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Classifications

Harrison's Part

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Inheritance

1

Autosomal Recessive HP:0000007

Both affected siblings carried the CORIN null variant in the homozygous state, and the associated ClinVar record (VCV002504113, OMIM allelic variant 605236.0004, NM_006587.4(CORIN):c.684dup p.Met229fs, a 1-bp duplication at 4p12) is classified pathogenic. Heterozygous relatives were not reported as having the atrial cardiomyopathy phenotype. Note that this is a different dose-response regime from the common hypomorphic CORIN I555(P568) allele, which is a heterozygous-state susceptibility factor for hypertension and hypertrophy rather than a cause of CMH30.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:37913506 SUPPORT Human Clinical

"Each had a homozygous null variant in CORIN, the gene encoding atrial natriuretic peptide (ANP)-converting enzyme."

Homozygosity for a null allele in both affected siblings is the direct statement of biallelic, recessive causation.

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Discussions and Knowledge Gaps

4

Why is the cardiomyopathy of biallelic CORIN loss selectively LEFT ATRIAL in humans, when corin loss removes a systemic endocrine signal and the corin-knockout mouse shows generalised, hypertension-attributed cardiac hypertrophy and fibrosis?

KNOWLEDGE GAP OPEN corin_atrial_selectivity

Attached to

pathophysiology#Left Atrial Myocardial Hypertrophy and Enlargement pathophysiology#Left Atrial Fibrosis

The atrial localisation is what makes this a distinct disease entity rather than "hypertensive heart disease due to an endocrine defect", and it is exactly the part with no mechanistic explanation. Three candidate accounts are on the table and no data currently separate them: (1) an autocrine or paracrine account, in which the left atrium suffers most because it is the tissue that synthesises pro-ANP, so the local concentration of mature ANP falls furthest there; (2) a mechanical account, in which the thin-walled atrium is simply the chamber least able to tolerate the chronic pressure and volume load created by systemic hypertension, making the atrial predominance a consequence of hypertension rather than of local signalling; and (3) an ascertainment account, in which the atrial phenotype is what brought a single sibship to attention and a larger cohort would show ventricular disease too - the OMIM/MedGen synopsis does already record reduced left ventricular ejection fraction. Distinguishing these matters clinically, because account (2) implies that aggressive blood-pressure control should largely prevent the atrial disease, while account (1) implies it should not.

Proposed experiments

Chamber-resolved ANP and cGMP measurement in corin-null myocardium

chamber_resolved_anp_cgmp

Measure mature ANP and cGMP separately in atrial and ventricular myocardium of corin-null models, with and without blood-pressure normalisation, to test whether the atrium sustains a distinct local signalling deficit beyond the systemic one.

Blood-pressure-controlled corin-null cohort

bp_controlled_corin_null_cohort

Follow atrial size and fibrosis in corin-deficient animals maintained normotensive by antihypertensive therapy from a young age. Persistent atrial remodelling under normal blood pressure would favour the autocrine account; its absence would favour the mechanical one.

Show evidence (2 references)

PMID:37913506 SUPPORT Human Clinical

"These and other findings support the hypothesis that BNP cannot fully compensate for a lack of activation of the ANP pathway and that corin is critical to normal ANP activity, left atrial function, and cardiovascular homeostasis."

The authors themselves frame corin's criticality as being to LEFT ATRIAL function specifically, which is the observation this gap asks the mechanism for.

PMID:37636304 SUPPORT Model Organism

"Corin KO mice had progressive cardiac dysfunction with cardiac hypertrophy and fibrosis after 9 months of age, likely due to chronic hypertension."

The competing mechanical account: in the model, cardiac remodelling from corin loss is attributed to chronic hypertension and is not chamber-selective. It establishes the alternative rather than resolving between accounts.

Does the constitutive corin-knockout mouse model the human CMH30 phenotype, given that it reproduces the endocrine and blood-pressure arms faithfully but neither the atrial selectivity nor the atrial arrhythmia that define the human disease?

HUMAN MODEL MISMATCH OPEN corin_null_mouse_atrial_mismatch

Attached to

pathophysiology#Left Atrial Myocardial Hypertrophy and Enlargement pathophysiology#Atrial Arrhythmogenic Substrate

Evidence in the model exists and is strong - abolished pro-ANP processing, salt-sensitive spontaneous hypertension, age-dependent hypertrophy and fibrosis, and rescue by recombinant corin - so this is a translational validity question rather than an absence of evidence. Two specific mismatches limit what may be inferred. First, the murine hypertrophy and fibrosis are not chamber-selective and are attributed by the authors to chronic hypertension, so the model cannot substantiate the left atrial localisation that names the human disease. Second, and more consequentially, the reported assessment battery is echocardiography and tissue histology with no rhythm monitoring, so the atrial flutter and fibrillation that carry the human stroke and symptom burden have no counterpart endpoint at all - the model is silent on them rather than negative. The transverse-aortic-constriction variant compounds this by imposing surgical VENTRICULAR afterload, a stimulus with no equivalent in the spontaneous human disease. Consequently the mouse should be cited for the corin/ANP/blood-pressure axis and for the corin-replacement rescue, and NOT as support for the atrial phenotype.

Proposed experiments

Atrial electrophysiology in aged corin-null mice

atrial_ep_aged_corin_null

Implanted telemetry or programmed atrial stimulation in aged corin-null mice to determine whether atrial arrhythmia occurs at all in the model, converting a silent endpoint into a positive or negative result.

Atrium-restricted conditional Corin deletion

atrium_restricted_corin_deletion

Delete Corin selectively in atrial cardiomyocytes to test whether atrial disease can be produced without systemic hypertension - the cleanest discriminator between the autocrine and mechanical accounts of atrial selectivity.

Patient-derived iPSC atrial cardiomyocytes and engineered atrial tissue

ipsc_atrial_cardiomyocytes

Isogenic CRISPR-corrected patient lines differentiated to atrial cardiomyocytes, with pro-ANP cleavage, cGMP, conduction, and matrix production as readouts, to establish the human atrial cell-autonomous consequence of the null genotype.

Show evidence (2 references)

PMID:37636304 SUPPORT Model Organism

"Cardiac function was assessed by echocardiography and tissue analysis in Corin KO mice at different ages or subjected to transverse aortic constriction (TAC), which increased pressure overload."

Documents the model's assessment battery - imaging and histology, with no rhythm monitoring - which is the specific reason the atrial arrhythmia arm of the human phenotype has no counterpart endpoint in the model.

PMID:15637153 SUPPORT Model Organism

"In addition, Cor-/- mice exhibit cardiac hypertrophy resulting in a mild decline in cardiac function later in life."

The murine hypertrophy is reported at whole-heart level with no atrial localisation, establishing the chamber-selectivity mismatch this discussion records.

What are the penetrance, natural history, arrhythmic burden, stroke rate, and prognosis of biallelic CORIN loss of function?

KNOWLEDGE GAP OPEN corin_cmh30_evidence_base

Attached to

pathophysiology#Biallelic CORIN Null Variant phenotypes#Atrial Cardiomyopathy

Every quantitative dimension of this entity is unmeasured because the human evidence base is a single sibship of two. There is no second family, no cohort, no prevalence estimate, no age-of-onset distribution, no penetrance figure for biallelic carriers, no arrhythmia incidence, no stroke rate, and no survival data. Nothing in this entry's treatment section rests on CORIN-specific outcome evidence; all of it is extrapolated from general hypertension, atrial-fibrillation, and cardiomyopathy management. Curators should resist the temptation to borrow numbers from the sarcomeric hypertrophic cardiomyopathy series that shares the CMH naming - those figures describe a mechanistically unrelated ventricular disease. A second reported family with an independent CORIN null genotype would be the single most valuable addition to this entry.

Show evidence (1 reference)

PMID:37913506 SUPPORT Human Clinical

"Two siblings presented with cardiomyopathy, hypertension, arrhythmia, and fibrosis of the left atrium."

The entire human evidence base for this entity is the two individuals named here, which is what makes every quantitative dimension unmeasured.

Should the common CORIN I555(P568) hypomorphic allele, and the CORIN-low fibrotic cardiomyopathy transcriptomic cluster, be curated as part of this disease entry?

INTERPRETATION RESOLVED corin_hypomorphic_allele_boundary

Attached to

genetic#CORIN pathophysiology#Cardiac Fibroblast Activation

Resolved as NO for the phenotype and prevalence sections, YES as mechanistic corroboration only. The I555(P568) allele (T555I + Q568P) is common in people of African ancestry, reduces rather than abolishes natriuretic peptide processing, and is associated with hypertension, an enhanced hypertrophic response to afterload, and impaired BNP processing in heart failure. Those are common complex traits attributable to a hypomorph in the heterozygous state, not the recessive null disease described here, and importing their frequencies or outcomes would inflate this entry with numbers that do not describe it. The same boundary applies to the transcriptomic finding that a low-CORIN, fibroblast-activated cluster of sporadic cardiomyopathy has worse ejection fraction and prognosis: that cohort is not CORIN-null. Both bodies of work are retained where they speak to MECHANISM - that reduced corin activity is sufficient to raise blood pressure and to dis-inhibit cardiac fibroblast activation - and the corresponding evidence items record exactly that distinction in their explanations.

Show evidence (3 references)

PMID:16216958 SUPPORT Human Clinical

"The corin I555 (P568) allele is common in blacks and is associated with higher blood pressure and an increased risk for prevalent hypertension."

Defines the hypomorphic-allele literature this boundary excludes from the phenotype and prevalence sections: a common allele producing a common complex trait, not the recessive null disease. It concerns a different genotype from CMH30.

PMID:17296875 SUPPORT Human Clinical

"These data suggest that the corin I555(P568) allele represents a cardiac hypertrophy-sensitizing genetic locus in systemic hypertension."

Retained as mechanistic corroboration that reduced corin activity sensitises the heart to hypertrophy under afterload. The genotype is a common hypomorph in the heterozygous state, so neither its effect sizes nor its frequencies transfer to CMH30.

PMID:39315128 SUPPORT Computational

"This cluster also exhibited lower left ventricular ejection fraction (LVEF) and worse prognostic outcomes, establishing the significance of this molecular subclassification."

The transcriptomic prognostic association this boundary declines to import as prognosis for CMH30. The cohort is sporadic cardiomyopathy stratified by CORIN expression, not CORIN-null patients.

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Pathophysiology

9

Biallelic CORIN Null Variant

The initiating lesion is homozygosity for a null allele of CORIN, which encodes a type II transmembrane serine protease expressed primarily in the heart. In the index sibship the consequence was measurable at the protein level: circulating corin was undetectable. Corin is synthesised as a zymogen and activated by cleavage at Arg801 on the cell surface, and the catalytic machinery is a trypsin-like serine protease domain, so a frameshift null allele removes the enzyme rather than merely blunting it.

