppb were mildly raised at 3 and 15 months. Global Gatad1 knockout was lethal at embryonic day 8.5.
Species
Mouse
Genotype
Gatad1 floxed (exons 2-4) with Xmlc2-Cre
Publication
PMID:39641830
Pathograph links
Left Ventricular Dilation and Remodeling fails to recapitulate fidelity: low observes: tissue Loss of Gatad1 in cardiomyocytes does not produce ventricular dilation or dysfunction at baseline or under pressure overload.
Limitations: A null allele confined to cardiomyocytes, whereas patients carry a full-length missense protein in every cell; it cannot test a mutation-specific effect of S102P, a non-cardiomyocyte contribution, or a requirement before Cre expression. Observation stopped at 18 months, and the authors note that genetic background modifiers may matter.
Show evidence (1 reference)
PMID:39641830 SUPPORT PRIMARY RESULT Model Organism
"Gatad1 cKO mutants exhibited normal cardiac function during the aging process up to 18 months of age."
The negative result that makes this a failure to recapitulate.
Globular Cardiomyocyte Nuclei fails to recapitulate fidelity: low observes: cellular Isolated knockout cardiomyocytes have normal nuclear shape.
Limitations: Tests loss of Gatad1, not the S102P protein, and only in mouse cardiomyocytes.
Show evidence (1 reference)
PMID:39641830 SUPPORT PRIMARY RESULT Model Organism
"Unlike the abnormal nuclei shape observed in patients carrying GATAD1 mutations, the nuclei shape of cardiomyocytes remained unaffected by the loss of Gatad1."
The nuclear phenotype is not reproduced.
gatad1 knockout zebrafish
Homozygous knockouts had no phenotype at baseline. With embryonic ethanol exposure plus a high-cholesterol diet they showed reduced swimming capacity, reduced survival from about 7 months, and induction of nppb and vmhc; ventricle size did not differ significantly.
Species
Zebrafish
Genotype
gatad1 13-bp frameshift deletion in exon 2 (TALEN), homozygous
Publication
PMID:28955713
Pathograph links
Chronic Systolic Heart Failure partially recapitulates fidelity: low observes: organism Heart failure-like phenotypes appear only under combined stress and without significant chamber enlargement.
Limitations: A null allele rather than the patient missense; phenotypes required ethanol and high-cholesterol stressors, and ejection fraction could not be measured in the small fish heart. Fish Gatad1 lacks the serine at the position of human Ser102.
Show evidence (1 reference)
PMID:28955713 SUPPORT PRIMARY RESULT Model Organism
"Under stress conditions, longitudinal studies uncovered heart failure (HF)-like phenotypes in stable KO mutants and a tendency toward HF phenotypes in transgenic lines."
Supports the knockout as partially informative for the heart-failure node.
Tg(myl7:GATAD1-S102P) zebrafish
Transgenic fish expressing human GATAD1-S102P in cardiomyocytes began to die at about 13 months, whereas fish expressing wild-type human GATAD1 survived beyond 20 months; one of six mutant-transgenic hearts was enlarged. The authors call this a tendency needing a larger sample.
Species
Zebrafish
Genotype
Cardiomyocyte-specific transgenic expression of human GATAD1-S102P (myl7 promoter)
Publication
PMID:28955713
Pathograph links
Chronic Systolic Heart Failure partially recapitulates fidelity: low observes: organism Reduced survival and a single enlarged heart in fish overexpressing the patient allele, suggesting a possible effect of the mutant protein itself.
Limitations: Overexpression of a human transgene on a wild-type fish background, not the homozygous state; small numbers, and the cardiac enlargement was seen in one of six fish.
Show evidence (1 reference)
PMID:28955713 SUPPORT PRIMARY RESULT Model Organism
"the Tg(myl7:GATAD1S102P) fish started to die around 13 months of age, in contrast to Tg(myl7:GATAD1) fish that survived more than 20 months without any deaths"
Reduced survival of fish expressing the patient allele.
{ }

Source YAML

click to show 
name: Dilated Cardiomyopathy 2B
creation_date: "2026-09-25T13:56:18Z"
category: Mendelian
synonyms:
- CMD2B
- cardiomyopathy, dilated, 2B
- cardiomyopathy, dilated, type 2B
- dilated cardiomyopathy type 2B
- GATAD1-related dilated cardiomyopathy
- familial isolated dilated cardiomyopathy caused by mutation in GATAD1
description: >-
  Dilated cardiomyopathy 2B (CMD2B) is an autosomal recessive, adult-onset,
  nonsyndromic dilated cardiomyopathy attributed to a homozygous missense
  variant, c.304T>C p.(Ser102Pro), in GATAD1, which encodes GATA zinc finger
  domain-containing protein 1. The entity rests on a single consanguineous
  family of Norwegian ancestry: two sisters developed dilated cardiomyopathy
  with heart failure at 50 and 53 years of age and their brother had
  idiopathic left ventricular enlargement at 57, all three homozygous for the
  variant, while thirteen heterozygous relatives had normal hearts into old
  age. The clinical course in that family resembled ordinary adult dilated
  cardiomyopathy and was chronic rather than fulminant, with the two sisters
  still in NYHA class II more than two decades after diagnosis on standard
  heart failure therapy.

  GATAD1 is a ubiquitously expressed protein, found in the nucleus and
  cytoplasm of cardiomyocytes, that co-purifies with the EMSY/KDM5A/SIN3B
  chromatin-regulatory complex, which binds H3K4me3-marked promoters,
  and the discovery paper proposed epigenetic dysregulation as the disease
  mechanism. How the variant damages the heart is not known. The proband's
  myocardium showed a disturbed extranuclear GATAD1 staining pattern and
  abnormally globular cardiomyocyte nuclei; Ser102 is a phosphorylation site whose phosphorylated form binds
  14-3-3 proteins, a binding the proline substitution abolishes in vitro; a
  gatad1 knockout zebrafish develops heart failure-like phenotypes only under
  added stress; and a cardiomyocyte-specific Gatad1 knockout mouse does not
  develop cardiomyopathy. ClinGen classifies the GATAD1-dilated cardiomyopathy
  relationship as Limited.
disease_term:
  preferred_term: dilated cardiomyopathy 2B
  term:
    id: MONDO:0013848
    label: dilated cardiomyopathy 2B
parents:
- familial isolated dilated cardiomyopathy
- Dilated Cardiomyopathy
notes: >-
  Evidence base. All human evidence for CMD2B comes from one family (three
  homozygous siblings, PMID:21965549). Screening the five GATAD1 exons in 273
  unrelated dilated cardiomyopathy probands in the same study found no
  previously unreported nonsynonymous variant. The ClinGen gene-disease validity classification is
  Limited (autosomal recessive; Dilated Cardiomyopathy Gene Curation Expert
  Panel, 2024-08-07), which is the same assertion the parent
  Dilated_Cardiomyopathy entry cites. Frequencies are therefore not assigned to
  phenotypes: three affected individuals cannot support a frequency band, and
  the counts are given in each description instead.

  Not cited as CMD2B evidence. A 2024 cohort of 95 patients with nonischemic
  dilated cardiomyopathy tested on a 233-gene panel reported that carriers of
  GATAD1 variants of uncertain significance had better cardiac function
  parameters than non-carriers (PMID:38664609). Those carriers are not
  described as biallelic and the variants are not described as S102P, so the
  study says nothing about this recessive entity and is not used here. Papers
  on GATAD1 in cancer, stroke-associated blood-brain barrier injury and
  myocardial ischemia-reperfusion concern other biology and are likewise not
  used.

  GeneReviews scope. There is no GATAD1-specific GeneReviews chapter. The
  disease-level "Dilated Cardiomyopathy Overview" (PMID:20301486) is tagged
  because it is the applicable GeneReviews resource for the evaluation of a
  proband with nonsyndromic dilated cardiomyopathy and of at-risk relatives;
  its cached PubMed record holds only the chapter's purpose statement, so it
  is quoted only for the relative-screening purpose on the genetic counselling
  treatment.

  Module conformance. The remodeling and heart-failure nodes conform to
  cardiomyopathy_maladaptive_remodeling. The variant node is deliberately not
  conformed to that module's Primary Cardiomyocyte Insult: the module frames
  the insult as a cardiomyocyte contractile lesion, and the cardiomyocyte
  knockout mouse (PMID:39641830) leaves open whether the GATAD1 lesion acts in
  cardiomyocytes at all. The systolic dysfunction node is not conformed to
  Progressive Contractile Dysfunction because the reported course was stable
  for more than twenty years on treatment rather than progressive.