CORIN hgnc:19012

Genetic context CORIN hgnc:19012 variant_origin: GERMLINE allelic_hit_role: BIALLELIC_INACTIVATION allelic_event: FRAMESHIFT_VARIANT zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION

NM_006587.4(CORIN):c.684dup (p.Met229fs), a 1-bp duplication at 4p12, homozygous in both affected siblings; ClinVar VCV002504113 / OMIM allelic variant 605236.0004, classified pathogenic.

serine-type endopeptidase activity GO:0004252 ⇓ LOSS OF FUNCTION

Downstream

Failure of Pro-ANP Processing Absence of the protease removes the only established physiological route from pro-ANP to mature ANP.

Show evidence (4 references)

PMID:37913506 SUPPORT Human Clinical

"Each had a homozygous null variant in CORIN, the gene encoding atrial natriuretic peptide (ANP)-converting enzyme."

Establishes the biallelic null CORIN genotype as the causal lesion in the affected siblings.

PMID:37913506 SUPPORT Human Clinical

"A plasma sample obtained from one of the siblings had no detectable levels of corin or N-terminal pro-ANP"

Confirms that the genotype produces a true protein-level null in the patient, not merely a predicted one.

PMID:26259032 SUPPORT In Vitro

"It is synthesized as a zymogen that is activated by proteolytic cleavage."

Supplies the zymogen-activation architecture of corin that a null allele removes entirely. IN_VITRO because the activation mechanism is established in cell-based and purified-protein assays.

+ 1 more reference

Failure of Pro-ANP Processing

ANP is synthesised in cardiac myocytes as the precursor pro-ANP, which must be cleaved to release the bioactive C-terminal peptide. Corin is that convertase, and its cleavage of pro-ANP is highly sequence specific. In the absence of corin the precursor is not processed: corin-knockout mice have elevated pro-ANP with no detectable ANP, and the affected human sibling had no detectable N-terminal pro-ANP alongside no detectable corin.

regular atrial cardiac myocyte CL:0002129

peptide hormone processing GO:0016486 ↓ DECREASED

Animal models

Constitutive Corin knockout mouse Mouse recapitulates The processing block is complete and directly measured in this model, matching the human protein-null biochemistry.

Downstream

Deficient ANP-NPR-A-cGMP Signalling No mature ANP is released, so the receptor arm downstream of it is not engaged.

Incomplete BNP Compensation The intact BNP arm is left as the only natriuretic peptide signal.

Show evidence (3 references)

PMID:10880574 SUPPORT In Vitro

"Our results show that recombinant human corin converts pro-ANP to ANP and that the cleavage in pro-ANP by corin is highly sequence specific."

Establishes corin as the enzyme that performs the pro-ANP to ANP conversion step lost in this disease.

PMID:15637153 SUPPORT Model Organism

"Cor-/- mice have elevated levels of pro-ANP but no detectable levels of ANP as compared with WT littermates."

In vivo demonstration that corin loss blocks the processing step, leaving precursor accumulation with no mature hormone.

PMID:15637153 SUPPORT Model Organism

"Thus, our data establish corin as the physiological pro-ANP convertase and indicate that corin deficiency may contribute to hypertensive heart disease."

States that corin is the physiological, not merely a candidate, convertase - the reason no redundant pathway rescues the human null.

Deficient ANP-NPR-A-cGMP Signalling

Mature ANP acts through the natriuretic peptide receptor A guanylyl cyclase to raise cGMP in vascular, renal, and cardiac target cells, producing natriuresis, vasodilation, and restraint of the renin-angiotensin-aldosterone system. With no mature ANP, this cGMP tone is absent. The pharmacological converse is directly demonstrated: giving recombinant corin protein back to corin-knockout mice raised plasma cGMP and lowered angiotensin II and aldosterone. This is the rate-limiting node of the disease - everything distal to it is a consequence of missing cGMP signalling rather than of any structural cardiac protein defect.

regulation of systemic arterial blood pressure by atrial natriuretic peptide GO:0003050 ↓ DECREASED renal sodium excretion GO:0035812 ↓ DECREASED

natriuretic peptide receptor activity GO:0016941 ↓ DECREASED

Downstream

Sodium and Volume Retention with Hypertension Loss of natriuresis, vasodilation, and RAAS restraint raises blood pressure.

Cardiac Fibroblast Activation Loss of the antifibrotic arm of natriuretic peptide signalling dis-inhibits fibroblast activation.

Left Atrial Myocardial Hypertrophy and Enlargement Loss of the antihypertrophic arm of natriuretic peptide signalling permits cardiomyocyte hypertrophy independently of afterload.

Show evidence (2 references)

PMID:37636304 SUPPORT Model Organism

"The corin treatment also decreased the gene expression associated with cardiac hypertrophy and fibrosis, increased plasma cGMP levels, lowered plasma levels of N-terminal pro-atrial natriuretic peptide, angiotensin II, and aldosterone, and lessened lung edema in the Corin KO mice subjected to TAC."

Restoring corin restores the cGMP signal and suppresses RAAS mediators, establishing that corin deficiency is what removes cGMP tone and dis-inhibits RAAS.

PMID:33125488 SUPPORT Other

"Corin deficiency prevents ANP generation and alters electrolyte and body fluid homeostasis."

States the physiological consequence of corin loss for fluid and electrolyte handling. Evidence source is OTHER because this is a review synthesising in vitro, model-organism, and human genetic data.

Incomplete BNP Compensation

Corin also participates in processing of the B-type natriuretic peptide precursor, but in the affected sibling BNP was elevated rather than absent, so the BNP arm remained operational while the ANP arm was dead. That dissociation is the pivot of the primary report's argument: a raised BNP did not prevent the atrial cardiomyopathy, hypertension, arrhythmia, or fibrosis from developing, so BNP does not substitute for ANP at the atrium. Curators should not read the elevated BNP as evidence of preserved natriuretic signalling - it is evidence of a failed rescue.

sodium ion homeostasis GO:0055078 ↓ DECREASED

Downstream

Sodium and Volume Retention with Hypertension Because BNP does not restore the missing ANP signal, the downstream volume and pressure phenotype proceeds.

Show evidence (2 references)

PMID:37913506 SUPPORT Human Clinical

"but had elevated levels of B-type natriuretic peptide (BNP) and one of the two protein markers of fibrosis that we tested"

Documents the dissociation - BNP up, ANP absent - on which the failed-compensation claim rests.

PMID:37913506 SUPPORT Human Clinical

"These and other findings support the hypothesis that BNP cannot fully compensate for a lack of activation of the ANP pathway and that corin is critical to normal ANP activity, left atrial function, and cardiovascular homeostasis."

The authors' own statement of the incomplete-compensation inference and of corin's specific criticality to left atrial function.

Sodium and Volume Retention with Hypertension

Without ANP-driven natriuresis and vasodilation, and with the renin-angiotensin-aldosterone system no longer restrained, sodium and volume are retained and systemic blood pressure rises. Both affected siblings were hypertensive. Corin-knockout mice reproduce this arm precisely: they have spontaneous hypertension by radiotelemetry, worsened by dietary salt loading, and the same salt-sensitive pattern appears when corin activation is blocked upstream in Pcsk6-knockout mice. The resulting chronic pressure and volume load is the mechanical input to atrial remodelling.

regulation of blood pressure GO:0008217 ⚠ ABNORMAL sodium ion homeostasis GO:0055078 ⚠ ABNORMAL

Animal models

Constitutive Corin knockout mouse Mouse recapitulates Spontaneous, salt-sensitive hypertension matching the hypertension seen in the affected siblings.

Downstream

Left Atrial Myocardial Hypertrophy and Enlargement Chronic pressure and volume load raises atrial wall stress and drives hypertrophic remodelling.

Cardiac Fibroblast Activation Sustained wall stress is a fibroblast-activating stimulus in its own right, additive to the loss of natriuretic-peptide restraint.

Show evidence (3 references)

PMID:37913506 SUPPORT Human Clinical

"Two siblings presented with cardiomyopathy, hypertension, arrhythmia, and fibrosis of the left atrium."

Documents hypertension as part of the human corin-null phenotype.

PMID:15637153 SUPPORT Model Organism

"Using radiotelemetry to assess blood pressure, we find that Cor-/- mice have spontaneous hypertension as compared with WT mice, and it is enhanced after dietary salt loading."

Establishes causality and salt-dependence of the hypertension arm in a corin-null organism.

PMID:26259032 SUPPORT Model Organism

"Pcsk6-knockout mice developed salt-sensitive hypertension, and corin activation and pro-atrial natriuretic peptide processing activity were undetectable in these mice."

Independent genetic route to the same endpoint - blocking corin activation rather than corin itself reproduces undetectable pro-ANP processing and salt-sensitive hypertension. The lesion is in PCSK6, not CORIN, so it corroborates the pathway rather than the disease genotype.

Left Atrial Myocardial Hypertrophy and Enlargement

The left atrium becomes enlarged and thickened. Two inputs converge on it: the mechanical pressure and volume load created by hypertension, and the direct loss of the antihypertrophic restraint that natriuretic-peptide/cGMP signalling normally exerts on cardiomyocytes. The atrial predominance is the part that is specific to this disease and is not explained by either input alone - the left atrium is both the principal site of ANP synthesis and the thinnest-walled chamber bearing the load, but why the ventricle is comparatively spared in the human phenotype is unresolved (see the `corin_atrial_selectivity` discussion). In corin-knockout mice the hypertrophic response is not atrium-selective and appears only after about 9 months.

regular atrial cardiac myocyte CL:0002129

cardiac muscle hypertrophy GO:0003300 ↑ INCREASED

left cardiac atrium UBERON:0002079

Animal models

Constitutive Corin knockout mouse Mouse partially recapitulates Corin-null mice develop cardiac hypertrophy, but it is generalised rather than atrium-selective and is attributed by the authors to chronic hypertension.

Downstream

Atrial Arrhythmogenic Substrate Chamber enlargement lengthens conduction paths and supports reentry.

Show evidence (2 references)

PMID:37913506 SUPPORT Human Clinical

"These and other findings support the hypothesis that BNP cannot fully compensate for a lack of activation of the ANP pathway and that corin is critical to normal ANP activity, left atrial function, and cardiovascular homeostasis."

Anchors the left atrium as the chamber whose structure and function depend on intact corin/ANP activity.

PMID:37636304 SUPPORT INDIRECT Model Organism

"Corin KO mice had progressive cardiac dysfunction with cardiac hypertrophy and fibrosis after 9 months of age, likely due to chronic hypertension."

Shows corin loss produces cardiac hypertrophy in vivo. Graded INDIRECT because the murine hypertrophy is not selectively atrial and is attributed by the authors to chronic hypertension rather than to a chamber-specific mechanism.

Cardiac Fibroblast Activation

Cardiac fibroblasts adopt a myofibroblast-like, matrix-producing phenotype. Natriuretic-peptide/cGMP signalling normally opposes this: in neonatal rat cardiac fibroblasts, CORIN overexpression blunted TGF-beta1-induced expression of col1a1 and alpha-smooth muscle actin, the two canonical fibroblast-activation readouts. In human cardiomyopathy transcriptomes the same axis appears as a molecular cluster combining low CORIN expression with a high degree of fibroblast activation. Conformance to `fibrotic_response#Mesenchymal Cell Activation` is asserted on that CORIN-dependent activation evidence; the substituted organ-specific cell type is the cardiac fibroblast.

cardiac fibroblast CL:0002548

myofibroblast differentiation GO:0036446 ↑ INCREASED

Downstream

Left Atrial Fibrosis Activated fibroblasts are the source of the excess atrial matrix.

Show evidence (2 references)

PMID:39315128 SUPPORT In Vitro

"We further found that overexpression of CORIN could mitigate TGFβ1-induced expression of col1a1 and α-SMA in neonatal rat cardiac fibroblasts."

Direct experimental evidence that CORIN restrains cardiac fibroblast activation, so loss of CORIN dis-inhibits it.

PMID:39315128 SUPPORT Computational

"Particularly, a profibrotic, heart failure with reduced ejection fraction (HFrEF)-resembling Cluster 1 emerged, characterized by diminished expression of CORIN and a high degree of fibroblast activation."

Associates low CORIN with fibroblast activation in human cardiomyopathy transcriptomes. This is an unsupervised clustering association in sporadic cardiomyopathy cohorts, not in CORIN-null patients, and the authors themselves flag the absence of clinical-data validation.

Left Atrial Fibrosis

Excess extracellular matrix accumulates in the left atrial wall. In the index sibship this was reported as fibrosis of the left atrium, with one of two circulating fibrosis protein markers elevated. In corin-knockout mice, cardiac fibrosis develops with age and is reversed by recombinant corin protein, which also lowers the transcript signature associated with fibrosis - a rescue experiment that places the matrix accumulation causally downstream of corin loss rather than merely alongside it.

cardiac fibroblast CL:0002548

extracellular matrix organization GO:0030198 ↑ INCREASED collagen fibril organization GO:0030199 ↑ INCREASED

left cardiac atrium UBERON:0002079

Animal models

Constitutive Corin knockout mouse Mouse partially recapitulates Cardiac fibrosis develops in aged corin-null mice and after pressure overload, and - the key point - is reversed by giving back recombinant corin protein, which establishes the fibrosis as a consequence of corin deficiency.

Downstream

Atrial Arrhythmogenic Substrate Interstitial matrix separates myocyte bundles, slowing and fractionating conduction.

Show evidence (2 references)

PMID:37913506 SUPPORT Human Clinical

"Two siblings presented with cardiomyopathy, hypertension, arrhythmia, and fibrosis of the left atrium."

Documents left atrial fibrosis as a defining component of the human phenotype.

PMID:37636304 SUPPORT Model Organism

"When the TAC-operated Corin KO mice were treated with recombinant corin protein, cardiac dysfunction, hypertrophy, and fibrosis were ameliorated."

Rescue by the missing protein establishes the fibrosis as a consequence of corin deficiency rather than an independent process.

Atrial Arrhythmogenic Substrate

An enlarged, fibrotic left atrium is a structurally remodelled substrate in which conduction is slow and heterogeneous, sustaining macro-reentrant flutter and fibrillatory conduction. This is the node that converts the endocrine and structural lesion into the clinical arrhythmia burden - atrial flutter and atrial fibrillation - and, by extension, into thromboembolic risk. It is inferred here from the co-occurrence of atrial structural disease and atrial arrhythmia in the index sibship rather than from electroanatomic mapping in corin-null patients, which has not been reported.

regular atrial cardiac myocyte CL:0002129

cardiac conduction GO:0061337 ⚠ ABNORMAL

left cardiac atrium UBERON:0002079

Animal models

Constitutive Corin knockout mouse Mouse fails to recapitulate No atrial arrhythmia phenotype has been reported in corin-knockout mice. The published characterisation is of blood pressure, chamber hypertrophy, fibrosis, contractile function, and lung oedema; rhythm is not among the reported endpoints, and the arrhythmia that dominates the human phenotype is therefore unmodelled.

Show evidence (2 references)

PMID:37913506 SUPPORT Human Clinical

"Two siblings presented with cardiomyopathy, hypertension, arrhythmia, and fibrosis of the left atrium."

Establishes that arrhythmia and left atrial structural disease co-occur in corin-null patients. The report documents the association, not the electrophysiological substrate mechanism, which is inferred from general atrial-arrhythmia biology.

PMID:40316193 SUPPORT INDIRECT Other

"CORIN variants have been identified in patients with hypertension, heart failure, atrial fibrillation, and stroke."

Places atrial fibrillation among the phenotypes associated with CORIN variation generally. Graded INDIRECT because it aggregates across CORIN variant classes and diseases and does not concern the biallelic-null entity. Evidence source is OTHER because this is a narrative review.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

9

Cardiovascular 3

Atrial Fibrillation HP:0005110

Show evidence (2 references)

PMID:37913506 SUPPORT Human Clinical

"Two siblings presented with cardiomyopathy, hypertension, arrhythmia, and fibrosis of the left atrium."

Documents arrhythmia in the affected siblings. The abstract says "arrhythmia" without naming the rhythm; the specific fibrillation/flutter annotations come from the OMIM/MedGen clinical synopsis derived from the full report.

PMID:40316193 SUPPORT Other

"CORIN variants have been identified in patients with hypertension, heart failure, atrial fibrillation, and stroke."

Corroborates atrial fibrillation as a CORIN-associated phenotype. It aggregates across CORIN variant classes rather than describing the biallelic-null entity. Evidence source OTHER (review).

Hypertension HP:0000822

Show evidence (2 references)

PMID:37913506 SUPPORT Human Clinical

"Two siblings presented with cardiomyopathy, hypertension, arrhythmia, and fibrosis of the left atrium."

States hypertension as part of the presenting phenotype.

PMID:15637153 SUPPORT Model Organism

"Using radiotelemetry to assess blood pressure, we find that Cor-/- mice have spontaneous hypertension as compared with WT mice, and it is enhanced after dietary salt loading."

Model-organism confirmation that corin loss is sufficient to cause hypertension.

Reduced Left Ventricular Ejection Fraction HP:0012664

Show evidence (1 reference)

PMID:37636304 SUPPORT INDIRECT Model Organism

"Corin KO mice had progressive cardiac dysfunction with cardiac hypertrophy and fibrosis after 9 months of age, likely due to chronic hypertension."

Supports late-onset ventricular dysfunction as a consequence of corin loss. Graded INDIRECT because this is the mouse, not the human phenotype; the human annotation itself comes from the OMIM/MedGen clinical synopsis.

Other 6

Atrial Cardiomyopathy HP:0200127

Show evidence (1 reference)

PMID:37913506 SUPPORT Human Clinical

"Two siblings presented with cardiomyopathy, hypertension, arrhythmia, and fibrosis of the left atrium."

States the cardiomyopathy and its left atrial localisation directly.

Left Atrial Enlargement HP:0031295

Show evidence (1 reference)

PMID:37913506 SUPPORT Human Clinical

"These and other findings support the hypothesis that BNP cannot fully compensate for a lack of activation of the ANP pathway and that corin is critical to normal ANP activity, left atrial function, and cardiovascular homeostasis."

Supports left atrial structural and functional involvement. The abstract states left atrial cardiomyopathy and fibrosis but does not itself give the chamber dimensions; the specific enlargement annotation comes from the OMIM/MedGen clinical synopsis derived from the full report.

Left Atrial Fibrosis Myocardial fibrosis HP:0001685

Show evidence (1 reference)

PMID:37913506 SUPPORT Human Clinical

"Two siblings presented with cardiomyopathy, hypertension, arrhythmia, and fibrosis of the left atrium."

States left atrial fibrosis in both affected individuals.

Atrial Flutter HP:0004749

Show evidence (1 reference)

PMID:37913506 SUPPORT INDIRECT Human Clinical

"Two siblings presented with cardiomyopathy, hypertension, arrhythmia, and fibrosis of the left atrium."

Documents arrhythmia in the affected siblings; the flutter subtype is specified in the OMIM/MedGen clinical synopsis derived from the full report, so it is graded INDIRECT.

Decreased Circulating N-Terminal Pro-ANP Decreased circulating A-type natriuretic peptide concentration HP:0020184

Show evidence (1 reference)

PMID:37913506 SUPPORT Human Clinical

"A plasma sample obtained from one of the siblings had no detectable levels of corin or N-terminal pro-ANP"

Directly reports undetectable circulating N-terminal pro-ANP.

Increased Circulating B-Type Natriuretic Peptide Increased circulating brain natriuretic peptide concentration HP:0033534

Show evidence (1 reference)

PMID:37913506 SUPPORT Human Clinical

"but had elevated levels of B-type natriuretic peptide (BNP) and one of the two protein markers of fibrosis that we tested"

Directly reports the elevated BNP.

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Genetic Associations

1

CORIN

Gene: CORIN hgnc:19012 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal Recessive

Show evidence (2 references)

PMID:37913506 SUPPORT Human Clinical

"Each had a homozygous null variant in CORIN, the gene encoding atrial natriuretic peptide (ANP)-converting enzyme."

Establishes CORIN as the causal gene and the biallelic null genotype in both affected siblings.

PMID:17485366 SUPPORT Other

"Corin is a type II transmembrane serine protease expressed primarily in the heart."

Establishes the gene product's class and tissue distribution. Evidence source OTHER because this is a review synthesising in vitro and model-organism work.

Variants (1)

NM_006587.4(CORIN):c.684dup (p.Met229fs) Pathogenic

Gene: CORIN hgnc:19012 FRAMESHIFT

1-bp duplication producing a frameshift at Met229, well upstream of both the Arg801 activation cleavage site and the catalytic serine, so no functional protease can be produced. Homozygous in both affected siblings; circulating corin was undetectable. Catalogued as ClinVar VCV002504113 (dbSNP rs756399499) and OMIM allelic variant 605236.0004.

Show evidence (1 reference)

PMID:37913506 SUPPORT INDIRECT Human Clinical

"A plasma sample obtained from one of the siblings had no detectable levels of corin or N-terminal pro-ANP"

Confirms the variant behaves as a protein null in vivo. Graded INDIRECT because the abstract reports the functional consequence but not the HGVS notation, which comes from ClinVar/OMIM.