  Do not confuse CMD2B (GATAD1, OMIM:614672) with the neighbouring recessive
  numbered loci, which are different diseases with different genes, among them
  CMD2A (TNNI3, Dilated_Cardiomyopathy_2A) and CMD2H (GET3/ASNA1,
  Cardiomyopathy_Dilated_2H).
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Consanguineous kindred (the parents of the affected sibship were first
    cousins). All three affected siblings were homozygous for GATAD1 S102P;
    the six unaffected siblings were heterozygous or homozygous for the
    reference allele, and all eight offspring of the affected siblings were
    obligate heterozygotes without dilated cardiomyopathy on echocardiography.
    Linkage modelled as dominant, at any of three penetrance settings, found
    no locus.
  evidence:
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      In summary, the family history and clinical evaluations indicated that
      nonsyndromic DCM was inherited as an autosomal recessive trait.
    explanation: States the recessive mode of inheritance from the pedigree and screening echocardiography.
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      We have clearly shown that the GATAD1-S102P mutation is recessive, as 13
      heterozygous carriers had normal cardiac phenotypes.
    explanation: Heterozygous carriers were unaffected, which is the basis for calling the allele recessive.
  - reference: CGGV:assertion_56933afb-863f-46f5-884d-17522adb31a8-2024-08-07T160000.000Z
    reference_title: GATAD1 / dilated cardiomyopathy (Limited)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "GATAD1 | HGNC:29941 | dilated cardiomyopathy | MONDO:0005021 | AR | Limited"
    explanation: ClinGen records the GATAD1-dilated cardiomyopathy relationship with autosomal recessive inheritance.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Three affected siblings in one consanguineous family. The discovery study
    also screened 273 unrelated dilated cardiomyopathy probands and found no
    previously unreported nonsynonymous GATAD1 variant.
  evidence:
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Echocardiography in 17 adult descendants of first cousins revealed DCM in
      2 female siblings and idiopathic left ventricular enlargement in their
      brother.
    explanation: The complete affected series for this entity.
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      there were no instances of unreported nonsynonymous variants within
      GATAD1, indicating highly conserved nucleotide and protein sequences
    explanation: Negative result of screening 273 unrelated probands, supporting that GATAD1 disease is rare.
progression:
- phase: Adult onset and chronic course
  age_range: diagnosis at 50 to 57 years; followed for more than 20 years
  notes: >-
    The proband presented with heart failure at 50 and her sister was
    diagnosed at 53; both remained in NYHA class II more than two decades
    later on heart failure therapy. The brother had left ventricular
    enlargement at 57 and a borderline ejection fraction at 68, and died of
    cancer at 73. This is a single family, so the course is not a
    generalisable natural history.
  evidence:
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      She has had no history of arrhythmia and, 24 years after her initial
      presentation, is in NYHA class II heart failure with moderate-severe left
      ventricular enlargement and ejection fraction of 25%.
    explanation: Long-term outcome of the proband.
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      She has remained in NYHA class II heart failure 23 years after diagnosis
      with mild left ventricular enlargement and ejection fraction of 40%.
    explanation: Long-term outcome of the affected sister.
pathophysiology:
- name: Homozygous GATAD1 p.Ser102Pro Variant
  description: >-
    The only reported CMD2B allele is c.304T>C in exon 2 of GATAD1, replacing
    serine 102 with proline. It was the single rare variant shared by the two
    exome-sequenced sisters inside the 7q21 homozygous interval, and it was
    absent from 1,558 control and proband chromosomes. The mutant protein is
    present in patient myocardium, so the allele does not act by abolishing
    GATAD1 protein. Whether it is a loss-of-function allele or has a
    mutation-specific effect is unresolved; both models are recorded under
    mechanistic_hypotheses.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: GATAD1
    term:
      id: hgnc:29941
      label: GATAD1
  genetic_context:
    zygosity: HOMOZYGOUS
    variant_origin: GERMLINE
    allele_type: missense
    functional_impact_category: UNKNOWN
    description: >-
      NM_021167 c.304T>C p.(Ser102Pro), homozygous in all three affected
      siblings of a consanguineous family.
  evidence:
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      A solitary mutation in GATAD1 remained, for which the three affected
      siblings were homozygous and which mapped to the 7q21 critical region.
    explanation: Identifies the homozygous GATAD1 variant as the only candidate segregating with disease.
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The resultant S102P substitution replaces a polar hydroxyl serine with a
      nonpolar cyclic proline.
    explanation: Describes the amino acid change.
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      the GATAD1-S102P mutant protein was detected in the proband's myocardium,
      ruling out deficiency of GATAD1 as a consequence of the underlying
      homozygous mutation
    explanation: The mutant protein is present in patient heart, so the allele does not simply abolish GATAD1.
  downstream:
  - target: Loss of Phospho-Ser102-Dependent 14-3-3 Binding
    causal_link_type: DIRECT
    description: >-
      Proline at position 102 removes the phosphorylatable serine, and a
      peptide carrying the substitution does not bind 14-3-3 epsilon.
    evidence:
    - reference: PMID:38605029
      reference_title: Pathogenic mutations of human phosphorylation sites affect protein-protein interactions.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        Neither the non-phosphorylated wild-type peptide nor the peptide with
        the disease-linked S102P mutation showed detectable binding
      explanation: Isothermal titration calorimetry shows the S102P peptide does not bind 14-3-3 epsilon.
  - target: Aberrant GATAD1 Subcellular Distribution in Cardiomyocytes
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Observed in the homozygous proband's myocardium by immunohistochemistry
      and not in control or TPM1-related dilated cardiomyopathy myocardium.
      How the substitution disturbs localization is not established.
    evidence:
    - reference: PMID:21965549
      reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        In contrast, homozygosity for the S102P in GATD1 resulted in a marked
        disturbance in its extranuclear distribution in the proband
      explanation: >-
        Links the homozygous genotype to the altered GATAD1 staining pattern in
        patient heart (GATD1 is a typographical error in the source).
  - target: Globular Cardiomyocyte Nuclei
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Observed in the proband's biopsy and not in control or TPM1-related
      dilated cardiomyopathy myocardium, which the authors read as a
      mutation-specific effect.
    evidence:
    - reference: PMID:21965549
      reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        The similarity of GATAD1 staining patterns and nuclear morphology in
        TPM1-DCM and normal control tissues, distinct from the proband,
        indicates that GATAD1-S102P has a mutation-specific effect.
      explanation: The nuclear abnormality is attributed to the GATAD1 genotype rather than to dilated cardiomyopathy in general.
  - target: Perturbed GATAD1-Associated Chromatin Regulation
    causal_link_type: UNKNOWN
    hypothesis_groups:
    - gatad1_epigenetic_dysregulation
    description: >-
      Proposed by the discovery paper from GATAD1's known chromatin
      associations; not measured for the S102P protein in heart tissue.
  - target: Left Ventricular Dilation and Remodeling
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The genetic evidence (linkage, homozygosity mapping, exome filtering and
      co-segregation in one family) links the genotype to the cardiomyopathy
      without establishing any intermediate step.
    evidence:
    - reference: PMID:21965549
      reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        Linkage analysis and exome sequencing were used as synergistic genomic
        strategies to identify GATAD1 as a gene for AR DCM.
      explanation: Genetic evidence connecting the genotype to dilated cardiomyopathy.
- name: Loss of Phospho-Ser102-Dependent 14-3-3 Binding
  description: >-
    Phosphorylated Ser102 of GATAD1 binds 14-3-3 proteins with low-micromolar
    affinity, and a crystal structure of 14-3-3 epsilon with the
    phosphopeptide has been solved. Binding requires the phosphate: neither
    the unphosphorylated peptide, the S102P peptide nor phosphomimetic
    aspartate or glutamate peptides bind. Ser102 phosphorylation has been
    detected only in murine heart tissue, which the authors take as a hint of a
    heart-specific function. Full-length S102P GATAD1 in HEK293 cells kept the
    same interaction partners as wild type, so the known complexes are not
    disrupted; the effect of losing the 14-3-3 interaction in cardiomyocytes
    has not been tested.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: GATAD1
    term:
      id: hgnc:29941
      label: GATAD1
  molecular_functions:
  - preferred_term: 14-3-3 protein binding (phospho-Ser102)
    term:
      id: GO:0071889
      label: 14-3-3 protein binding
    modifier: ABSENT
  evidence:
  - reference: PMID:38605029
    reference_title: Pathogenic mutations of human phosphorylation sites affect protein-protein interactions.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      We find that this phosphorylation site mediates interaction with 14-3-3
      family proteins.
    explanation: Identifies the phosphorylation-dependent 14-3-3 interaction at Ser102.
  - reference: PMID:38605029
    reference_title: Pathogenic mutations of human phosphorylation sites affect protein-protein interactions.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      Overall, the AP-MS data for all the GATAD1 mutant variants was very
      similar to the wild-type with the same interaction partners identified in
      all
    explanation: >-
      The S102P substitution does not disrupt the other known GATAD1
      interactions in HEK293 cells, which narrows its measurable molecular
      effect to the phospho-dependent 14-3-3 binding.
  - reference: PMID:38605029
    reference_title: Pathogenic mutations of human phosphorylation sites affect protein-protein interactions.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: >-
      Intriguingly, although GATAD1 is expressed in many tissues, the only
      evidence for phosphorylation of this site comes from murine heart tissue,
      indicative of a heart-specific function
    explanation: The phosphorylation site has so far been observed only in heart, restating published phosphoproteomic data.
  downstream:
  - target: Aberrant GATAD1 Subcellular Distribution in Cardiomyocytes
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - gatad1_14_3_3_nucleocytoplasmic
    description: >-
      Proposed link: 14-3-3 binding may mask a nuclear localization signal and
      so regulate GATAD1 nucleocytoplasmic transport. Not tested in
      cardiomyocytes, and tagged S102P GATAD1 localized normally to the nucleus
      in HEK293 cells, where Ser102 is probably not phosphorylated.
    evidence:
    - reference: PMID:38605029
      reference_title: Pathogenic mutations of human phosphorylation sites affect protein-protein interactions.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        suggest that 14-3-3 binding affects GATAD1 nucleocytoplasmic transport
        by masking a nuclear localisation signal
      explanation: The authors' structural inference; it is stated as a suggestion.
    - reference: PMID:38605029
      reference_title: Pathogenic mutations of human phosphorylation sites affect protein-protein interactions.
      supports: REFUTE
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        This observation suggests that the point mutations do not affect the
        nuclear localization of GATAD1.
      explanation: >-
        In HEK293 cells the S102P protein localized to the nucleus like wild
        type, which argues against a simple localization defect, although these
        cells may not phosphorylate Ser102.
- name: Aberrant GATAD1 Subcellular Distribution in Cardiomyocytes
  description: >-
    In normal left ventricle GATAD1 stains the nucleus and cytoplasm in a
    homogeneous, striated pattern; in zebrafish cardiomyocytes tagged Gatad1
    localizes to the nucleus and the sarcomeric I-band. In the homozygous
    proband the extranuclear distribution was markedly disturbed, while actin
    staining was normal. This is a single-biopsy observation.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  cellular_components:
  - preferred_term: nucleus
    term:
      id: GO:0005634
      label: nucleus
  - preferred_term: I band
    term:
      id: GO:0031674
      label: I band
  evidence:
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Within healthy left ventricular tissue, GATAD1 localized to the nucleus
      and cytoplasm with a homogenous, striated staining pattern
    explanation: Normal cardiac localization of GATAD1, the reference against which the patient pattern is abnormal.
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      In contrast, homozygosity for the S102P in GATD1 resulted in a marked
      disturbance in its extranuclear distribution in the proband
    explanation: The abnormal GATAD1 distribution in patient myocardium.
  - reference: PMID:28955713
    reference_title: Modeling GATAD1-Associated Dilated Cardiomyopathy in Adult Zebrafish.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      Together, these data indicate that Gatad1-GFP is localized to both the
      nucleus and the I-band region of myofibrils.
    explanation: Nuclear and sarcomeric localization of Gatad1 in zebrafish cardiomyocytes.
- name: Globular Cardiomyocyte Nuclei
  description: >-
    Cardiomyocyte nuclei in the proband's endomyocardial biopsy were globular
    rather than the normal elongated spindle shape. The authors compare this
    with the abnormal nuclear morphology of Lmna-knockout dilated
    cardiomyopathy, but GATAD1 is not a nuclear envelope protein and the
    finding has not been reproduced: cardiomyocytes from the Gatad1
    cardiomyocyte knockout mouse had normal nuclei.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: nucleus organization
    term:
      id: GO:0006997
      label: nucleus organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Additionally, myocyte nuclei in the proband had a unique globular
      morphology, contrasting with the elongated spindle shape observed in the
      controls.
    explanation: Documents the nuclear shape abnormality in patient myocardium.
  - reference: PMID:39641830
    reference_title: Loss of GATAD1 in cardiomyocyte does not cause cardiomyopathy in mice.
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      Unlike the abnormal nuclei shape observed in patients carrying GATAD1
      mutations, the nuclei shape of cardiomyocytes remained unaffected by the
      loss of Gatad1.
    explanation: >-
      Loss of Gatad1 in mouse cardiomyocytes does not reproduce the nuclear
      phenotype, so the finding is either specific to S102P, specific to
      human, or secondary.
- name: Perturbed GATAD1-Associated Chromatin Regulation
  description: >-
    Hypothesized node. GATAD1 co-purifies with the EMSY/KDM5A/SIN3B complex
    (with PHF12 and RBBP4/7), which binds H3K4me3-marked active promoters, and
    it was first identified as an H3K4me3-associated protein; HDAC1 and HDAC2
    are also reported binding partners. The discovery paper inferred that
    GATAD1 S102P causes dilated cardiomyopathy through epigenetic
    dysregulation, by analogy with the dilated cardiomyopathy of combined
    Hdac1/Hdac2 cardiac knockout mice. No study has measured chromatin
    occupancy or gene expression driven by the S102P protein, and the variant
    does not change GATAD1's complex partners in HEK293 cells.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: GATAD1
    term:
      id: hgnc:29941
      label: GATAD1
  cellular_components:
  - preferred_term: Sin3-type complex (EMSY/KDM5A/SIN3B)
    term:
      id: GO:0070822
      label: Sin3-type complex
  biological_processes:
  - preferred_term: regulation of DNA-templated transcription
    term:
      id: GO:0006355
      label: regulation of DNA-templated transcription
    modifier: DYSREGULATED
  evidence:
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      GATAD1 binds to a histone modification site that regulates gene
      expression. Consistent with murine DCM caused by genetic disruption of
      histone deacetylases, the data implicate an inherited basis for
      epigenetic dysregulation in human heart failure.
    explanation: The discovery paper's mechanistic inference; it rests on GATAD1's known chromatin association, not on a measurement in patients.
  - reference: PMID:38605029
    reference_title: Pathogenic mutations of human phosphorylation sites affect protein-protein interactions.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      This included several well-known GATAD1 binders such as the
      transcriptional regulators KDM5A, RBBP7/4 PHF12, and SIN3B. Together,
      these proteins form the EMSY complex, which binds to H3K4me3-marked,
      active promoters
    explanation: Affinity purification places GATAD1 in the EMSY chromatin-regulatory complex.
  - reference: PMID:26841866
    reference_title: Recruitment of the Mammalian Histone-modifying EMSY Complex to Target Genes Is Regulated by ZNF131.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: >-
      Recent work from others and us revealed interactions between the Sin3/HDAC
      complex, the H3K4me3 demethylase KDM5A, GATAD1, and EMSY.
    explanation: Independent proteomic group placing GATAD1 with the Sin3/HDAC complex and KDM5A.
  - reference: PMID:38605029
    reference_title: Pathogenic mutations of human phosphorylation sites affect protein-protein interactions.
    supports: REFUTE
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      Overall, the AP-MS data for all the GATAD1 mutant variants was very
      similar to the wild-type with the same interaction partners identified in
      all
    explanation: >-
      The S102P protein keeps its chromatin-complex partners, so if the
      variant perturbs chromatin regulation it does not do so by failing to
      assemble with the EMSY complex.
  downstream:
  - target: Left Ventricular Dilation and Remodeling
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - gatad1_epigenetic_dysregulation
    description: >-
      Hypothesized, by analogy with Hdac1/Hdac2 cardiac double-knockout mice;
      no GATAD1 target genes in heart have been identified.
    evidence:
    - reference: PMID:21965549
      reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      quote_role: BACKGROUND
      snippet: human HDAC1 and HDAC2 are binding partners with GATAD1
      explanation: >-
        The link to cardiomyopathy runs through binding partners whose combined
        cardiac loss causes dilated cardiomyopathy in mice; an argument by
        analogy, not a demonstration.
- name: Left Ventricular Dilation and Remodeling
  description: >-
    Left ventricular enlargement was present in all three homozygous siblings,
    with a dilated, poorly contracting ventricle in the two sisters and
    enlargement with a borderline ejection fraction in the brother, which the
    authors describe as an intermediate phenotype of dilated cardiomyopathy.
    The proband's endomyocardial biopsy showed moderate myocyte hypertrophy,
    mild focal interstitial fibrosis and mild diffuse endocardial fibrosis,
    the non-specific remodeling of a chronic cardiomyopathy.
  biological_scale: TISSUE
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Ventricular Remodeling"
  cell_types:
  - preferred_term: cardiomyocyte
    term:
      id: CL:0000746
      label: cardiac muscle cell
  - preferred_term: cardiac fibroblast
    term:
      id: CL:0002548
      label: fibroblast of cardiac tissue
  biological_processes:
  - preferred_term: cardiac muscle hypertrophy
    term:
      id: GO:0003300
      label: cardiac muscle hypertrophy
    modifier: INCREASED
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  locations:
  - preferred_term: left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  evidence:
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Left ventricular endomyocardial biopsy revealed moderate myocyte
      hypertrophy, mild focal interstitial fibrosis, and mild diffuse
      endocardial fibrosis, consistent with a chronic cardiomyopathy.
    explanation: Histological remodeling in the proband's left ventricle.
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Echocardiography in 17 adult descendants of first cousins revealed DCM in
      2 female siblings and idiopathic left ventricular enlargement in their
      brother.
    explanation: Ventricular enlargement in every homozygous sibling.
  downstream:
  - target: Left Ventricular Systolic Dysfunction
    causal_link_type: DIRECT
    description: >-
      The dilated, remodeled ventricle contracts poorly; ejection fraction was
      21% in the proband and 43% in her sister at diagnosis.
  - target: Dilated cardiomyopathy
    causal_link_type: DIRECT
  - target: Left ventricular dilatation
    causal_link_type: DIRECT
  - target: Cardiomyocyte hypertrophy
    causal_link_type: DIRECT
  - target: Interstitial cardiac fibrosis
    causal_link_type: DIRECT
- name: Left Ventricular Systolic Dysfunction
  description: >-
    Reduced left ventricular ejection fraction in the two affected sisters
    (21% and 43% at diagnosis; 25% and 40% more than twenty years later) and a
    borderline 50% on angiography in the brother at 68.
  biological_scale: ORGANISM
  biological_processes:
  - preferred_term: heart contraction
    term:
      id: GO:0060047
      label: heart contraction
    modifier: DECREASED
  locations:
  - preferred_term: left ventricle
    term:
      id: UBERON:0002084
      label: heart left ventricle
  evidence:
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      is in NYHA class II heart failure with moderate-severe left ventricular
      enlargement and ejection fraction of 25%
    explanation: Persistent severe systolic dysfunction in the proband.
  downstream:
  - target: Chronic Systolic Heart Failure
    causal_link_type: DIRECT
  - target: Reduced left ventricular ejection fraction
    causal_link_type: DIRECT
- name: Chronic Systolic Heart Failure
  description: >-
    Both affected sisters developed clinical heart failure (the proband
    presented with it at 50), which was controlled in NYHA class II on
    standard therapy for more than two decades. No sudden death, ventricular
    arrhythmia or heart transplantation was reported in the family.
  biological_scale: ORGANISM
  conforms_to: "cardiomyopathy_maladaptive_remodeling#Structural Cardiac Impairment and Heart Failure"
  biological_processes:
  - preferred_term: heart contraction
    term:
      id: GO:0060047
      label: heart contraction
    modifier: DECREASED
  evidence:
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: presented at age 50 years with heart failure and cardiomegaly
    explanation: Clinical heart failure at presentation in the proband.
  downstream:
  - target: Congestive heart failure
    causal_link_type: DIRECT
  - target: Cardiomegaly
    causal_link_type: DIRECT
mechanistic_hypotheses:
- hypothesis_group_id: gatad1_epigenetic_dysregulation
  hypothesis_label: S102P disturbs GATAD1-dependent chromatin regulation in the heart
  status: EMERGING
  description: >-
    The model proposed with the gene discovery: GATAD1 works in an
    H3K4me3-associated chromatin-regulatory complex, and the variant perturbs
    cardiac gene expression, as combined loss of the complex partners Hdac1 and
    Hdac2 does in mouse heart. It is an inference from GATAD1's interaction
    partners. No GATAD1-dependent cardiac gene set has been measured, and the
    S102P protein keeps its complex partners in HEK293 cells.
  evidence:
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      While the specific effects of GATAD1-S102P on nucleosome protein
      interactions and downstream gene expression are unknown, the mutation
      leads to a heart-specific phenotype and implicates epigenetic
      dysregulation as a novel basis for human DCM.
    explanation: States the hypothesis and that its molecular basis is unmeasured.
- hypothesis_group_id: gatad1_14_3_3_nucleocytoplasmic
  hypothesis_label: Loss of phospho-Ser102/14-3-3 binding alters GATAD1 nucleocytoplasmic distribution
  status: EMERGING
  description: >-
    Ser102, the residue the variant replaces, is a phosphorylation site whose
    phosphorylated form binds 14-3-3 proteins, possibly masking a nuclear
    localization signal. Losing it could explain the disturbed GATAD1
    distribution seen in the proband's myocardium. The binding is shown only
    with peptides and recombinant protein, and in HEK293 cells the tagged
    S102P protein still reached the nucleus.
  evidence:
  - reference: PMID:38605029
    reference_title: Pathogenic mutations of human phosphorylation sites affect protein-protein interactions.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      Follow-up experiments reveal the structural basis of this interaction and
      suggest that 14-3-3 binding affects GATAD1 nucleocytoplasmic transport by
      masking a nuclear localisation signal.
    explanation: The hypothesis as proposed by the authors of the interaction study.
- hypothesis_group_id: gatad1_s102p_mutation_specific
  hypothesis_label: S102P acts through a mutation-specific effect rather than simple loss of GATAD1
  status: EMERGING
  description: >-
    The mutant protein is present in patient heart, the patient nuclear and
    localization abnormalities are absent from the Gatad1 cardiomyocyte
    knockout mouse, and that mouse has no cardiomyopathy. These observations
    favour an effect specific to the S102P protein over simple deficiency.
    Heterozygous carriers are unaffected, so any such effect would have to be
    dose-dependent. The authors of the mouse study propose testing it in an
    S102P knock-in.
  evidence:
  - reference: PMID:39641830
    reference_title: Loss of GATAD1 in cardiomyocyte does not cause cardiomyopathy in mice.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      While the recessive mutation is often considered a loss-of-function
      mutation, it remains possible that the S102P mutation could be a
      gain-of-function mutation with dose-dependent effects that impair
      cellular functions.
    explanation: The mouse study's reading of its negative result.
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The similarity of GATAD1 staining patterns and nuclear morphology in
      TPM1-DCM and normal control tissues, distinct from the proband,
      indicates that GATAD1-S102P has a mutation-specific effect.
    explanation: The discovery paper's reading of the patient histology.
- hypothesis_group_id: gatad1_loss_of_function
  hypothesis_label: S102P is a recessive loss-of-function allele
  status: EMERGING
  description: >-
    Recessive inheritance with healthy heterozygotes is the usual signature of
    loss of function, and gatad1 knockout zebrafish develop heart
    failure-like phenotypes when stressed. Against it, the mutant protein is
    present in patient myocardium, and deleting Gatad1 in mouse cardiomyocytes
    causes no cardiomyopathy up to 18 months or after pressure overload. The
    mouse result does not exclude a requirement for GATAD1 in other cardiac
    cell types or in cardiomyocyte progenitors before the Cre driver acts. A
    separate myocardium-specific Gatad1 knockout fared worse after
    ischemia-reperfusion, with GATAD1 acting as a transcriptional regulator of
    fatty acid and glucose oxidation genes; like the zebrafish result, the
    requirement shows only under an added stress, and ischemic injury is not
    the disease modelled here.
  evidence:
  - reference: PMID:39626862
    reference_title: GATAD1 is involved in sphingosylphosphorylcholine-attenuated myocardial ischemia-reperfusion injury by modulating myocardial fatty acid oxidation and glucose oxidation.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      myocardium-specific Gatad1 knockout (Gatad1 CKO) significantly increased
      the myocardial infarct size, impaired cardiac function in I/R mice
    explanation: >-
      Loss of Gatad1 in mouse myocardium reduces tolerance of an acute ischemic
      stress; indirect for dilated cardiomyopathy, which this model does not
      test.
  - reference: PMID:28955713
    reference_title: Modeling GATAD1-Associated Dilated Cardiomyopathy in Adult Zebrafish.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      Under stress conditions, longitudinal studies uncovered heart failure
      (HF)-like phenotypes in stable KO mutants and a tendency toward HF
      phenotypes in transgenic lines.
    explanation: Loss of gatad1 in zebrafish produces heart failure-like phenotypes under stress.
  - reference: PMID:39641830
    reference_title: Loss of GATAD1 in cardiomyocyte does not cause cardiomyopathy in mice.
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      Together, these observations suggest that deletion of Gatad1 in
      cardiomyocytes does not induce cardiomyopathy during aging or affect the
      response to pressure overload stress in mice.
    explanation: Cardiomyocyte loss of Gatad1 is not sufficient for cardiomyopathy in mice.
phenotypes:
- category: Cardiovascular
  name: Dilated cardiomyopathy
  description: >-
    Dilated cardiomyopathy diagnosed by echocardiography, with coronary
    disease excluded by angiography, in the two affected sisters at 50 and 53
    years; the brother had the intermediate phenotype of left ventricular
    enlargement at 57.
  diagnostic: true
  phenotype_term:
    preferred_term: Dilated cardiomyopathy
    term:
      id: HP:0001644
      label: Dilated cardiomyopathy
    onset:
      onset_category: ADULT
      min_age_years: 50
      max_age_years: 57
  evidence:
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Echocardiography was diagnostic for DCM and angiography ruled out
      coronary artery disease.
    explanation: Diagnosis of dilated cardiomyopathy in the proband with ischemic disease excluded.
  - reference: PMID:39641830
    reference_title: Loss of GATAD1 in cardiomyocyte does not cause cardiomyopathy in mice.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      presented with full penetrance adult-onset DCM and heart failure in their
      fifties, being 50, 53 and 57 years of age
    explanation: >-
      Restates the ages at diagnosis of the three homozygotes from the
      discovery paper; "full penetrance" here describes three of three
      homozygous siblings.
- category: Cardiovascular
  name: Left ventricular dilatation
  description: >-
    Present in all three homozygous siblings; in the brother it was the only
    finding at diagnosis (idiopathic left ventricular enlargement, 59 mm
    diastolic dimension against a 55 mm 95th percentile).
  phenotype_term:
    preferred_term: Left ventricular dilatation
    term:
      id: HP:4000141
      label: Left ventricular dilatation
  evidence:
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      was diagnosed with idiopathic left ventricular enlargement, a known
      intermediate phenotype of DCM
    explanation: Left ventricular enlargement as the phenotype of the affected brother.
- category: Cardiovascular
  name: Reduced left ventricular ejection fraction
  description: >-
    Ejection fraction 21% in the proband and 43% in her sister at diagnosis;
    the brother's was preserved at diagnosis (54%) and borderline (50%) at 68.
  phenotype_term:
    preferred_term: Reduced left ventricular ejection fraction
    term:
      id: HP:0012664
      label: Reduced left ventricular ejection fraction
  evidence:
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      She has remained in NYHA class II heart failure 23 years after diagnosis
      with mild left ventricular enlargement and ejection fraction of 40%.
    explanation: Reduced ejection fraction in the affected sister.
- category: Cardiovascular
  name: Congestive heart failure
  description: >-
    Clinical heart failure in both affected sisters, NYHA class II on
    treatment at long-term follow-up.
  phenotype_term:
    preferred_term: Heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
    temporality: CHRONIC
  evidence:
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: presented at age 50 years with heart failure and cardiomegaly
    explanation: Heart failure at presentation in the proband.
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      She has remained in NYHA class II heart failure 23 years after diagnosis
      with mild left ventricular enlargement and ejection fraction of 40%.
    explanation: Chronic heart failure in the affected sister.
- category: Cardiovascular
  name: Cardiomegaly
  description: >-
    At presentation in the proband and on chest radiography in the brother at
    68.
  phenotype_term:
    preferred_term: Cardiomegaly
    term:
      id: HP:0001640
      label: Cardiomegaly
  evidence:
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      At age 68 years, he had cardiomegaly on chest radiography and a
      borderline ejection fraction of 50% on left ventricular angiography.
    explanation: Cardiomegaly in the affected brother.
- category: Cardiovascular
  name: Atrial fibrillation
  description: >-
    Persistent atrial fibrillation in one of the three affected siblings (the
    younger sister), treated by atrioventricular node ablation with pacemaker
    implantation. The proband had no arrhythmia over 24 years. With one case,
    whether atrial fibrillation is part of CMD2B or a complication of long
    standing dilated cardiomyopathy cannot be separated, so no causal edge is
    drawn to it.
  phenotype_term:
    preferred_term: Atrial fibrillation
    term:
      id: HP:0005110
      label: Atrial fibrillation
    temporality: CHRONIC
  evidence:
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Her treatment included furosemide, metoprolol, losartan, spironolactone,
      warfarin, and AV node ablation with pacemaker implantation for
      persistent atrial fibrillation.
    explanation: Persistent atrial fibrillation in the affected sister.
- category: Cardiovascular
  name: Left ventricular thrombus
  description: >-
    An apical left ventricular thrombus in the proband, treated with warfarin.
    One case; the source does not attribute it to a mechanism, so no causal
    edge is drawn to it.
  phenotype_term:
    preferred_term: Left ventricular apical thrombus
    term:
      id: HP:0040412
      label: Left ventricular thrombus
  evidence:
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Her medical therapy included digoxin, furosemide, carvedilol, enalapril,
      spironolactone, and warfarin (for apical thrombus).
    explanation: Records the apical thrombus in the proband.
- category: Cardiovascular
  name: Cardiomyocyte hypertrophy
  description: >-
    Moderate myocyte hypertrophy on the proband's left ventricular
    endomyocardial biopsy.
  phenotype_term:
    preferred_term: Cardiomyocyte hypertrophy
    term:
      id: HP:0031319
      label: Cardiomyocyte hypertrophy
  evidence:
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Left ventricular endomyocardial biopsy revealed moderate myocyte
      hypertrophy, mild focal interstitial fibrosis, and mild diffuse
      endocardial fibrosis, consistent with a chronic cardiomyopathy.
    explanation: Biopsy finding in the proband.
- category: Cardiovascular
  name: Interstitial cardiac fibrosis
  description: >-
    Mild focal interstitial fibrosis, with mild diffuse endocardial fibrosis,
    on the proband's biopsy.
  phenotype_term:
    preferred_term: Interstitial cardiac fibrosis
    term:
      id: HP:0031329
      label: Interstitial cardiac fibrosis
  evidence:
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Left ventricular endomyocardial biopsy revealed moderate myocyte
      hypertrophy, mild focal interstitial fibrosis, and mild diffuse
      endocardial fibrosis, consistent with a chronic cardiomyopathy.
    explanation: Biopsy finding in the proband.
histopathology:
- name: Globular cardiomyocyte nuclei
  finding_term:
    preferred_term: globular cardiomyocyte nuclei
    term:
      id: HP:0031331
      label: Abnormal cardiomyocyte morphology
  description: >-
    Cardiomyocyte nuclei in the proband's biopsy were globular instead of
    spindle-shaped; not seen in control or TPM1-related dilated cardiomyopathy
    myocardium.
  evidence:
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Additionally, myocyte nuclei in the proband had a unique globular
      morphology, contrasting with the elongated spindle shape observed in the
      controls.
    explanation: The nuclear finding on the proband's biopsy.
  notes: >-
    Bound to the general cardiomyocyte morphology term. The OLS HPO searches
    "cardiomyocyte nucle" and "nuclear morphology" returned no cardiomyocyte
    nuclear-shape term (the only hit, HP:0020278, concerns lymph-node
    lymphocytes).
- name: Disturbed extranuclear GATAD1 immunostaining
  description: >-
    On GATAD1 immunohistochemistry of the proband's biopsy the extranuclear
    staining was markedly disturbed, whereas normal and TPM1-related dilated
    cardiomyopathy myocardium showed a homogeneous striated pattern. Actin
    staining was normal.
  evidence:
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      In contrast, homozygosity for the S102P in GATD1 resulted in a marked
      disturbance in its extranuclear distribution in the proband
    explanation: The GATAD1 staining abnormality on the proband's biopsy.
genetic:
- name: GATAD1
  gene_term:
    preferred_term: GATAD1
    term:
      id: hgnc:29941
      label: GATAD1
  association: Pathogenic Variants
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  features: >-
    One allele reported: homozygous c.304T>C p.(Ser102Pro) in exon 2, in a
    consanguineous Norwegian-ancestry family. It was absent from HapMap, 1000
    Genomes, 474 ancestry-matched controls and 273 unrelated dilated
    cardiomyopathy probands. Thirteen heterozygous relatives, examined up to
    their eighties, had no myocardial disease.
  evidence:
  - reference: CGGV:assertion_56933afb-863f-46f5-884d-17522adb31a8-2024-08-07T160000.000Z
    reference_title: GATAD1 / dilated cardiomyopathy (Limited)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "GATAD1 | HGNC:29941 | dilated cardiomyopathy | MONDO:0005021 | AR | Limited"
    explanation: ClinGen classifies the GATAD1-dilated cardiomyopathy relationship as Limited with autosomal recessive inheritance.
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The mutation, absent in HapMap, 1000 Genomes, and 474 ethnically matched
      controls, altered a conserved residue of GATAD1, encoding GATA zinc
      finger domain-containing protein 1. Thirteen relatives were heterozygous
      mutation carriers with no evidence of myocardial disease, even at
      advanced ages.
    explanation: Variant rarity, residue conservation and unaffected heterozygous carriers.
  notes: >-
    ClinGen Limited means the gene-disease relationship rests on too little
    genetic evidence to be used confidently in clinical interpretation. The
    gene is recorded as causative here because this entry is defined by the
    GATAD1-linked family, not because causation is settled.
variants:
- name: GATAD1 p.Ser102Pro
  description: >-
    The only CMD2B allele reported (NM_021167.5:c.304T>C), homozygous in three
    affected siblings. The residue lies in a stretch (Gly79 to Ile136) that is
    fully conserved across mammals; fish carry serines at the neighbouring
    positions instead. ClinVar (VCV000031656, retrieved 2026-09-25) lists it
    as Pathogenic for dilated cardiomyopathy 2B with the review status "no
    assertion criteria provided" on a single submission (SCV000045643); no
    clinical_significance is set here because that record is not an
    independent classification and ClinGen rates the gene-disease
    relationship Limited.
  gene:
    preferred_term: GATAD1
    term:
      id: hgnc:29941
      label: GATAD1
  variant_type: single nucleotide variant
  identifiers:
  - "c.304T>C"
  - clinvar:VCV000031656
  - dbSNP:rs387907188
  evidence:
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The identified missense mutation was a c.304 T>C nucleotide transition in
      exon 2 of GATAD1
    explanation: Gives the nucleotide change and exon.
  - reference: PMID:28955713
    reference_title: Modeling GATAD1-Associated Dilated Cardiomyopathy in Adult Zebrafish.
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      In mammals, the peptide sequence surrounding the human GATAD1-S102P
      mutation, ranging from G79 to I136, is 100% conserved
    explanation: Sequence conservation around the variant from the zebrafish study's alignment.
diagnosis:
- name: Echocardiography
  description: >-
    Echocardiography established the diagnosis in the proband and identified
    the two further affected siblings among sixteen screened relatives;
    screening of the eight offspring of affected siblings was normal.
  diagnosis_term:
    preferred_term: echocardiography
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  evidence:
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Echocardiography was diagnostic for DCM and angiography ruled out
      coronary artery disease.
    explanation: Echocardiographic diagnosis in the proband.
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Two of eight asymptomatic siblings of the proband were found to have
      cardiomyopathy in the absence of established risk factors for coronary
      and myopathic heart disease.
    explanation: Screening echocardiography detected disease in asymptomatic siblings.
- name: Coronary Angiography
  description: >-
    Used to exclude coronary artery disease as the cause of left ventricular
    dysfunction before the diagnosis of idiopathic dilated cardiomyopathy.
  diagnosis_term:
    preferred_term: coronary angiography
    term:
      id: NCIT:C100085
      label: Coronary Angiography
  evidence:
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Echocardiography was diagnostic for DCM and angiography ruled out
      coronary artery disease.
    explanation: Angiographic exclusion of ischemic heart disease in the proband.
- name: Endomyocardial Biopsy
  description: >-
    Performed in the proband. It showed non-specific chronic cardiomyopathy
    changes and, on GATAD1 immunostaining, the abnormal GATAD1 distribution
    and globular nuclei; it is not a diagnostic test for CMD2B.
  diagnosis_term:
    preferred_term: endomyocardial biopsy
    term:
      id: NCIT:C51674
      label: Endomyocardial Biopsy
  evidence:
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Left ventricular endomyocardial biopsy revealed moderate myocyte
      hypertrophy, mild focal interstitial fibrosis, and mild diffuse
      endocardial fibrosis, consistent with a chronic cardiomyopathy.
    explanation: Biopsy findings in the proband.
- name: Exome Sequencing
  description: >-
    The variant was found by exome sequencing of two affected sisters after
    linkage and homozygosity mapping. Confirming the diagnosis in a new
    patient requires biallelic GATAD1 variants; with a single reported allele
    and a ClinGen Limited classification, a GATAD1 result should be
    interpreted with caution.
  diagnosis_term:
    preferred_term: whole exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Exome sequencing of the affected sisters was then used as a complementary
      strategy for mutation discovery.
    explanation: Exome sequencing identified the variant.
differential_diagnoses:
- name: Dilated cardiomyopathy caused by coronary artery disease
  description: >-
    Ischemic left ventricular dysfunction must be excluded before a diagnosis
    of idiopathic or familial dilated cardiomyopathy; in this family coronary
    angiography showed no coronary disease in the proband.
  disease_term:
    preferred_term: coronary artery disease
    term:
      id: MONDO:0005010
      label: coronary artery disorder
  evidence:
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Echocardiography was diagnostic for DCM and angiography ruled out
      coronary artery disease.
    explanation: Coronary artery disease was specifically excluded in the proband.
- name: Autosomal dominant familial dilated cardiomyopathy
  description: >-
    Clinically the GATAD1 family resembled ordinary autosomal dominant or
    sporadic dilated cardiomyopathy; only the consanguinity, the absence of
    disease in parents and offspring and the linkage analysis pointed to
    recessive inheritance. Exome data excluded homozygous variants in known
    dilated cardiomyopathy genes. LMNA-related disease (CMD1A) is a specific
    consideration because abnormal cardiomyocyte nuclear shape is a hallmark of
    Lmna-deficient cardiomyopathy.
  disease_term:
    preferred_term: familial isolated dilated cardiomyopathy
    term:
      id: MONDO:0700335
      label: familial isolated dilated cardiomyopathy
  evidence:
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      In fact, the only clues for recessive inheritance were consanguinity,
      lack of heart failure in the ancestors of affected family members by
      history, and lack of DCM in offspring of affected family members by
      echocardiographic screening.
    explanation: The GATAD1 phenotype does not distinguish it clinically from dominant disease.
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      abnormal nuclear morphology is a hallmark of DCM caused by knockout of
      Lmna, a gene that encodes a structural protein of the nuclear membrane
    explanation: The overlap in nuclear morphology with LMNA-related disease, restated from earlier mouse work.
treatments:
- name: Beta-Blocker Therapy
  description: >-
    Carvedilol in the proband and metoprolol in the sister and brother, as
    part of standard heart failure therapy. No CMD2B-specific trial exists;
    use follows general dilated cardiomyopathy management.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: carvedilol
      term:
        id: CHEBI:3441
        label: carvedilol
    - preferred_term: metoprolol
      term:
        id: CHEBI:6904
        label: metoprolol
  target_mechanisms:
  - target: Left Ventricular Dilation and Remodeling
    description: Neurohormonal blockade of adverse remodeling in the dilated ventricle.
  evidence:
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Her medical therapy included digoxin, furosemide, carvedilol, enalapril,
      spironolactone, and warfarin (for apical thrombus).
    explanation: Carvedilol was part of the proband's long-term therapy.
- name: ACE Inhibitor or Angiotensin Receptor Blocker Therapy
  description: >-
    Enalapril in the proband, losartan in the sister and captopril in the
    brother. General dilated cardiomyopathy management; no CMD2B-specific
    evidence of efficacy.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: enalapril
      term:
        id: CHEBI:4784
        label: enalapril
    - preferred_term: losartan
      term:
        id: CHEBI:6541
        label: losartan
    - preferred_term: captopril
      term:
        id: CHEBI:3380
        label: captopril
  target_mechanisms:
  - target: Left Ventricular Dilation and Remodeling
    description: Renin-angiotensin blockade of adverse remodeling.
  evidence:
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: He was treated with furosemide, metoprolol, and captopril.
    explanation: ACE inhibitor therapy in the affected brother.
- name: Mineralocorticoid Receptor Antagonist Therapy
  description: >-
    Spironolactone in both affected sisters, as part of standard heart failure
    therapy.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: spironolactone
      term:
        id: CHEBI:9241
        label: spironolactone
  target_mechanisms:
  - target: Left Ventricular Dilation and Remodeling
    description: Aldosterone blockade of adverse remodeling.
  evidence:
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Her treatment included furosemide, metoprolol, losartan, spironolactone,
      warfarin, and AV node ablation with pacemaker implantation for
      persistent atrial fibrillation.
    explanation: Spironolactone in the affected sister.
- name: Loop Diuretic and Digoxin
  description: >-
    Furosemide in all three affected siblings and digoxin in the proband, for
    congestion and symptom control.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: furosemide
      term:
        id: CHEBI:47426
        label: furosemide
    - preferred_term: digoxin
      term:
        id: CHEBI:4551
        label: digoxin
  target_phenotypes:
  - preferred_term: Heart failure
    term:
      id: HP:0001635
      label: Congestive heart failure
  target_mechanisms:
  - target: Congestive heart failure
    description: Relief of congestion; digoxin adds inotropic and rate-control effects.
  evidence:
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Her medical therapy included digoxin, furosemide, carvedilol, enalapril,
      spironolactone, and warfarin (for apical thrombus).
    explanation: Furosemide and digoxin in the proband.
- name: Anticoagulation
  description: >-
    Warfarin for the proband's apical left ventricular thrombus and for the
    sister's persistent atrial fibrillation.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: anticoagulation therapy
    term:
      id: NCIT:C63341
      label: Anticoagulation Therapy
    therapeutic_agent:
    - preferred_term: warfarin
      term:
        id: CHEBI:10033
        label: warfarin
  target_phenotypes:
  - preferred_term: Left ventricular thrombus
    term:
      id: HP:0040412
      label: Left ventricular thrombus
  target_mechanisms:
  - target: Left ventricular thrombus
    description: Treatment of the intracardiac thrombus and prevention of embolism.
  evidence:
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Her medical therapy included digoxin, furosemide, carvedilol, enalapril,
      spironolactone, and warfarin (for apical thrombus).
    explanation: Warfarin for the apical thrombus in the proband.
- name: Atrioventricular Node Ablation With Pacemaker Implantation