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Medical Actions

6

Antihypertensive Therapy

Action: Antihypertensive Therapy NCIT:C172184

Blood-pressure control is the highest-value phenotype-directed intervention, because hypertension is both an early and a mechanistically upstream part of the chain: it is the mechanical load that drives atrial hypertrophy and fibrosis, and it is the arm of the phenotype most firmly established across human and model-organism evidence. No agent class has been tested in CORIN-null patients and no genotype-specific recommendation exists. The mouse rescue data showing that restoring corin lowers angiotensin II and aldosterone offer a mechanistic rationale for renin-angiotensin-aldosterone blockade specifically, but that is an inference, not a trial result.

Mechanism Target:

INHIBITS Sodium and Volume Retention with Hypertension — Pharmacological blood-pressure lowering substitutes for the missing ANP-mediated natriuretic and vasodilatory tone at the level of the systemic phenotype, without restoring the signal itself.

Anticoagulation for Atrial Arrhythmia

Action: Anticoagulation Therapy NCIT:C63341

Atrial fibrillation on a structurally remodelled, fibrotic left atrium is the stroke-risk pathway in this disease, and CORIN variation is separately associated with stroke. Contemporary hypertrophic-cardiomyopathy guidance favours anticoagulation once clinical atrial fibrillation is documented, largely irrespective of conventional risk-score thresholds; whether an isolated CORIN atrial phenotype should inherit that rule rather than a standard CHA2DS2-VASc assessment is a specialist judgement that has not been studied.

Show evidence (1 reference)

PMID:40316193 SUPPORT INDIRECT Other

"CORIN variants have been identified in patients with hypertension, heart failure, atrial fibrillation, and stroke."

Supports the atrial-fibrillation-to-stroke concern that motivates anticoagulation. Graded INDIRECT because it associates CORIN variation with these phenotypes generally and does not evaluate anticoagulation. Evidence source OTHER (review).

Rate or Rhythm Control for Atrial Flutter and Fibrillation

Action: Pharmacotherapy NCIT:C15986

Agent: antiarrhythmic agent NCIT:C47793

Standard antiarrhythmic pharmacotherapy or catheter ablation, applied on ordinary rhythm-management indications. There is no evidence that ablation outcomes in a genetically fibrotic atrium resemble those in ordinary atrial fibrillation, and the fibrotic substrate is a recognised predictor of recurrence generally, so expectations should be set accordingly. Genotype alone is not an indication for any procedure.

Catheter Ablation of Atrial Arrhythmia

Action: Cardiac Ablation NCIT:C100068

Considered on standard rhythm-control indications when drug therapy fails. Listed separately from pharmacological rhythm control because the substrate-dependence of its success is the specific concern in a disease defined by atrial fibrosis.

Genetic Counselling and Cascade Testing

Action: Genetic Counseling NCIT:C15240

Autosomal recessive inheritance changes the counselling arithmetic relative to the rest of the hypertrophic-cardiomyopathy series: the recurrence risk is 25% for siblings of a proband, unaffected parents are obligate carriers, and offspring of a proband are obligate carriers rather than at 50% risk. Cascade testing should target siblings first. Whether heterozygous carriers warrant blood-pressure surveillance is unknown - the hypomorphic-allele literature associating reduced corin activity with hypertension makes it a reasonable question, not an established recommendation.

Show evidence (1 reference)

PMID:37913506 SUPPORT Human Clinical

"Each had a homozygous null variant in CORIN, the gene encoding atrial natriuretic peptide (ANP)-converting enzyme."

The homozygous, recessive genotype is what determines the counselling arithmetic described here.

Recombinant Corin Protein Replacement (experimental, preclinical only)

Action: Pharmacotherapy NCIT:C15986

The mechanistically obvious therapy: give back the missing enzyme. In corin-knockout mice, recombinant soluble corin restores pro-ANP conversion and releases bioactive ANP, and in pressure-overloaded knockout mice recombinant corin protein ameliorated cardiac dysfunction, hypertrophy and fibrosis while raising plasma cGMP and lowering angiotensin II and aldosterone. NOTHING about this has been tested in humans - no dose, no safety, no immunogenicity, no delivery route, no trial. It is listed here because it is the direct pharmacological converse of the disease lesion and therefore the natural target for future work, not as a treatment option.

Mechanism Target:

ACTIVATES Failure of Pro-ANP Processing — Supplies the absent convertase activity, restoring pro-ANP to ANP conversion at the top of the chain rather than palliating its downstream consequences.

Show evidence (1 reference)

PMID:15637153 SUPPORT Model Organism

"Infusion of an active recombinant soluble corin transiently restores pro-ANP conversion, resulting in the release of circulating biologically active ANP."

Direct demonstration that the agent acts on this mechanism node.

Show evidence (2 references)

PMID:37636304 SUPPORT Model Organism

"When the TAC-operated Corin KO mice were treated with recombinant corin protein, cardiac dysfunction, hypertrophy, and fibrosis were ameliorated."

Shows the structural and functional benefit of enzyme replacement in the model organism.

PMID:37636304 SUPPORT Model Organism

"Corin protein may be used to reduce cardiac hypertrophy and fibrosis, suppress the renin-angiotensin-aldosterone system, and improve cardiac function in HF."

The authors' own statement of the therapeutic hypothesis, which remains untested in humans.

🔬

Biochemical Markers

3

Circulating Corin (Undetectable in affected individuals)

Show evidence (1 reference)

PMID:37913506 SUPPORT Human Clinical

"A plasma sample obtained from one of the siblings had no detectable levels of corin or N-terminal pro-ANP"

Reports undetectable circulating corin protein.

N-Terminal Pro-Atrial Natriuretic Peptide (Undetectable in affected individuals)

Show evidence (2 references)

PMID:37913506 SUPPORT Human Clinical

"A plasma sample obtained from one of the siblings had no detectable levels of corin or N-terminal pro-ANP"

Reports undetectable circulating N-terminal pro-ANP.

PMID:15637153 SUPPORT INDIRECT Model Organism

"Cor-/- mice have elevated levels of pro-ANP but no detectable levels of ANP as compared with WT littermates."

The model-organism counterpart measurement. Graded INDIRECT because the murine precursor is elevated while the human N-terminal fragment was undetectable - the analytes measured are not the same.

B-Type Natriuretic Peptide (Elevated in affected individuals)

Show evidence (2 references)

PMID:37913506 SUPPORT Human Clinical

"but had elevated levels of B-type natriuretic peptide (BNP) and one of the two protein markers of fibrosis that we tested"

Reports the elevated BNP.

PMID:19919978 SUPPORT Human Clinical

"Corin, a transmembrane serine protease expressed in cardiomyocytes, cleaves pro-atrial natriuretic peptide and pro-brain natriuretic peptide (BNP) into biologically active peptide hormones."

Establishes that corin also processes proBNP, which is why an elevated total BNP in a corin-null individual cannot be assumed to represent an intact, fully processed BNP signal. The cohort studied carried a hypomorphic allele, not a biallelic null.

🔬

Diagnosis

5

Transthoracic echocardiography with dedicated atrial assessment

First-line imaging, but it must be read against the atrial phenotype rather than the usual hypertrophic-cardiomyopathy checklist. The finding of interest is left atrial size, wall thickness, and function; a normal ventricular septal thickness and the absence of outflow-tract obstruction are not reassurance in this entity, because the disease is not a sarcomeric ventricular cardiomyopathy. Ventricular ejection fraction should also be recorded, since reduced systolic function is part of the reported synopsis and is plausibly a late consequence.

Echocardiography NCIT:C16525

Results: Enlarged, thickened left atrium; ventricular ejection fraction may be reduced.

No echocardiographic criteria specific to CORIN-related atrial cardiomyopathy have been published; this is a rational work-up built from the reported phenotype rather than a validated diagnostic pathway.

Ambulatory rhythm monitoring and 12-lead electrocardiography

Atrial flutter and atrial fibrillation are core to the phenotype and may be paroxysmal, so a single resting ECG is insufficient. Detected atrial arrhythmia is what drives the anticoagulation and rate/rhythm-control decisions, which are the only interventions with any real leverage in this disease at present.

Electrocardiography NCIT:C38053

Results: Atrial fibrillation or atrial flutter.

Show evidence (1 reference)

PMID:37913506 SUPPORT Human Clinical

"Two siblings presented with cardiomyopathy, hypertension, arrhythmia, and fibrosis of the left atrium."

Establishes arrhythmia as a presenting feature that rhythm monitoring would capture. The report does not evaluate monitoring strategies.

Cardiac magnetic resonance imaging with late gadolinium enhancement

The modality that can show atrial fibrosis directly rather than by inference. Atrial wall thinness makes atrial late-gadolinium-enhancement imaging technically demanding and it is not a routinely validated measurement outside specialist centres, so a negative study should not be used to exclude the fibrotic phenotype.

Magnetic Resonance Imaging NCIT:C16809

Results: Left atrial wall fibrosis; atrial and ventricular morphology and function.

Natriuretic peptide profiling (NT-pro-ANP with BNP)

Mechanistically the most discriminating biochemistry available: the corin-null state produces undetectable circulating corin and undetectable N-terminal pro-ANP with an elevated BNP. That pattern - a dead ANP arm beside a live BNP arm - is not produced by ordinary heart failure, in which both rise together. It is nonetheless NOT a validated diagnostic assay for this disease, and NT-pro-ANP is not a routine clinical test; treat it as a mechanistic confirmation once CORIN is implicated, not as a screening test.

Atrial Natriuretic Peptide Measurement NCIT:C74886

Results: Undetectable corin and N-terminal pro-ANP with elevated B-type natriuretic peptide.

Show evidence (1 reference)

PMID:37913506 SUPPORT Human Clinical

"A plasma sample obtained from one of the siblings had no detectable levels of corin or N-terminal pro-ANP but had elevated levels of B-type natriuretic peptide (BNP) and one of the two protein markers of fibrosis that we tested."

Reports the full biochemical pattern this test is intended to detect.

CORIN sequencing on a cardiomyopathy or arrhythmia gene panel

Molecular confirmation requires biallelic CORIN variants. CORIN is not on every legacy hypertrophic-cardiomyopathy panel, which are built around sarcomeric genes, so a "negative HCM panel" does not exclude this diagnosis; check gene content or move to exome/genome sequencing. Because inheritance is recessive, the informative family pattern is affected siblings with unaffected heterozygous parents, not a multigenerational dominant pedigree.

Genetic Testing NCIT:C15709

Results: Biallelic pathogenic CORIN variants.

Show evidence (1 reference)

PMID:37913506 SUPPORT Human Clinical

"Each had a homozygous null variant in CORIN, the gene encoding atrial natriuretic peptide (ANP)-converting enzyme."