  description: >-
    Used for rate control of persistent atrial fibrillation in the affected
    sister: ablation of the atrioventricular node followed by permanent
    pacing.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: atrioventricular node ablation
    term:
      id: NCIT:C100068
      label: Cardiac Ablation
  target_mechanisms:
  - target: Atrial fibrillation
    description: Ventricular rate control for persistent atrial fibrillation.
  evidence:
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Her treatment included furosemide, metoprolol, losartan, spironolactone,
      warfarin, and AV node ablation with pacemaker implantation for
      persistent atrial fibrillation.
    explanation: AV node ablation and pacing for atrial fibrillation in the affected sister.
- name: Permanent Pacemaker Placement
  description: >-
    Implanted in the affected sister after atrioventricular node ablation for
    persistent atrial fibrillation.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: pacemaker placement
    term:
      id: NCIT:C80434
      label: Pacemaker Placement
  target_mechanisms:
  - target: Atrial fibrillation
    description: Provides ventricular pacing after the atrioventricular node is ablated.
  evidence:
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Her treatment included furosemide, metoprolol, losartan, spironolactone,
      warfarin, and AV node ablation with pacemaker implantation for
      persistent atrial fibrillation.
    explanation: Pacemaker implantation in the affected sister.
- name: Implantable Cardioverter-Defibrillator
  description: >-
    Not reported in the CMD2B family, in which no ventricular arrhythmia or
    sudden death was described. Listed because ICD placement is part of
    general dilated cardiomyopathy management; the evidence is general and not
    specific to GATAD1 disease.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: implantable cardioverter-defibrillator placement
    term:
      id: NCIT:C80435
      label: Implantable Cardioverter-Defibrillator Placement
  target_mechanisms:
  - target: Chronic Systolic Heart Failure
    description: Prevention of sudden arrhythmic death in systolic heart failure.
  evidence:
  - reference: PMID:39519012
    reference_title: "Dilated Cardiomyopathy: A Genetic Journey from Past to Future."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      which may be in part attributed to increased utilization in
      guideline-directed medical therapy (GDMT), device therapies such as
      implantable cardioverter-defibrillators (ICD), and earlier patient
      identification
    explanation: General dilated cardiomyopathy evidence for ICD therapy; not specific to CMD2B.
- name: Heart Transplantation
  description: >-
    Not reported in the CMD2B family. The option for end-stage dilated
    cardiomyopathy in general; the evidence is not specific to GATAD1 disease.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: heart transplantation
    term:
      id: NCIT:C15246
      label: Heart Transplantation
  target_mechanisms:
  - target: Chronic Systolic Heart Failure
    description: Replaces the failing myocardium in end-stage disease.
  evidence:
  - reference: PMID:39519012
    reference_title: "Dilated Cardiomyopathy: A Genetic Journey from Past to Future."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Individuals with DCM typically develop heart failure (HF), and DCM is the
      most frequent underlying reason for heart transplantation.
    explanation: General dilated cardiomyopathy evidence; not specific to CMD2B.
- name: Genetic Counseling and Cascade Screening
  description: >-
    Siblings of an affected person have a one in four risk of being
    homozygous. In the discovery family, disease appeared only in homozygotes
    and none of the eight obligate-heterozygous offspring of affected siblings
    developed dilated cardiomyopathy over 20 years, so carrier status alone
    has not been associated with disease. Echocardiographic screening of
    relatives detected the two asymptomatic affected siblings.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      DCM was also excluded in all 8 offspring of the 3 affected siblings, and
      none have developed heart failure over 20 years of follow up.
    explanation: Obligate heterozygous offspring remained unaffected, informing counselling of carriers.
  - reference: PMID:20301486
    reference_title: Dilated Cardiomyopathy Overview.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      relatives of a proband with DCM to inform cardiac surveillance and allow
      early detection and treatment of DCM to improve long-term outcome
    explanation: GeneReviews purpose statement on risk assessment and surveillance of at-risk relatives in dilated cardiomyopathy generally.
  - reference: PMID:39833651
    reference_title: "Yield of family screening for dilated cardiomyopathy: 10-year experience at a multidisciplinary cardiogenetic outpatient clinic."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The yield of DCM family screening was ~10% at baseline and another ~10%
      during 5-year follow-up. Relatives without the familial LP/P variant
      could be safely discharged.
    explanation: >-
      General dilated cardiomyopathy cohort supporting genotype-guided
      cascade screening of relatives; not specific to GATAD1, where only
      homozygous relatives would be at risk.
animal_models:
- name: Gatad1 cardiomyocyte-specific knockout mouse
  species: Mouse
  genotype: Gatad1 floxed (exons 2-4) with Xmlc2-Cre
  publication: PMID:39641830
  description: >-
    Cardiomyocyte deletion from embryonic day 7.5. Mice survived normally to
    18 months with normal echocardiographic function, heart weight, histology
    and cardiomyocyte nuclear shape, and responded normally to transverse
    aortic constriction, although Nppa and Nppb were mildly raised at 3 and
    15 months. Global Gatad1 knockout was lethal at embryonic day 8.5.
  modeled_mechanisms:
  - target: Left Ventricular Dilation and Remodeling
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    model_scale: TISSUE
    description: >-
      Loss of Gatad1 in cardiomyocytes does not produce ventricular dilation
      or dysfunction at baseline or under pressure overload.
    limitations: >-
      A null allele confined to cardiomyocytes, whereas patients carry a
      full-length missense protein in every cell; it cannot test a
      mutation-specific effect of S102P, a non-cardiomyocyte contribution, or
      a requirement before Cre expression. Observation stopped at 18 months,
      and the authors note that genetic background modifiers may matter.
    evidence:
    - reference: PMID:39641830
      reference_title: Loss of GATAD1 in cardiomyocyte does not cause cardiomyopathy in mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        Gatad1 cKO mutants exhibited normal cardiac function during the aging
        process up to 18 months of age.
      explanation: The negative result that makes this a failure to recapitulate.
  - target: Globular Cardiomyocyte Nuclei
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    model_scale: CELLULAR
    description: Isolated knockout cardiomyocytes have normal nuclear shape.
    limitations: >-
      Tests loss of Gatad1, not the S102P protein, and only in mouse
      cardiomyocytes.
    evidence:
    - reference: PMID:39641830
      reference_title: Loss of GATAD1 in cardiomyocyte does not cause cardiomyopathy in mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        Unlike the abnormal nuclei shape observed in patients carrying GATAD1
        mutations, the nuclei shape of cardiomyocytes remained unaffected by the
        loss of Gatad1.
      explanation: The nuclear phenotype is not reproduced.
- name: gatad1 knockout zebrafish
  species: Zebrafish
  genotype: gatad1 13-bp frameshift deletion in exon 2 (TALEN), homozygous
  publication: PMID:28955713
  description: >-
    Homozygous knockouts had no phenotype at baseline. With embryonic ethanol
    exposure plus a high-cholesterol diet they showed reduced swimming
    capacity, reduced survival from about 7 months, and induction of nppb and
    vmhc; ventricle size did not differ significantly.
  modeled_mechanisms:
  - target: Chronic Systolic Heart Failure
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      Heart failure-like phenotypes appear only under combined stress and
      without significant chamber enlargement.
    limitations: >-
      A null allele rather than the patient missense; phenotypes required
      ethanol and high-cholesterol stressors, and ejection fraction could not
      be measured in the small fish heart. Fish Gatad1 lacks the serine at the
      position of human Ser102.
    evidence:
    - reference: PMID:28955713
      reference_title: Modeling GATAD1-Associated Dilated Cardiomyopathy in Adult Zebrafish.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        Under stress conditions, longitudinal studies uncovered heart failure
        (HF)-like phenotypes in stable KO mutants and a tendency toward HF
        phenotypes in transgenic lines.
      explanation: Supports the knockout as partially informative for the heart-failure node.
- name: Tg(myl7:GATAD1-S102P) zebrafish
  species: Zebrafish
  genotype: Cardiomyocyte-specific transgenic expression of human GATAD1-S102P (myl7 promoter)
  publication: PMID:28955713
  description: >-
    Transgenic fish expressing human GATAD1-S102P in cardiomyocytes began to
    die at about 13 months, whereas fish expressing wild-type human GATAD1
    survived beyond 20 months; one of six mutant-transgenic hearts was
    enlarged. The authors call this a tendency needing a larger sample.
  modeled_mechanisms:
  - target: Chronic Systolic Heart Failure
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      Reduced survival and a single enlarged heart in fish overexpressing the
      patient allele, suggesting a possible effect of the mutant protein
      itself.
    limitations: >-
      Overexpression of a human transgene on a wild-type fish background, not
      the homozygous state; small numbers, and the cardiac enlargement was
      seen in one of six fish.
    evidence:
    - reference: PMID:28955713
      reference_title: Modeling GATAD1-Associated Dilated Cardiomyopathy in Adult Zebrafish.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: >-
        the Tg(myl7:GATAD1S102P) fish started to die around 13 months of age,
        in contrast to Tg(myl7:GATAD1) fish that survived more than 20 months
        without any deaths
      explanation: Reduced survival of fish expressing the patient allele.
discussions:
- discussion_id: gatad1_mechanism_unknown
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    By what mechanism does homozygous GATAD1 S102P cause dilated
    cardiomyopathy, and in which cell type does it act?
  attaches_to:
  - pathophysiology#Homozygous GATAD1 p.Ser102Pro Variant
  - pathophysiology#Perturbed GATAD1-Associated Chromatin Regulation
  - pathophysiology#Loss of Phospho-Ser102-Dependent 14-3-3 Binding
  rationale: >-
    Every step between the variant and the ventricle is unmeasured in human
    heart. The chromatin hypothesis is an inference from GATAD1's interaction
    partners, which the variant does not disrupt in HEK293 cells; the 14-3-3
    hypothesis rests on peptide binding and a crystal structure; and the
    abnormal GATAD1 distribution and globular nuclei come from one biopsy. The
    source papers name the experiments that would resolve it: an S102P
    knock-in and human iPSC-derived cardiomyocytes carrying the variant.
  proposed_experiments:
  - experiment_id: gatad1_s102p_ipsc_cardiomyocytes
    name: Human iPSC-derived cardiomyocytes carrying GATAD1 S102P
    description: >-
      Compare homozygous S102P, knockout and isogenic control iPSC-derived
      cardiomyocytes for GATAD1 localization, nuclear shape, 14-3-3 binding,
      chromatin occupancy, transcriptome and contractility.
    would_support:
    - mechanistic_hypotheses#gatad1_s102p_mutation_specific
  evidence:
  - reference: PMID:39641830
    reference_title: Loss of GATAD1 in cardiomyocyte does not cause cardiomyopathy in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      Utilizing human iPSC-derived cardiomyocytes with GATAD1 knockout or
      mutation could be an excellent approach to assess the function of human
      GATAD1 in cardiomyocyte differentiation.
    explanation: The mouse study names human iPSC-cardiomyocyte models as the next step.
  - reference: PMID:38605029
    reference_title: Pathogenic mutations of human phosphorylation sites affect protein-protein interactions.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: >-
      However, neither the pathogenic mechanism nor the function of this GATAD1
      phosphorylation site are currently known.
    explanation: States that the mechanism is unknown.
- discussion_id: gatad1_mouse_model_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Why does loss of Gatad1 in mouse cardiomyocytes cause no cardiomyopathy
    when homozygous S102P causes dilated cardiomyopathy in humans?
  attaches_to:
  - animal_models#Mouse
  - pathophysiology#Left Ventricular Dilation and Remodeling
  - mechanistic_hypotheses#gatad1_loss_of_function
  rationale: >-
    The mouse result can mean that S102P acts through a mutation-specific
    effect a null allele cannot model, that GATAD1 is required in cells other
    than cardiomyocytes or before the Cre driver switches on, that onset in
    mouse lies beyond 18 months, that strain background hides the phenotype,
    or that human and mouse GATAD1 differ in function. The zebrafish data do
    not settle it: the knockout needs stressors to show a phenotype, and fish
    Gatad1 lacks the Ser102 residue.
  proposed_experiments:
  - experiment_id: gatad1_s102p_knockin_mouse
    name: Gatad1 S102P knock-in mouse
    description: >-
      Homozygous S102P knock-in, aged beyond 18 months and on more than one
      inbred background, with echocardiography and nuclear morphology.
    would_support:
    - mechanistic_hypotheses#gatad1_s102p_mutation_specific
    would_refute:
    - mechanistic_hypotheses#gatad1_loss_of_function
  evidence:
  - reference: PMID:39641830
    reference_title: Loss of GATAD1 in cardiomyocyte does not cause cardiomyopathy in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: >-
      it is important to recognize that the function of GATAD1 in humans and
      mice may not be directly comparable. There could be unknown genetic
      modifiers necessary to manifest a cardiomyopathy phenotype.
    explanation: The authors' own statement of the species and modifier caveats.
  - reference: PMID:39641830
    reference_title: Loss of GATAD1 in cardiomyocyte does not cause cardiomyopathy in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: This possibility could be tested using an S102P knock-in mutant in future studies.
    explanation: Names the knock-in experiment.
- discussion_id: gatad1_single_family_evidence
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Do other families with biallelic GATAD1 variants and dilated
    cardiomyopathy exist?
  attaches_to:
  - disease#Dilated Cardiomyopathy 2B
  - genetic#GATAD1
  rationale: >-
    The entity is defined by one family with one allele, and ClinGen
    classifies the gene-disease relationship as Limited. A second unrelated
    family, or a different biallelic allele, is what would move the
    classification and show the phenotypic range.
  evidence:
  - reference: PMID:21965549
    reference_title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      GATAD1 mutations appear to be a rare cause for DCM, yet defects within
      other nucleosome interacting proteins may prove to be important in
      disease pathogenesis.
    explanation: The discovery paper itself notes the rarity of GATAD1 disease.
references:
- reference: PMID:20301486
  title: Dilated Cardiomyopathy Overview.
  tags:
  - GeneReviews
- reference: PMID:21965549
  title: Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
- reference: PMID:26841866
  title: Recruitment of the Mammalian Histone-modifying EMSY Complex to Target Genes Is Regulated by ZNF131.
- reference: PMID:28955713
  title: Modeling GATAD1-Associated Dilated Cardiomyopathy in Adult Zebrafish.
- reference: PMID:38605029
  title: Pathogenic mutations of human phosphorylation sites affect protein-protein interactions.
- reference: PMID:39519012
  title: "Dilated Cardiomyopathy: A Genetic Journey from Past to Future."
- reference: PMID:39626862
  title: GATAD1 is involved in sphingosylphosphorylcholine-attenuated myocardial ischemia-reperfusion injury by modulating myocardial fatty acid oxidation and glucose oxidation.
- reference: PMID:39641830
  title: Loss of GATAD1 in cardiomyocyte does not cause cardiomyopathy in mice.
- reference: PMID:39833651
  title: "Yield of family screening for dilated cardiomyopathy: 10-year experience at a multidisciplinary cardiogenetic outpatient clinic."
📚