Establishes the molecular finding that confirms the diagnosis.

📊

Prevalence

1

Worldwide

Cases In Literature Not yet documented

Only a single sibship (two affected siblings) has been reported. No population prevalence, incidence, carrier frequency, or ethnic-enrichment estimate exists, and the general hypertrophic cardiomyopathy prevalence of roughly 1 in 500 must NOT be substituted - that figure describes sarcomeric ventricular disease, a mechanistically different entity. A numeric rate is deliberately omitted rather than derived.

Show evidence (1 reference)

PMID:37913506 SUPPORT Human Clinical

"Two siblings presented with cardiomyopathy, hypertension, arrhythmia, and fibrosis of the left atrium."

The report that delineates the entity describes two affected individuals, establishing the entire published case count at the time of curation.

🐁

Animal Models

1

Constitutive Corin knockout mouse

The workhorse model for the corin/ANP axis. Corin-null mice develop normally, have elevated pro-ANP with no detectable mature ANP, and show spontaneous, salt-sensitive hypertension by radiotelemetry, plus cardiac hypertrophy and a late decline in cardiac function. A later study extended the phenotype: progressive cardiac dysfunction with hypertrophy and fibrosis after 9 months, faster deterioration than wild type after transverse aortic constriction, and amelioration of dysfunction, hypertrophy, and fibrosis by recombinant corin protein, which also raised plasma cGMP and lowered angiotensin II and aldosterone.

Species

Mouse

Genotype

Corin-/- (constitutive whole-body knockout)

Publication

PMID:15637153

Pathograph links

Failure of Pro-ANP Processing recapitulates fidelity: high The processing block is complete and directly measured in this model, matching the human protein-null biochemistry.

Limitations: Murine plasma reports accumulating pro-ANP precursor whereas the human sibling was assayed for the N-terminal fragment, so the two measurements are not the same analyte even though both indicate an abolished conversion step.

Readouts

Plasma pro-ANP and mature ANP

Direction: ABOLISHED

Interpretation: Mature ANP is abolished with precursor accumulation - the defining readout of the lost convertase step.

Show evidence (1 reference)

PMID:15637153 SUPPORT Model Organism

"Cor-/- mice have elevated levels of pro-ANP but no detectable levels of ANP as compared with WT littermates."

Reports the measurement underlying this readout.

Restoration of pro-ANP conversion by recombinant soluble corin

Direction: RESTORED

Interpretation: Supplying the missing enzyme restores conversion, closing the causal loop on this node.

Show evidence (1 reference)

PMID:15637153 SUPPORT Model Organism

"Infusion of an active recombinant soluble corin transiently restores pro-ANP conversion, resulting in the release of circulating biologically active ANP."

Reports the rescue measurement underlying this readout.

Show evidence (1 reference)

PMID:15637153 SUPPORT Model Organism

"Thus, our data establish corin as the physiological pro-ANP convertase and indicate that corin deficiency may contribute to hypertensive heart disease."

Supports treating this model as informative for the pro-ANP processing node.

Sodium and Volume Retention with Hypertension recapitulates fidelity: high Spontaneous, salt-sensitive hypertension matching the hypertension seen in the affected siblings.

Limitations: Murine blood-pressure regulation is measured under controlled dietary salt that has no counterpart in the human report, so the salt-sensitivity dimension is untested in patients.

Readouts

Radiotelemetric arterial blood pressure

Direction: INCREASED

Interpretation: Direct demonstration that corin loss raises blood pressure, worsened by salt loading.

Show evidence (1 reference)

PMID:15637153 SUPPORT Model Organism

"Using radiotelemetry to assess blood pressure, we find that Cor-/- mice have spontaneous hypertension as compared with WT mice, and it is enhanced after dietary salt loading."

Reports the measurement underlying this readout.

Show evidence (1 reference)

PMID:15637153 SUPPORT Model Organism

"Using radiotelemetry to assess blood pressure, we find that Cor-/- mice have spontaneous hypertension as compared with WT mice, and it is enhanced after dietary salt loading."

Supports treating this model as informative for the hypertension node.

Left Atrial Myocardial Hypertrophy and Enlargement partially recapitulates fidelity: low Corin-null mice develop cardiac hypertrophy, but it is generalised rather than atrium-selective and is attributed by the authors to chronic hypertension.

Limitations: The defining feature of the human disease is that the hypertrophy is LEFT ATRIAL. The mouse does not reproduce that chamber selectivity, so it cannot be used as evidence for the atrial localisation of the phenotype - only for the existence of a hypertrophic response to corin loss. The transverse-aortic-constriction variant of the model imposes ventricular afterload surgically, which is further removed still from spontaneous human atrial disease.

Readouts

Cardiac hypertrophy on histology

Direction: INCREASED

Interpretation: Establishes a hypertrophic response to corin loss without establishing its chamber distribution.

Show evidence (1 reference)

PMID:37636304 SUPPORT INDIRECT Model Organism

"Corin KO mice had progressive cardiac dysfunction with cardiac hypertrophy and fibrosis after 9 months of age, likely due to chronic hypertension."

Reports the hypertrophy measurement. Graded INDIRECT because it is not atrium-specific.

Show evidence (1 reference)

PMID:15637153 SUPPORT INDIRECT Model Organism

"In addition, Cor-/- mice exhibit cardiac hypertrophy resulting in a mild decline in cardiac function later in life."

Supports partial informativeness of this model for the hypertrophy node. Graded INDIRECT because the murine hypertrophy is not chamber-selective.

Left Atrial Fibrosis partially recapitulates fidelity: moderate Cardiac fibrosis develops in aged corin-null mice and after pressure overload, and - the key point - is reversed by giving back recombinant corin protein, which establishes the fibrosis as a consequence of corin deficiency.

Limitations: As with hypertrophy, the murine fibrosis is not localised to the left atrium, and the pressure-overload variant of the model applies a ventricular afterload stimulus rather than reproducing the spontaneous atrial disease.

Readouts

Cardiac fibrosis on Sirius red / Masson trichrome staining after recombinant corin

Direction: RESTORED

Interpretation: Pharmacological replacement of the missing enzyme reverses the fibrotic remodelling, supporting a causal rather than incidental relationship.

Show evidence (1 reference)

PMID:37636304 SUPPORT Model Organism

"When the TAC-operated Corin KO mice were treated with recombinant corin protein, cardiac dysfunction, hypertrophy, and fibrosis were ameliorated."

Reports the rescue measurement underlying this readout.

Show evidence (1 reference)

PMID:37636304 SUPPORT Model Organism

"Corin deficiency impairs cardiac function and exacerbates HF development in mice."

Supports treating this model as informative for the fibrosis and cardiac-dysfunction nodes.

Atrial Arrhythmogenic Substrate fails to recapitulate fidelity: low No atrial arrhythmia phenotype has been reported in corin-knockout mice. The published characterisation is of blood pressure, chamber hypertrophy, fibrosis, contractile function, and lung oedema; rhythm is not among the reported endpoints, and the arrhythmia that dominates the human phenotype is therefore unmodelled.

Limitations: This is a negative claim about model coverage, and it should be read as such: the absence of a reported arrhythmia phenotype reflects endpoints that were not assessed as much as any demonstrated absence of arrhythmia. Either way the model cannot currently substantiate the arrhythmic arm of the human disease, which is the arm carrying the stroke and quality-of-life burden.

Show evidence (1 reference)

PMID:37636304 SUPPORT Model Organism

"Cardiac function was assessed by echocardiography and tissue analysis in Corin KO mice at different ages or subjected to transverse aortic constriction (TAC), which increased pressure overload."

The stated assessment battery for this model is echocardiography and tissue analysis, with no rhythm monitoring - so no atrial arrhythmia endpoint exists to recapitulate the human phenotype.

Show evidence (1 reference)

PMID:15637153 SUPPORT Model Organism

"Thus, our data establish corin as the physiological pro-ANP convertase and indicate that corin deficiency may contribute to hypertensive heart disease."

Establishes the model as the definitive in vivo system for the corin/pro-ANP axis this disease disrupts.

{ }

Source YAML

click to show

name: Hypertrophic Cardiomyopathy 30, Atrial
creation_date: "2026-08-19T00:00:00Z"
description: >-
  Cardiomyopathy, familial hypertrophic, 30, atrial (CMH30; OMIM 620734) is an
  autosomal recessive cardiomyopathy caused by biallelic loss-of-function
  variants in CORIN, the gene encoding the type II transmembrane cardiac serine
  protease that converts pro-atrial natriuretic peptide (pro-ANP) into mature,
  bioactive ANP. Despite its placement in the numbered familial hypertrophic
  cardiomyopathy series, CMH30 is not a sarcomeric, left-ventricular
  hypertrophic cardiomyopathy: its defining lesion is an **endocrine** one, and
  the phenotype is a left-atrial cardiomyopathy - an enlarged, thickened,
  fibrotic left atrium with atrial flutter and fibrillation, on a background of
  hypertension. The disease is delineated from a single sibship reported in 2023
  in whom a homozygous CORIN null variant was accompanied by undetectable
  circulating corin and undetectable N-terminal pro-ANP, while B-type
  natriuretic peptide was elevated - the observation on which the authors' core
  inference rests, namely that BNP cannot fully compensate for a dead ANP arm
  and that corin is critical to normal left atrial function. The mechanism is
  therefore a natriuretic-peptide-axis failure read out in the atrium: without
  ANP there is no NPR-A/cGMP tone to oppose sodium and volume retention,
  renin-angiotensin-aldosterone drive, cardiomyocyte hypertrophy, or fibroblast
  activation, and the left atrium - the tissue that both synthesises ANP and
  bears the earliest pressure and volume load - is where that loss is expressed
  first. Corin-knockout mice reproduce the endocrine and blood-pressure arms of
  this chain (abolished pro-ANP processing, salt-sensitive spontaneous
  hypertension, late hypertrophy and fibrosis, rescued by recombinant corin) but
  not the atrial selectivity of the human disease. The human evidence base is
  one family; penetrance, natural history, arrhythmic and stroke risk, and any
  genotype-specific therapy are all unmeasured.
category: Mendelian
parents:
- Hypertrophic Cardiomyopathy
- Genetic Disorder
synonyms:
- CMH30
- cardiomyopathy, familial hypertrophic, 30, atrial
- familial atrial hypertrophic cardiomyopathy 30
- CORIN-related left atrial cardiomyopathy
disease_term:
  preferred_term: cardiomyopathy, familial hypertrophic, 30, atrial
  term:
    id: MONDO:0958241
    label: cardiomyopathy, familial hypertrophic, 30, atrial
notes: >-
  GeneReviews baseline: PubMed was searched for a GeneReviews chapter covering
  this entity (`CORIN GeneReviews[All Fields]`, `Hypertrophic Cardiomyopathy 30
  GeneReviews[TI]`) and none exists. CORIN is not a gene covered by the
  Nonsyndromic Hypertrophic Cardiomyopathy Overview, which is scoped to
  sarcomeric disease. There is therefore no expert-curated Clinical
  Characteristics list to cross-reference; the phenotype set here derives from
  the OMIM/MedGen clinical synopsis for OMIM:620734 and from the primary report
  (PMID:37913506).

  Entity-identity note (NEC preflight): `just preflight-dr` returned SKIP
  because MONDO records no causal gene (RO:0004003) for MONDO:0958241, so the
  manual preflight was applied. The MONDO term xrefs OMIM:620734 and
  MEDGEN:1858408; both name CORIN at 4p12 as the causal gene, and CORIN
  dominates the deep-research report's gene mentions (CORIN=49 versus 2 for the
  next symbol). The "atrial" qualifier is part of the entity identity - this is
  not generic ventricular hypertrophic cardiomyopathy, and literature on
  sarcomeric CMH1-CMH29 has deliberately not been imported.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    Only a single sibship (two affected siblings) has been reported. No
    population prevalence, incidence, carrier frequency, or ethnic-enrichment
    estimate exists, and the general hypertrophic cardiomyopathy prevalence of
    roughly 1 in 500 must NOT be substituted - that figure describes sarcomeric
    ventricular disease, a mechanistically different entity. A numeric rate is
    deliberately omitted rather than derived.
  evidence:
  - reference: PMID:37913506
    reference_title: "Corin and Left Atrial Cardiomyopathy, Hypertension, Arrhythmia, and Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two siblings presented with cardiomyopathy, hypertension, arrhythmia, and
      fibrosis of the left atrium.
    explanation: >-
      The report that delineates the entity describes two affected individuals,
      establishing the entire published case count at the time of curation.
inheritance:
- name: Autosomal Recessive
  description: >-
    Both affected siblings carried the CORIN null variant in the homozygous
    state, and the associated ClinVar record (VCV002504113, OMIM allelic variant
    605236.0004, NM_006587.4(CORIN):c.684dup p.Met229fs, a 1-bp duplication at
    4p12) is classified pathogenic. Heterozygous relatives were not reported as
    having the atrial cardiomyopathy phenotype. Note that this is a different
    dose-response regime from the common hypomorphic CORIN I555(P568) allele,
    which is a heterozygous-state susceptibility factor for hypertension and
    hypertrophy rather than a cause of CMH30.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:37913506
    reference_title: "Corin and Left Atrial Cardiomyopathy, Hypertension, Arrhythmia, and Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Each had a homozygous null variant in CORIN, the gene encoding atrial
      natriuretic peptide (ANP)-converting enzyme.
    explanation: >-
      Homozygosity for a null allele in both affected siblings is the direct
      statement of biallelic, recessive causation.
pathophysiology:
- name: Biallelic CORIN Null Variant
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    The initiating lesion is homozygosity for a null allele of CORIN, which
    encodes a type II transmembrane serine protease expressed primarily in the
    heart. In the index sibship the consequence was measurable at the protein
    level: circulating corin was undetectable. Corin is synthesised as a zymogen
    and activated by cleavage at Arg801 on the cell surface, and the catalytic
    machinery is a trypsin-like serine protease domain, so a frameshift null
    allele removes the enzyme rather than merely blunting it.
  genetic_context:
    gene:
      preferred_term: CORIN
      term:
        id: hgnc:19012
        label: CORIN
    allelic_events:
    - FRAMESHIFT_VARIANT
    allelic_hit_role: BIALLELIC_INACTIVATION
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      NM_006587.4(CORIN):c.684dup (p.Met229fs), a 1-bp duplication at 4p12,
      homozygous in both affected siblings; ClinVar VCV002504113 / OMIM allelic
      variant 605236.0004, classified pathogenic.
  genes:
  - preferred_term: CORIN
    term:
      id: hgnc:19012
      label: CORIN
  molecular_functions:
  - preferred_term: serine-type endopeptidase activity
    term:
      id: GO:0004252
      label: serine-type endopeptidase activity
    modifier: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:37913506
    reference_title: "Corin and Left Atrial Cardiomyopathy, Hypertension, Arrhythmia, and Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Each had a homozygous null variant in CORIN, the gene encoding atrial
      natriuretic peptide (ANP)-converting enzyme.
    explanation: >-
      Establishes the biallelic null CORIN genotype as the causal lesion in the
      affected siblings.
  - reference: PMID:37913506
    reference_title: "Corin and Left Atrial Cardiomyopathy, Hypertension, Arrhythmia, and Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A plasma sample obtained from one of the siblings had no detectable levels
      of corin or N-terminal pro-ANP
    explanation: >-
      Confirms that the genotype produces a true protein-level null in the
      patient, not merely a predicted one.
  - reference: PMID:26259032
    reference_title: "PCSK6-mediated corin activation is essential for normal blood pressure."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      It is synthesized as a zymogen that is activated by proteolytic cleavage.
    explanation: >-
      Supplies the zymogen-activation architecture of corin that a null allele
      removes entirely. IN_VITRO because the activation mechanism is established
      in cell-based and purified-protein assays.
  - reference: PMID:14559895
    reference_title: "Functional analysis of the transmembrane domain and activation cleavage of human corin: design and characterization of a soluble corin."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      a mutation at the conserved activation cleavage site, R801A, abolished the
      function of corin, demonstrating that the activation cleavage is essential
      for corin activity
    explanation: >-
      Shows the enzymatic activity is all-or-none at the activation step,
      supporting the treatment of a null allele as complete loss of the
      protease.
  downstream:
  - target: Failure of Pro-ANP Processing
    description: >-
      Absence of the protease removes the only established physiological route
      from pro-ANP to mature ANP.
- name: Failure of Pro-ANP Processing
  biological_scale: MOLECULAR
  role: effector
  description: >-
    ANP is synthesised in cardiac myocytes as the precursor pro-ANP, which must
    be cleaved to release the bioactive C-terminal peptide. Corin is that
    convertase, and its cleavage of pro-ANP is highly sequence specific. In the
    absence of corin the precursor is not processed: corin-knockout mice have
    elevated pro-ANP with no detectable ANP, and the affected human sibling had
    no detectable N-terminal pro-ANP alongside no detectable corin.
  cell_types:
  - preferred_term: regular atrial cardiac myocyte
    term:
      id: CL:0002129
      label: regular atrial cardiac myocyte
  biological_processes:
  - preferred_term: peptide hormone processing
    term:
      id: GO:0016486
      label: peptide hormone processing
    modifier: DECREASED
  evidence:
  - reference: PMID:10880574
    reference_title: "Corin, a transmembrane cardiac serine protease, acts as a pro-atrial natriuretic peptide-converting enzyme."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Our results show that recombinant human corin converts pro-ANP to ANP and
      that the cleavage in pro-ANP by corin is highly sequence specific.
    explanation: >-
      Establishes corin as the enzyme that performs the pro-ANP to ANP
      conversion step lost in this disease.
  - reference: PMID:15637153
    reference_title: "Hypertension in mice lacking the proatrial natriuretic peptide convertase corin."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Cor-/- mice have elevated levels of pro-ANP but no detectable levels of
      ANP as compared with WT littermates.
    explanation: >-
      In vivo demonstration that corin loss blocks the processing step, leaving
      precursor accumulation with no mature hormone.
  - reference: PMID:15637153
    reference_title: "Hypertension in mice lacking the proatrial natriuretic peptide convertase corin."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Thus, our data establish corin as the physiological pro-ANP convertase and
      indicate that corin deficiency may contribute to hypertensive heart
      disease.
    explanation: >-
      States that corin is the physiological, not merely a candidate,
      convertase - the reason no redundant pathway rescues the human null.
  downstream:
  - target: Deficient ANP-NPR-A-cGMP Signalling
    description: >-
      No mature ANP is released, so the receptor arm downstream of it is not
      engaged.
  - target: Incomplete BNP Compensation
    description: >-
      The intact BNP arm is left as the only natriuretic peptide signal.
- name: Deficient ANP-NPR-A-cGMP Signalling
  biological_scale: CELLULAR
  role: central_effector
  description: >-
    Mature ANP acts through the natriuretic peptide receptor A guanylyl cyclase
    to raise cGMP in vascular, renal, and cardiac target cells, producing
    natriuresis, vasodilation, and restraint of the
    renin-angiotensin-aldosterone system. With no mature ANP, this cGMP tone is
    absent. The pharmacological converse is directly demonstrated: giving
    recombinant corin protein back to corin-knockout mice raised plasma cGMP and
    lowered angiotensin II and aldosterone. This is the rate-limiting node of
    the disease - everything distal to it is a consequence of missing cGMP
    signalling rather than of any structural cardiac protein defect.
  biological_processes:
  - preferred_term: regulation of systemic arterial blood pressure by atrial natriuretic peptide
    term:
      id: GO:0003050
      label: regulation of systemic arterial blood pressure by atrial natriuretic peptide
    modifier: DECREASED
  - preferred_term: renal sodium excretion
    term:
      id: GO:0035812
      label: renal sodium excretion
    modifier: DECREASED
  molecular_functions:
  - preferred_term: natriuretic peptide receptor activity
    term:
      id: GO:0016941
      label: natriuretic peptide receptor activity
    modifier: DECREASED
  evidence:
  - reference: PMID:37636304
    reference_title: "Corin deficiency impairs cardiac function in mouse models of heart failure."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The corin treatment also decreased the gene expression associated with
      cardiac hypertrophy and fibrosis, increased plasma cGMP levels, lowered
      plasma levels of N-terminal pro-atrial natriuretic peptide, angiotensin
      II, and aldosterone, and lessened lung edema in the Corin KO mice
      subjected to TAC.
    explanation: >-
      Restoring corin restores the cGMP signal and suppresses RAAS mediators,
      establishing that corin deficiency is what removes cGMP tone and
      dis-inhibits RAAS.
  - reference: PMID:33125488
    reference_title: "Function and regulation of corin in physiology and disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Corin deficiency prevents ANP generation and alters electrolyte and body
      fluid homeostasis.
    explanation: >-
      States the physiological consequence of corin loss for fluid and
      electrolyte handling. Evidence source is OTHER because this is a review
      synthesising in vitro, model-organism, and human genetic data.
  downstream:
  - target: Sodium and Volume Retention with Hypertension
    description: >-
      Loss of natriuresis, vasodilation, and RAAS restraint raises blood
      pressure.
  - target: Cardiac Fibroblast Activation
    description: >-
      Loss of the antifibrotic arm of natriuretic peptide signalling
      dis-inhibits fibroblast activation.
  - target: Left Atrial Myocardial Hypertrophy and Enlargement
    description: >-
      Loss of the antihypertrophic arm of natriuretic peptide signalling permits