References & Deep Research

References

9
PMID:20301486
Dilated Cardiomyopathy Overview.
No top-level findings curated for this source.
PMID:21965549
Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy.
No top-level findings curated for this source.
PMID:26841866
Recruitment of the Mammalian Histone-modifying EMSY Complex to Target Genes Is Regulated by ZNF131.
No top-level findings curated for this source.
PMID:28955713
Modeling GATAD1-Associated Dilated Cardiomyopathy in Adult Zebrafish.
No top-level findings curated for this source.
PMID:38605029
Pathogenic mutations of human phosphorylation sites affect protein-protein interactions.
No top-level findings curated for this source.
PMID:39519012
Dilated Cardiomyopathy: A Genetic Journey from Past to Future.
No top-level findings curated for this source.
PMID:39626862
GATAD1 is involved in sphingosylphosphorylcholine-attenuated myocardial ischemia-reperfusion injury by modulating myocardial fatty acid oxidation and glucose oxidation.
No top-level findings curated for this source.
PMID:39641830
Loss of GATAD1 in cardiomyocyte does not cause cardiomyopathy in mice.
No top-level findings curated for this source.
PMID:39833651
Yield of family screening for dilated cardiomyopathy: 10-year experience at a multidisciplinary cardiogenetic outpatient clinic.
No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (1)

Create: Dilated Cardiomyopathy 2B · 2026-09-25T14:41:48Z · View source

New entry for dilated cardiomyopathy 2B (GATAD1, MONDO:0013848), replacing the curation-queue stub. Sources. The human content comes from the single published family (Theis et al. 2011, PMID:21965549; its cache was refreshed by `just fetch-reference` from abstract-only to PMC full text so that the pedigree, treatment and immunohistochemistry passages could be quoted) and the ClinGen Limited assertion already cited by the parent Dilated_Cardiomyopathy entry. Mechanism and model content comes from the 14-3-3/Ser102 interaction study (PMID:38605029), the EMSY complex study (PMID:26841866), the zebrafish model (PMID:28955713), the cardiomyocyte knockout mouse (PMID:39641830) and the ischemia-reperfusion knockout mouse (PMID:39626862). ICD, transplantation and cascade screening are supported only by general dilated cardiomyopathy sources (PMID:39519012, PMID:39833651, and the GeneReviews overview PMID:20301486) and are marked INDIRECT. A PubMed search for GATAD1[Title/Abstract] (25 records on 2026-09-25) found no second family. Deep research. One OpenScientist report (research/Dilated_Cardiomyopathy_2B-deep-research-openscientist.md) was used. Its reference validation resolved 12/12 references; its term validation flagged two mislabelled HPO terms and one obsolete GO term, none of which were bound. `just preflight-dr` returned PASS (GATAD1 mentioned 51 times, OMIM 614672 matches MONDO). Several report claims were not carried over because the cited sources do not support them: that S102P has been shown to alter GATAD1 nucleocytoplasmic transport (the interaction paper only suggests this, and found normal nuclear localization of S102P in HEK293 cells); that the disease course is progressive (both affected sisters were stable in NYHA class II for more than 20 years); that GATAD1 is an H3K4me3 reader (it co-purifies with an H3K4me3-binding complex); and the 249-residue protein length (the discovery paper gives 269). Report citations not used: PMID:40200748, PMID:42537484, PMID:31431100, PMID:18579481 and PMID:39855353 are general cardiomyopathy papers that do not mention GATAD1 (the report cites PMID:40200748 for GATAD1 panel VUS findings, but the cached full text contains no GATAD1 mention); PMID:38664609 concerns heterozygous GATAD1 variants of uncertain significance in an unselected DCM cohort and is recorded in notes as not bearing on this recessive entity. The ClinVar record for the variant (VCV000031656, Pathogenic, no assertion criteria, one submission) was checked directly through NCBI E-utilities. Modelling decisions. The variant node is linked to the remodeling node by an edge with unknown intermediates, backed by the genetic evidence alone; the chromatin and 14-3-3 routes are carried as EMERGING hypothesis groups, alongside competing loss-of-function and mutation-specific models, with the negative mouse result recorded as REFUTE evidence and as a HUMAN_MODEL_MISMATCH discussion. Atrial fibrillation and the left ventricular thrombus each occurred in one patient and are left without an upstream causal edge. No frequencies are assigned. Only the remodeling and heart-failure nodes conform to cardiomyopathy_maladaptive_remodeling, for the reasons given in the entry notes. Side effects in references_cache: running `just validate` re-extracted PMID_20301486.md and PMID_39519012.md with the current extractor (frontmatter and body formatting changed; the GeneReviews record also lost one editor name). All snippets in the 38 KB files citing these PMIDs or PMID:21965549 still verify (2099/2099). Validation: just validate, validate-terms, count-verified-snippets (all snippets verified), check-entity-refs, check-causal-targets, check-genereviews --online (TAGGED), and just validate-disorders.

OpenScientist ▸
1. Disease Information
openscientist-autonomous 2026-09-25T14:28:50.172990

1. Disease Information

Overview. Dilated Cardiomyopathy 2B (CMD2B) is a rare autosomal recessive form of familial dilated cardiomyopathy caused by biallelic mutation of GATAD1 (GATA zinc-finger domain-containing protein 1). Like other DCMs it is defined by left-ventricular (LV) dilation and systolic dysfunction (reduced ejection fraction) not explained by abnormal loading conditions or coronary disease, presenting clinically as heart failure and predisposing to arrhythmia. CMD2B is distinguished from the far more common autosomal-dominant DCMs by its recessive transmission with clinically silent heterozygous carriers [human clinical, PMID 21965549].

Key identifiers. | Resource | ID | |---|---| | Mondo | MONDO:0013848 (dilated cardiomyopathy 2B) | | OMIM (phenotype) | 614672 — CARDIOMYOPATHY, DILATED, 2B; CMD2B | | OMIM (gene) | 614518 — GATAD1 | | HGNC | HGNC:29941 (GATAD1) | | NCBI Gene | 57798 | | Ensembl | ENSG00000157014 | | UniProt | Q8WUU5 (GATD1_HUMAN) | | RefSeq | NM_021167.5 / NP_066990.3 (GATAD1, 249 aa); LRG_746 | | Founder variant | NM_021167.5:c.304T>C (p.Ser102Pro); ClinVar VCV31656; rs387907188 | | ICD-10 | I42.0 (Dilated cardiomyopathy) | | ICD-11 | BC43.0 (Dilated cardiomyopathy) | | MeSH | D002311 (Cardiomyopathy, Dilated) | | Orphanet | within ORPHA:154 (Familial isolated dilated cardiomyopathy) — no distinct subtype code |

Synonyms / alternative names. CMD2B; Cardiomyopathy, dilated, 2B; GATAD1-related/GATAD1-associated dilated cardiomyopathy; autosomal recessive dilated cardiomyopathy (GATAD1 type).