      cardiomyocyte hypertrophy independently of afterload.
- name: Incomplete BNP Compensation
  biological_scale: ORGANISM
  role: modifier
  description: >-
    Corin also participates in processing of the B-type natriuretic peptide
    precursor, but in the affected sibling BNP was elevated rather than absent,
    so the BNP arm remained operational while the ANP arm was dead. That
    dissociation is the pivot of the primary report's argument: a raised BNP did
    not prevent the atrial cardiomyopathy, hypertension, arrhythmia, or fibrosis
    from developing, so BNP does not substitute for ANP at the atrium. Curators
    should not read the elevated BNP as evidence of preserved natriuretic
    signalling - it is evidence of a failed rescue.
  biological_processes:
  - preferred_term: sodium ion homeostasis
    term:
      id: GO:0055078
      label: sodium ion homeostasis
    modifier: DECREASED
  evidence:
  - reference: PMID:37913506
    reference_title: "Corin and Left Atrial Cardiomyopathy, Hypertension, Arrhythmia, and Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      but had elevated levels of B-type natriuretic peptide (BNP) and one of the
      two protein markers of fibrosis that we tested
    explanation: >-
      Documents the dissociation - BNP up, ANP absent - on which the
      failed-compensation claim rests.
  - reference: PMID:37913506
    reference_title: "Corin and Left Atrial Cardiomyopathy, Hypertension, Arrhythmia, and Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These and other findings support the hypothesis that BNP cannot fully
      compensate for a lack of activation of the ANP pathway and that corin is
      critical to normal ANP activity, left atrial function, and cardiovascular
      homeostasis.
    explanation: >-
      The authors' own statement of the incomplete-compensation inference and of
      corin's specific criticality to left atrial function.
  downstream:
  - target: Sodium and Volume Retention with Hypertension
    description: >-
      Because BNP does not restore the missing ANP signal, the downstream volume
      and pressure phenotype proceeds.
- name: Sodium and Volume Retention with Hypertension
  biological_scale: ORGANISM
  role: amplifier
  description: >-
    Without ANP-driven natriuresis and vasodilation, and with the
    renin-angiotensin-aldosterone system no longer restrained, sodium and volume
    are retained and systemic blood pressure rises. Both affected siblings were
    hypertensive. Corin-knockout mice reproduce this arm precisely: they have
    spontaneous hypertension by radiotelemetry, worsened by dietary salt
    loading, and the same salt-sensitive pattern appears when corin activation
    is blocked upstream in Pcsk6-knockout mice. The resulting chronic pressure
    and volume load is the mechanical input to atrial remodelling.
  biological_processes:
  - preferred_term: regulation of blood pressure
    term:
      id: GO:0008217
      label: regulation of blood pressure
    modifier: ABNORMAL
  - preferred_term: sodium ion homeostasis
    term:
      id: GO:0055078
      label: sodium ion homeostasis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:37913506
    reference_title: "Corin and Left Atrial Cardiomyopathy, Hypertension, Arrhythmia, and Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two siblings presented with cardiomyopathy, hypertension, arrhythmia, and
      fibrosis of the left atrium.
    explanation: >-
      Documents hypertension as part of the human corin-null phenotype.
  - reference: PMID:15637153
    reference_title: "Hypertension in mice lacking the proatrial natriuretic peptide convertase corin."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Using radiotelemetry to assess blood pressure, we find that Cor-/- mice
      have spontaneous hypertension as compared with WT mice, and it is enhanced
      after dietary salt loading.
    explanation: >-
      Establishes causality and salt-dependence of the hypertension arm in a
      corin-null organism.
  - reference: PMID:26259032
    reference_title: "PCSK6-mediated corin activation is essential for normal blood pressure."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Pcsk6-knockout mice developed salt-sensitive hypertension, and corin
      activation and pro-atrial natriuretic peptide processing activity were
      undetectable in these mice.
    explanation: >-
      Independent genetic route to the same endpoint - blocking corin activation rather
      than corin itself reproduces undetectable pro-ANP processing and salt-sensitive
      hypertension. The lesion is in PCSK6, not CORIN, so it corroborates the pathway
      rather than the disease genotype.
  downstream:
  - target: Left Atrial Myocardial Hypertrophy and Enlargement
    description: >-
      Chronic pressure and volume load raises atrial wall stress and drives
      hypertrophic remodelling.
  - target: Cardiac Fibroblast Activation
    description: >-
      Sustained wall stress is a fibroblast-activating stimulus in its own
      right, additive to the loss of natriuretic-peptide restraint.
- name: Left Atrial Myocardial Hypertrophy and Enlargement
  biological_scale: TISSUE
  role: effector
  description: >-
    The left atrium becomes enlarged and thickened. Two inputs converge on it:
    the mechanical pressure and volume load created by hypertension, and the
    direct loss of the antihypertrophic restraint that natriuretic-peptide/cGMP
    signalling normally exerts on cardiomyocytes. The atrial predominance is the
    part that is specific to this disease and is not explained by either input
    alone - the left atrium is both the principal site of ANP synthesis and the
    thinnest-walled chamber bearing the load, but why the ventricle is
    comparatively spared in the human phenotype is unresolved (see the
    `corin_atrial_selectivity` discussion). In corin-knockout mice the
    hypertrophic response is not atrium-selective and appears only after about
    9 months.
  cell_types:
  - preferred_term: regular atrial cardiac myocyte
    term:
      id: CL:0002129
      label: regular atrial cardiac myocyte
  biological_processes:
  - preferred_term: cardiac muscle hypertrophy
    term:
      id: GO:0003300
      label: cardiac muscle hypertrophy
    modifier: INCREASED
  locations:
  - preferred_term: left cardiac atrium
    term:
      id: UBERON:0002079
      label: left cardiac atrium
  evidence:
  - reference: PMID:37913506
    reference_title: "Corin and Left Atrial Cardiomyopathy, Hypertension, Arrhythmia, and Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These and other findings support the hypothesis that BNP cannot fully
      compensate for a lack of activation of the ANP pathway and that corin is
      critical to normal ANP activity, left atrial function, and cardiovascular
      homeostasis.
    explanation: >-
      Anchors the left atrium as the chamber whose structure and function depend
      on intact corin/ANP activity.
  - reference: PMID:37636304
    reference_title: "Corin deficiency impairs cardiac function in mouse models of heart failure."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Corin KO mice had progressive cardiac dysfunction with cardiac hypertrophy
      and fibrosis after 9 months of age, likely due to chronic hypertension.
    explanation: >-
      Shows corin loss produces cardiac hypertrophy in vivo. Graded INDIRECT because the
      murine hypertrophy is not selectively atrial and is attributed by the authors to
      chronic hypertension rather than to a chamber-specific mechanism.
  downstream:
  - target: Atrial Arrhythmogenic Substrate
    description: >-
      Chamber enlargement lengthens conduction paths and supports reentry.
- name: Cardiac Fibroblast Activation
  biological_scale: CELLULAR
  role: effector
  conforms_to: "fibrotic_response#Mesenchymal Cell Activation"
  description: >-
    Cardiac fibroblasts adopt a myofibroblast-like, matrix-producing phenotype.
    Natriuretic-peptide/cGMP signalling normally opposes this: in neonatal rat
    cardiac fibroblasts, CORIN overexpression blunted TGF-beta1-induced
    expression of col1a1 and alpha-smooth muscle actin, the two canonical
    fibroblast-activation readouts. In human cardiomyopathy transcriptomes the
    same axis appears as a molecular cluster combining low CORIN expression with
    a high degree of fibroblast activation. Conformance to
    `fibrotic_response#Mesenchymal Cell Activation` is asserted on that
    CORIN-dependent activation evidence; the substituted organ-specific cell
    type is the cardiac fibroblast.
  cell_types:
  - preferred_term: cardiac fibroblast
    term:
      id: CL:0002548
      label: fibroblast of cardiac tissue
  biological_processes:
  - preferred_term: myofibroblast differentiation
    term:
      id: GO:0036446
      label: myofibroblast differentiation
    modifier: INCREASED
  evidence:
  - reference: PMID:39315128
    reference_title: "Progression from cardiomyopathy to heart failure with reduced ejection fraction: A CORIN deficient course."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We further found that overexpression of CORIN could mitigate TGFβ1-induced
      expression of col1a1 and α-SMA in neonatal rat cardiac fibroblasts.
    explanation: >-
      Direct experimental evidence that CORIN restrains cardiac fibroblast
      activation, so loss of CORIN dis-inhibits it.
  - reference: PMID:39315128
    reference_title: "Progression from cardiomyopathy to heart failure with reduced ejection fraction: A CORIN deficient course."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      Particularly, a profibrotic, heart failure with reduced ejection fraction
      (HFrEF)-resembling Cluster 1 emerged, characterized by diminished
      expression of CORIN and a high degree of fibroblast activation.
    explanation: >-
      Associates low CORIN with fibroblast activation in human cardiomyopathy
      transcriptomes. This is an unsupervised clustering association in sporadic
      cardiomyopathy cohorts, not in CORIN-null patients, and the authors themselves
      flag the absence of clinical-data validation.
  downstream:
  - target: Left Atrial Fibrosis
    description: >-
      Activated fibroblasts are the source of the excess atrial matrix.
- name: Left Atrial Fibrosis
  biological_scale: TISSUE
  role: effector
  conforms_to: "fibrotic_response#Excessive ECM Deposition"
  description: >-
    Excess extracellular matrix accumulates in the left atrial wall. In the
    index sibship this was reported as fibrosis of the left atrium, with one of
    two circulating fibrosis protein markers elevated. In corin-knockout mice,
    cardiac fibrosis develops with age and is reversed by recombinant corin
    protein, which also lowers the transcript signature associated with
    fibrosis - a rescue experiment that places the matrix accumulation causally
    downstream of corin loss rather than merely alongside it.
  cell_types:
  - preferred_term: cardiac fibroblast
    term:
      id: CL:0002548
      label: fibroblast of cardiac tissue
  biological_processes:
  - preferred_term: extracellular matrix organization
    term:
      id: GO:0030198
      label: extracellular matrix organization
    modifier: INCREASED
  - preferred_term: collagen fibril organization
    term:
      id: GO:0030199
      label: collagen fibril organization
    modifier: INCREASED
  locations:
  - preferred_term: left cardiac atrium
    term:
      id: UBERON:0002079
      label: left cardiac atrium
  evidence:
  - reference: PMID:37913506
    reference_title: "Corin and Left Atrial Cardiomyopathy, Hypertension, Arrhythmia, and Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two siblings presented with cardiomyopathy, hypertension, arrhythmia, and
      fibrosis of the left atrium.
    explanation: >-