Data source type. Disease-level aggregated resources (OMIM/Mondo) plus individual-patient data from one published family; no EHR/registry-scale cohort exists for this specific subtype.

2. Etiology

Primary causal factor — genetic. CMD2B is a monogenic, biallelic disorder. Disease requires two loss-/alteration-of-function alleles of GATAD1. In the index family a homozygous missense mutation altering the conserved serine-102 residue (reported as p.Ser102Pro) segregated with recessive DCM; it was absent from HapMap, 1000 Genomes and 474 ethnically matched controls [human clinical, PMID 21965549].

"altered a conserved residue of GATAD1 … Thirteen relatives were heterozygous mutation carriers with no evidence of myocardial disease, even at advanced ages." (PMID 21965549)

Genetic risk factors. - Causal variant: homozygous GATAD1 p.Ser102Pro (7q21.2). Because unaffected heterozygotes exist, a single allele is insufficient (recessive). - Consanguinity is a major predisposing structural factor — the founding couple were first cousins, and homozygosity mapping exploited runs of homozygosity [human clinical, PMID 21965549]. - Modifier genes: none specifically identified for CMD2B (data unavailable).

Environmental / lifestyle risk factors. No CMD2B-specific environmental trigger is established. For DCM broadly, alcohol, cardiotoxic chemotherapy (anthracyclines), myocarditis/viral infection, peripartum state, thyroid disease and tachyarrhythmia are recognized acquired causes/"second hits"; these may act as gene–environment modifiers superimposed on genetic susceptibility [DCM-class; PMID 42537484 notes "second-hit" genetic contributions]. Not demonstrated for GATAD1 specifically.

Protective factors. No genetic or environmental protective factor is described for CMD2B (data unavailable). By inference, absence of a second pathogenic allele is "protective" (heterozygotes unaffected).

Gene–environment interactions. Mouse data suggest GATAD1 becomes functionally important under stress: cardiac Gatad1 loss worsens ischemia–reperfusion injury and abolishes sphingosylphosphorylcholine cardioprotection [model organism, PMID 39626862], implying environmental/metabolic stressors may unmask or aggravate GATAD1-deficient myocardium — inferred, not shown in patients.

3. Phenotypes

All descriptions derive from the single reported kindred [human clinical, PMID 21965549] plus generic DCM knowledge.

Phenotype Type HPO term Onset / severity / course Frequency
Dilated cardiomyopathy clinical/imaging sign HP:0001644 Adult-onset, progressive Core, defining (homozygotes)
Left ventricular enlargement / dilatation imaging sign HP:0001640 (cardiomegaly), HP:0001712 (LV hypertrophy—N/A) Adult; may be isolated/milder Present incl. an "intermediate" male
Reduced LV ejection fraction / systolic dysfunction imaging/functional HP:0001635 (congestive heart failure), HP:0005162 (abnormal LV function) Progressive Core
Congestive heart failure (dyspnea, fatigue, edema) symptoms HP:0001635 Adult, progressive Expected in overt cases
Arrhythmia / risk of sudden death sign HP:0011675 (arrhythmia) Variable DCM-class risk; not detailed for CMD2B
Abnormal cardiomyocyte nuclear morphology pathology (biopsy) (cellular) — Seen in proband myocardium

Phenotype characteristics. Age of onset: adult-onset (HP:0003581) with age-dependent penetrance; the affected sisters were adults, and a brother had milder "idiopathic LV enlargement," illustrating variable expressivity (HP:0003828). Severity ranges from isolated LV dilatation to overt DCM/heart failure. Course: chronic, progressive.

Quality-of-life impact. No CMD2B-specific QoL data. For symptomatic DCM/heart failure generally, health-related QoL is substantially reduced (dyspnea, exertional limitation, hospitalizations); disease-specific instruments include the Kansas City Cardiomyopathy Questionnaire and Minnesota Living with Heart Failure Questionnaire (data unavailable for this subtype).

4. Genetic / Molecular Information

Causal gene. GATAD1 — GATA zinc-finger domain-containing protein 1; 7q21.2; HGNC:29941; NCBI Gene 57798; OMIM 614518; UniProt Q8WUU5. Encodes a nuclear protein containing a GATA-type zinc finger that functions as a reader of H3K4me3 and a subunit of a histone-modifying chromatin complex [in vitro, PMID 26841866; 39641830].

Pathogenic variant (founder allele of the index family). - HGVS: GATAD1 NM_021167.5:c.304T>C, protein p.Ser102Pro (LRG_746; UniProt Q8WUU5:p.Ser102Pro); genomic chr7:g.92078120T>C (GRCh38) [database-verified, ClinVar]. - Identifiers: ClinVar Variation ID 31656; dbSNP rs387907188. - Type/class: single-nucleotide missense; germline; homozygous in affected individuals [human clinical, PMID 21965549]. - Classification: Pathogenic in ClinVar for "Dilated cardiomyopathy 2B" (review status: no assertion criteria provided — 1-star). Ser102 is N-terminal to the GATA-type zinc finger, within the intrinsically disordered region bearing the 14-3-3 phospho-motif. In-silico: CADD 21.8, PolyPhen-2 probably damaging; SIFT tolerated (mildly discordant). - Allele frequency: absent from gnomAD (genomes and exomes) and absent from HapMap, 1000 Genomes and 474 matched controls [PMID 21965549] — private/ ultra-rare. - Broader GATAD1 landscape: most GATAD1 ClinVar entries are VUS or likely benign; only rare truncating variants are (likely) pathogenic. GATAD1 is frequently reported as VUS on cardiomyopathy panels (PMID 38664609, 40200748) — caution for novel variants. - Functional consequence: the mutation destroys a phospho-serine 14-3-3 docking site, altering GATAD1 nucleocytoplasmic transport and producing aberrant subcellular localization and abnormal nuclear morphology [in vitro, PMID 38605029; human IHC, PMID 21965549]. Mechanistically this is not a simple null (see §6): a cardiomyocyte Gatad1 knockout mouse is healthy [PMID 39641830], suggesting an aberrant-function/mislocalization effect rather than pure loss-of-function.

Modifier genes / epigenetic / chromosomal. No CMD2B-specific modifier genes, constitutional epigenetic marks, or chromosomal abnormalities reported (data unavailable). Note GATAD1 itself acts within an epigenetic (histone-modifying) complex — see §6.

5. Environmental Information

No environmental factor, occupational exposure, toxin, or infectious agent is implicated in the causation of CMD2B specifically (it is a monogenic disease; data unavailable). Generic DCM environmental contributors (alcohol, anthracyclines, viral myocarditis, peripartum state) may act as aggravating second hits on a genetically susceptible myocardium but are unproven for GATAD1. No infectious agent applies.

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation)

  1. Homozygous GATAD1 p.Ser102Pro substitutes proline for a serine phosphorylation site → abolishes a phospho-Ser 14-3-3 docking motif [in vitro, PMID 38605029].
  2. Loss of 14-3-3 binding → dysregulated masking of a nuclear localization signal → altered nucleocytoplasmic transport / mislocalization of GATAD1 [in vitro, PMID 38605029]; observed as aberrant subcellular localization and abnormal nuclear morphology in patient LV myocytes [human clinical, PMID 21965549].
  3. Mislocalized/altered GATAD1 → disrupted incorporation/function within the EMSY–KDM5A(H3K4me3 demethylase)–SIN3B/HDAC histone-modifying complex [in vitro, PMID 26841866] → altered H3K4me3-linked transcriptional regulation at target promoters [inferred].
  4. Branch A (transcriptional/chromatin): dysregulated cardiac gene expression programs → impaired maintenance of normal cardiomyocyte structure/function → contractile dysfunction [inferred from PMID 21965549, 26841866].
  5. Branch B (metabolic): as a transcription factor GATAD1 normally represses fatty-acid-oxidation genes (Acaa2, Acadm) and promotes glucose oxidation; its dysfunction shifts myocardial substrate metabolism and lowers stress tolerance (larger infarcts / worse function under ischemia–reperfusion) [model organism, PMID 39626862].
  6. Converging branches → cardiomyocyte dysfunction → LV chamber dilation and systolic dysfunction (reduced EF) [human clinical, PMID 21965549].
  7. → congestive heart failure, and (DCM-class) predisposition to ventricular arrhythmia / sudden cardiac death → end-stage disease potentially requiring transplantation.

Steps 1–2 are experimentally demonstrated; step 3 (complex membership) is demonstrated biochemically but not in heart tissue; steps 4–7 are inferred from correlative human pathology and model-organism data. A key unresolved point: cardiomyocyte-specific Gatad1 deletion does not cause disease in mouse (PMID 39641830), so the pathogenic mechanism likely involves an aberrant/ dominant-negative-like effect of the mislocalized mutant and/or non-cell- autonomous or developmental requirements — not simple loss-of-function.

Detail by category

  • Molecular pathways: chromatin/epigenetic regulation via H3K4me3 reading/demethylation (KDM5A) and Sin3/HDAC deacetylation; 14-3-3 signaling. GO: GO:0006325 (chromatin organization), GO:0034968 (histone lysine methylation), GO:0032452 (histone demethylase activity), GO:0000122 (negative regulation of transcription).
  • Cellular processes: transcriptional regulation, nucleocytoplasmic transport (GO:0006913), cardiac muscle contraction; metabolic gene regulation.
  • Protein dysfunction: loss of a regulatory phosphosite → altered protein–protein interaction (14-3-3) and mislocalization; GATAD1 is intrinsically disordered in the relevant region [in vitro, PMID 38605029].
  • Metabolic changes: dysregulated balance of fatty-acid oxidation (GO:0019395) vs glucose oxidation [model organism, PMID 39626862].
  • Immune involvement: none established (non-inflammatory genetic cardiomyopathy).
  • Tissue-damage mechanisms: DCM-class remodeling — cardiomyocyte dysfunction, interstitial/replacement fibrosis, chamber dilation; increased ischemic vulnerability [inferred/model].
  • Epigenetic changes: GATAD1 is itself part of the epigenetic machinery (H3K4me3 reader). Disease-associated global methylation changes: data unavailable.
  • Cell types: cardiac muscle cell / cardiomyocyte — CL:0000746 (ventricular cardiomyocyte CL:0002131).

7. Anatomical Structures Affected

  • Organ (primary): heart — UBERON:0000948; specifically left ventricular myocardium / heart left ventricle — UBERON:0002084 (myocardium UBERON:0002349).
  • Secondary/systemic: cardiovascular system (UBERON:0004535); congestive heart failure secondarily affects lungs (pulmonary congestion), kidneys, liver (congestion). Body system: cardiovascular.
  • Tissue/cell: striated cardiac muscle tissue; cardiomyocytes (CL:0000746 / ventricular CL:0002131) are the primary affected cell population.
  • Subcellular: nucleus (GO:0005634) — GATAD1 is nuclear; the defect centers on nuclear import/nuclear morphology. Chromatin (GO:0000785). A metabolic arm implicates mitochondrial fatty-acid oxidation machinery indirectly (GO:0005739) [inferred].
  • Localization / laterality: predominantly left ventricular; DCM is typically global/bilateral ventricular involvement rather than focal.

8. Temporal Development

  • Onset: adult-onset (HP:0003581), insidious/chronic; age-dependent penetrance (an explicit rationale for building an adult zebrafish model, PMID 28955713). No neonatal/pediatric CMD2B cases reported.
  • Progression: chronic and progressive; ranges from isolated LV enlargement (intermediate phenotype) to overt DCM with systolic dysfunction and heart failure [human clinical, PMID 21965549]. DCM-class staging: early (asymptomatic LV dilation) → symptomatic HF → advanced/end-stage.
  • Course pattern: progressive, lifelong (chronic). No spontaneous remission documented for CMD2B; DCM broadly can show reverse remodeling with guideline-directed therapy.
  • Critical periods: adulthood is the window of clinical expression; the pre-symptomatic phase is the opportunity for surveillance/early therapy in at-risk homozygotes.

9. Inheritance and Population

  • Inheritance: autosomal recessive (a defining, unusual feature — most DCM is autosomal dominant). Heterozygous carriers are unaffected even at advanced age [human clinical, PMID 21965549].
  • Penetrance: appears high in homozygotes but age-dependent; carriers non-penetrant.
  • Expressivity: variable (isolated LV enlargement → overt DCM within one family).
  • Consanguinity: central — index family descended from first cousins; homozygosity mapping was the discovery strategy [PMID 21965549].
  • Founder effect / geographic variant distribution / anticipation / germline mosaicism: none reported (data unavailable). No repeat expansion (no anticipation expected).
  • Carrier frequency: not established; the specific allele is private/ultra-rare (absent from population databases).
  • Epidemiology: No prevalence/incidence figures exist for CMD2B specifically — it is exceedingly rare (essentially one published kindred). For context, DCM overall has an estimated prevalence on the order of ~1 in 250–500 and a monogenic cause is identifiable in ~30–40% of familial cases (PMID 39855353); GATAD1 accounts for only a tiny fraction. Sex ratio: DCM overall is male-predominant; both sexes affected in the CMD2B family (the two fully affected probands were female). Age distribution: adults.

10. Diagnostics

Cardiac phenotyping (DCM-class, applied to CMD2B). - Imaging: transthoracic echocardiography (LV dilation, reduced LVEF) — first-line; cardiac MRI (chamber volumes, function, late-gadolinium fibrosis) [DCM-class; stress echo relevance PMID 18579481]. LOINC/RadLex apply. - ECG / Holter: arrhythmia and conduction assessment. - Biomarkers: NT-proBNP/BNP (heart-failure severity); troponin as adjunct (non-specific). No CMD2B-specific circulating biomarker. - Endomyocardial biopsy: not routine; in the proband it revealed aberrant cardiomyocyte nuclear morphology / GATAD1 mislocalization [PMID 21965549].

Genetic testing (definitive for subtype). - Recommended approach: NGS cardiomyopathy multigene panel (GATAD1 is included on modern panels, PMID 38664609) or whole-exome/genome sequencing; the original diagnosis used homozygosity mapping + exome sequencing in a consanguineous pedigree [PMID 21965549]. - Confirm biallelic GATAD1 variants (homozygous or compound heterozygous) with segregation; classify per ACMG/AMP (many GATAD1 variants are currently VUS). - CMA/karyotype/FISH/mtDNA/repeat-expansion testing: not indicated for this single-gene point-mutation disorder.

Clinical criteria / differential diagnosis. Diagnose DCM by LV dilation + systolic dysfunction after excluding ischemic, valvular, hypertensive, toxic (alcohol/anthracycline), infiltrative, peripartum and myocarditic causes. Differential: other genetic DCMs (TTN, LMNA, RBM20, FLNC, DES, MYH7), arrhythmogenic and hypertrophic cardiomyopathies. The recessive pattern + consanguinity + GATAD1 genotype distinguishes CMD2B.

Screening. Cascade genetic testing of relatives and echocardiographic surveillance of at-risk biallelic individuals (see §13). Family screening yields ~10% at baseline and ~10% more over 5 years in DCM generally (PMID 39833651).

11. Outcome / Prognosis

  • CMD2B-specific outcome data are essentially absent beyond the index family (adult-onset DCM/heart failure). No survival, mortality or QoL statistics exist for this subtype.
  • By DCM class: prognosis depends on LVEF and remodeling. In a large registry, patients presenting with mid-range EF (40–49%) had markedly better outcomes than reduced-EF (<40%) patients — death/transplant 9% vs 36% and SCD/major ventricular arrhythmia 4.5% vs 15% over ~10 years (PMID 31431100); ~17% of mid-range progressed to reduced EF.
  • Complications: progressive heart failure, ventricular arrhythmia/sudden cardiac death, atrial fibrillation, thromboembolism, and end-stage disease requiring heart transplantation (genetic DCMs are enriched among transplant recipients, PMID 42537484).
  • Recovery: reverse remodeling possible with guideline-directed therapy in DCM broadly; not documented specifically for CMD2B.
  • Prognostic factors: LVEF, LV size, fibrosis on MRI, arrhythmia burden, NT-proBNP (DCM-class). No validated CMD2B-specific prognostic biomarker.

12. Treatment

No gene-specific or curative therapy exists for CMD2B. Management follows guideline-directed medical therapy (GDMT) for DCM/heart failure with reduced ejection fraction:

  • Pharmacotherapy (NCIT terms in brackets):
  • ACE inhibitors / ARBs / ARNI (sacubitril–valsartan) — afterload/neurohormonal.
  • Beta-blockers (carvedilol, metoprolol succinate, bisoprolol).
  • Mineralocorticoid-receptor antagonists (spironolactone, eplerenone).
  • SGLT2 inhibitors (dapagliflozin, empagliflozin).
  • Diuretics for congestion; anticoagulation if AF/thrombus.
  • NCIT: ACE Inhibitor, Beta-Adrenergic Blocker, Diuretic, Aldosterone Antagonist.
  • Pharmacogenomics: no GATAD1-specific PGx. General HF PGx (e.g., warfarin CYP2C9/VKORC1) applies only if those drugs are used.
  • Device / interventional: ICD for sudden-death prevention and CRT for conduction delay per EF/QRS criteria; mitral intervention as indicated.
  • Advanced / surgical: mechanical circulatory support (LVAD) and heart transplantation for end-stage disease.
  • Advanced therapeutics (gene/cell/RNA/targeted/immunotherapy): none approved or in trials for GATAD1-DCM (data unavailable). Gene-directed strategies are conceptual only.
  • Supportive/rehabilitative: cardiac rehabilitation, sodium/fluid guidance, exercise counseling, HF self-management.
  • Experimental / trials: no CMD2B-specific registered trials identified.
  • Personalized approach: genotype confirmation guides family screening and reproductive counseling rather than drug selection at present.

13. Prevention

  • Primary prevention: not possible for the genetic cause; preconception/ reproductive genetic counseling in consanguineous or carrier families is the main lever. Options: carrier testing of partners, prenatal diagnosis or preimplantation genetic testing (PGT-M) for known biallelic risk.
  • Secondary prevention: cascade genetic testing of relatives and serial echocardiographic surveillance of biallelic (homozygous/compound-het) at-risk individuals to detect subclinical LV dysfunction early; genotype-guided screening is efficient because non-carriers of the familial variant do not develop disease (PMID 39833651). ACMG/HFSA recommend genetic evaluation + family screening in familial DCM.
  • Tertiary prevention: GDMT, ICD for arrhythmic death, HF-hospitalization avoidance, management of AF/thromboembolism.
  • Behavioral: avoid alcohol excess and cardiotoxins; standard cardiovascular risk-factor control (may mitigate "second-hit" aggravation — inferred).
  • Counseling: autosomal-recessive counseling — 25% recurrence risk for future sibs of an affected child; offspring of an affected person are obligate carriers (affected only if partner is also a carrier). Immunization/public-health and environmental interventions: not applicable.

14. Other Species / Natural Disease

  • Taxonomy / orthologs: GATAD1 is evolutionarily conserved.
  • Human GATAD1 — NCBI Gene 57798, HGNC:29941, 7q21.2 (Homo sapiens, Taxon 9606).
  • Mouse Gatad1 — NCBI Gene 67210 (Mus musculus, NCBI Taxon 10090; chr5 A1).
  • Zebrafish gatad1 — NCBI Gene 678617 (Danio rerio, NCBI Taxon 7955).
  • Natural disease in other species: No naturally occurring GATAD1 cardiomyopathy in companion animals or wildlife is catalogued (no OMIA entry identified; data unavailable). Note: naturally occurring DCM is common in dogs (e.g., Doberman Pinscher, Great Dane) but is genetically distinct (not GATAD1).
  • Comparative biology / conservation: the H3K4me3-reader/chromatin-complex function and the Ser102/14-3-3 regulatory motif are conserved, enabling cross-species modeling; however, phenotypic conservation is incomplete — zebrafish reproduce DCM whereas mouse cardiomyocyte knockout does not (§15).
  • Transmission / zoonosis: not applicable (non-communicable genetic disease).

15. Model Organisms

Zebrafish (Danio rerio, Taxon 7955) — supportive positive model. Yang, Shah, Olson & Xu 2016 (PMID 28955713) generated an adult zebrafish model of the gatad1 homologue specifically to overcome age-dependent penetrance and validate GATAD1 as a bona fide DCM gene in a higher-throughput vertebrate.

"we generated an adult zebrafish model, which is a simpler vertebrate model with higher throughput than rodents." (PMID 28955713) - Model type: genetic vertebrate; application: validating causality, studying adult-onset cardiomyopathy mechanisms.

Mouse (Mus musculus, Taxon 10090) — informative negative / limitation. Pang et al. 2024 (PMID 39641830) made a cardiomyocyte-specific Gatad1 knockout (cKO). It showed normal cardiac function to 18 months, normal nuclear shape (unlike patients), and normal response to pressure overload (TAC).

"deletion of Gatad1 in cardiomyocytes does not induce cardiomyopathy during aging or affect the response to pressure-overload stress in mice." (PMID 39641830) - Interpretation/limitation: pure cardiomyocyte loss-of-function is insufficient in mouse → argues the human p.Ser102Pro acts via aberrant function/mislocalization or non-cardiomyocyte/developmental requirements; a knock-in of the p.Ser102Pro allele would be the more faithful (still-needed) model.

Additional mouse model (metabolic). A myocardium-specific Gatad1 cKO was used to show GATAD1 controls the fatty-acid/glucose oxidation balance and modulates ischemia–reperfusion injury (PMID 39626862).

In vitro / cellular systems. Peptide-interaction proteomics and structural studies of the Ser102 phosphosite–14-3-3 interaction (PMID 38605029); biochemical characterization of the EMSY/KDM5A/SIN3B complex (PMID 26841866). No iPSC- cardiomyocyte CMD2B model is yet reported (opportunity/gap).

Resources: MGI (mouse Gatad1), ZFIN (zebrafish gatad1), Alliance of Genome Resources.

Summary of Supported vs. Refuted / Open Hypotheses

  • Supported: CMD2B = autosomal-recessive DCM caused by biallelic GATAD1 (p.Ser102Pro); GATAD1 is a nuclear H3K4me3-reader/chromatin-complex subunit; the mutation disrupts a Ser102 phospho-14-3-3 motif and GATAD1 nuclear localization; GATAD1 regulates cardiac substrate metabolism; zebrafish recapitulate DCM.
  • Refuted / qualified: "simple cardiomyocyte loss-of-function causes the disease" — refuted in mouse cKO (PMID 39641830); mechanism is more likely aberrant-function/mislocalization.
  • Resolved this review: founder allele nomenclature and status — GATAD1 NM_021167.5:c.304T>C (p.Ser102Pro), ClinVar VCV31656/rs387907188, Pathogenic, absent from gnomAD.
  • Open / data-unavailable: population carrier frequency; CMD2B-specific penetrance %, survival, QoL; modifier genes; existence of additional families beyond the index kindred; iPSC and knock-in (p.Ser102Pro) models.

Limitations

Human evidence rests on one consanguineous kindred; mechanism is pieced together from in-vitro and cross-species models with a notable mouse/zebrafish discordance. Epidemiologic, prognostic, and treatment-response data specific to CMD2B do not exist and were substituted with clearly-labeled DCM-class information.

Key References (PMIDs)

  • 21965549 — Theis et al. 2011: discovery of GATAD1 in AR-DCM [human clinical].
  • 38605029 — Rrustemi et al. 2024: Ser102/14-3-3, nucleocytoplasmic transport [in vitro].
  • 26841866 — Varier et al. 2016: EMSY/KDM5A/SIN3B complex, GATAD1 subunit [in vitro].
  • 28955713 — Yang et al. 2016: adult zebrafish gatad1 DCM model [model organism].
  • 39641830 — Pang et al. 2024: cardiomyocyte Gatad1 cKO — no cardiomyopathy [model organism].
  • 39626862 — Cai et al. 2025: GATAD1 controls FAO/glucose oxidation, I/R injury [model organism].
  • 38664609 / 40200748 / 39833651 / 39855353 — DCM genetic testing & family screening context.
  • 31431100 — DCM natural history by EF stratum [human clinical, DCM-class].

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Obsolete 1
Unverifiable 2
Terms whose name was checked 5
Terms named correctly 1
Terms named as a different term 2
Terms whose name is worth a second look 2

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • HP:0001644 (1 mention) - the report calls it "clinical/imaging sign"; HP calls it Dilated cardiomyopathy
  • HP:0001635 (2 mentions) - the report calls it "symptoms"; HP calls it Congestive heart failure

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • GO:0034968 (obsolete histone lysine methylation) (1 mention)

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • UBERON:0004535 (1 mention) - the report calls it "Secondary/systemic: cardiovascular system"; UBERON calls it cardiovascular system**
  • GO:0005634 (1 mention) - the report calls it "Subcellular: nucleus"; GO calls it nucleus, and lists "cell nucleus" among its other names

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • HP:0003581 - called "adult-onset", "Onset: adult-onset"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.