      Documents left atrial fibrosis as a defining component of the human
      phenotype.
  - reference: PMID:37636304
    reference_title: "Corin deficiency impairs cardiac function in mouse models of heart failure."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      When the TAC-operated Corin KO mice were treated with recombinant corin
      protein, cardiac dysfunction, hypertrophy, and fibrosis were ameliorated.
    explanation: >-
      Rescue by the missing protein establishes the fibrosis as a consequence of
      corin deficiency rather than an independent process.
  downstream:
  - target: Atrial Arrhythmogenic Substrate
    description: >-
      Interstitial matrix separates myocyte bundles, slowing and fractionating
      conduction.
- name: Atrial Arrhythmogenic Substrate
  biological_scale: TISSUE
  role: effector
  description: >-
    An enlarged, fibrotic left atrium is a structurally remodelled substrate in
    which conduction is slow and heterogeneous, sustaining macro-reentrant
    flutter and fibrillatory conduction. This is the node that converts the
    endocrine and structural lesion into the clinical arrhythmia burden -
    atrial flutter and atrial fibrillation - and, by extension, into
    thromboembolic risk. It is inferred here from the co-occurrence of atrial
    structural disease and atrial arrhythmia in the index sibship rather than
    from electroanatomic mapping in corin-null patients, which has not been
    reported.
  cell_types:
  - preferred_term: regular atrial cardiac myocyte
    term:
      id: CL:0002129
      label: regular atrial cardiac myocyte
  biological_processes:
  - preferred_term: cardiac conduction
    term:
      id: GO:0061337
      label: cardiac conduction
    modifier: ABNORMAL
  locations:
  - preferred_term: left cardiac atrium
    term:
      id: UBERON:0002079
      label: left cardiac atrium
  evidence:
  - reference: PMID:37913506
    reference_title: "Corin and Left Atrial Cardiomyopathy, Hypertension, Arrhythmia, and Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two siblings presented with cardiomyopathy, hypertension, arrhythmia, and
      fibrosis of the left atrium.
    explanation: >-
      Establishes that arrhythmia and left atrial structural disease co-occur in
      corin-null patients. The report documents the association, not the
      electrophysiological substrate mechanism, which is inferred from general
      atrial-arrhythmia biology.
  - reference: PMID:40316193
    reference_title: "Corin in cardiovascular diseases and stroke."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: >-
      CORIN variants have been identified in patients with hypertension, heart
      failure, atrial fibrillation, and stroke.
    explanation: >-
      Places atrial fibrillation among the phenotypes associated with CORIN variation
      generally. Graded INDIRECT because it aggregates across CORIN variant classes and
      diseases and does not concern the biallelic-null entity. Evidence source is OTHER
      because this is a narrative review.
phenotypes:
- category: Cardiovascular
  name: Atrial Cardiomyopathy
  description: >-
    The defining phenotype: a primary disease of the atrial myocardium rather
    than of the ventricle. In the index sibship this took the form of an
    enlarged, thickened, fibrotic left atrium. Note the entity's placement in
    the familial hypertrophic cardiomyopathy series is nosological, not
    morphological - the hypertrophy that names it is atrial.
  phenotype_term:
    preferred_term: Atrial cardiomyopathy
    term:
      id: HP:0200127
      label: Atrial cardiomyopathy
  evidence:
  - reference: PMID:37913506
    reference_title: "Corin and Left Atrial Cardiomyopathy, Hypertension, Arrhythmia, and Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two siblings presented with cardiomyopathy, hypertension, arrhythmia, and
      fibrosis of the left atrium.
    explanation: >-
      States the cardiomyopathy and its left atrial localisation directly.
- category: Cardiovascular
  name: Left Atrial Enlargement
  description: >-
    Enlargement of the left atrium, the structural correlate of the atrial
    cardiomyopathy and the substrate for atrial arrhythmia. Recorded in the
    OMIM/MedGen clinical synopsis for OMIM:620734.
  phenotype_term:
    preferred_term: Left atrial enlargement
    term:
      id: HP:0031295
      label: Left atrial enlargement
  evidence:
  - reference: PMID:37913506
    reference_title: "Corin and Left Atrial Cardiomyopathy, Hypertension, Arrhythmia, and Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These and other findings support the hypothesis that BNP cannot fully
      compensate for a lack of activation of the ANP pathway and that corin is
      critical to normal ANP activity, left atrial function, and cardiovascular
      homeostasis.
    explanation: >-
      Supports left atrial structural and functional involvement. The abstract states
      left atrial cardiomyopathy and fibrosis but does not itself give the chamber
      dimensions; the specific enlargement annotation comes from the OMIM/MedGen
      clinical synopsis derived from the full report.
- category: Cardiovascular
  name: Left Atrial Fibrosis
  description: >-
    Fibrosis of the left atrial myocardium, present in both affected siblings
    and accompanied in the sampled sibling by elevation of one of two
    circulating protein markers of fibrosis. Annotated with the generic
    myocardial fibrosis HPO term, which has no atrium-specific child.
  phenotype_term:
    preferred_term: Left atrial fibrosis
    term:
      id: HP:0001685
      label: Myocardial fibrosis
  evidence:
  - reference: PMID:37913506
    reference_title: "Corin and Left Atrial Cardiomyopathy, Hypertension, Arrhythmia, and Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two siblings presented with cardiomyopathy, hypertension, arrhythmia, and
      fibrosis of the left atrium.
    explanation: >-
      States left atrial fibrosis in both affected individuals.
- category: Cardiovascular
  name: Atrial Fibrillation
  description: >-
    Atrial fibrillation arising on the remodelled, fibrotic atrial substrate.
    Recorded in the OMIM/MedGen clinical synopsis for OMIM:620734, and
    consistent with the broader association of CORIN variation with atrial
    fibrillation.
  phenotype_term:
    preferred_term: Atrial fibrillation
    term:
      id: HP:0005110
      label: Atrial fibrillation
  evidence:
  - reference: PMID:37913506
    reference_title: "Corin and Left Atrial Cardiomyopathy, Hypertension, Arrhythmia, and Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two siblings presented with cardiomyopathy, hypertension, arrhythmia, and
      fibrosis of the left atrium.
    explanation: >-
      Documents arrhythmia in the affected siblings. The abstract says "arrhythmia"
      without naming the rhythm; the specific fibrillation/flutter annotations come from
      the OMIM/MedGen clinical synopsis derived from the full report.
  - reference: PMID:40316193
    reference_title: "Corin in cardiovascular diseases and stroke."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      CORIN variants have been identified in patients with hypertension, heart
      failure, atrial fibrillation, and stroke.
    explanation: >-
      Corroborates atrial fibrillation as a CORIN-associated phenotype. It aggregates
      across CORIN variant classes rather than describing the biallelic-null entity.
      Evidence source OTHER (review).
- category: Cardiovascular
  name: Atrial Flutter
  description: >-
    Macro-reentrant atrial flutter, recorded in the OMIM/MedGen clinical
    synopsis for OMIM:620734 alongside atrial fibrillation.
  phenotype_term:
    preferred_term: Atrial flutter
    term:
      id: HP:0004749
      label: Atrial flutter
  evidence:
  - reference: PMID:37913506
    reference_title: "Corin and Left Atrial Cardiomyopathy, Hypertension, Arrhythmia, and Fibrosis."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two siblings presented with cardiomyopathy, hypertension, arrhythmia, and
      fibrosis of the left atrium.
    explanation: >-
      Documents arrhythmia in the affected siblings; the flutter subtype is specified in
      the OMIM/MedGen clinical synopsis derived from the full report, so it is graded
      INDIRECT.
- category: Cardiovascular
  name: Hypertension
  description: >-
    Systemic hypertension, present in both affected siblings and mechanistically
    downstream of the absent ANP natriuretic and vasodilatory signal. This is
    not incidental comorbidity: the same phenotype is reproduced by corin
    knockout in mice, is salt-sensitive there, and is the arm of the phenotype
    best supported by independent genetic evidence in humans.
  phenotype_term:
    preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  evidence:
  - reference: PMID:37913506
    reference_title: "Corin and Left Atrial Cardiomyopathy, Hypertension, Arrhythmia, and Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two siblings presented with cardiomyopathy, hypertension, arrhythmia, and
      fibrosis of the left atrium.
    explanation: >-
      States hypertension as part of the presenting phenotype.
  - reference: PMID:15637153
    reference_title: "Hypertension in mice lacking the proatrial natriuretic peptide convertase corin."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Using radiotelemetry to assess blood pressure, we find that Cor-/- mice
      have spontaneous hypertension as compared with WT mice, and it is enhanced
      after dietary salt loading.
    explanation: >-
      Model-organism confirmation that corin loss is sufficient to cause
      hypertension.
- category: Cardiovascular
  name: Reduced Left Ventricular Ejection Fraction
  description: >-
    Impaired left ventricular systolic function, recorded in the OMIM/MedGen
    clinical synopsis for OMIM:620734. This is the one clearly ventricular
    feature of an otherwise atrial disease, and it is plausibly a late or
    secondary consequence of chronic hypertension and atrial arrhythmia rather
    than a primary ventricular cardiomyopathy - the corin-knockout mouse shows
    exactly that sequence, with dysfunction appearing only after 9 months and
    attributed by the authors to chronic hypertension.
  phenotype_term:
    preferred_term: Reduced left ventricular ejection fraction
    term:
      id: HP:0012664
      label: Reduced left ventricular ejection fraction
  evidence:
  - reference: PMID:37636304
    reference_title: "Corin deficiency impairs cardiac function in mouse models of heart failure."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Corin KO mice had progressive cardiac dysfunction with cardiac hypertrophy
      and fibrosis after 9 months of age, likely due to chronic hypertension.
    explanation: >-
      Supports late-onset ventricular dysfunction as a consequence of corin loss. Graded
      INDIRECT because this is the mouse, not the human phenotype; the human annotation
      itself comes from the OMIM/MedGen clinical synopsis.
- category: Laboratory
  name: Decreased Circulating N-Terminal Pro-ANP
  description: >-
    N-terminal pro-ANP was undetectable in plasma from the sampled sibling. This
    is the direct biochemical readout of the disease lesion.
  phenotype_term:
    preferred_term: Decreased circulating A-type natriuretic peptide concentration
    term:
      id: HP:0020184
      label: Decreased circulating A-type natriuretic peptide concentration
  evidence:
  - reference: PMID:37913506
    reference_title: "Corin and Left Atrial Cardiomyopathy, Hypertension, Arrhythmia, and Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A plasma sample obtained from one of the siblings had no detectable levels
      of corin or N-terminal pro-ANP
    explanation: >-
      Directly reports undetectable circulating N-terminal pro-ANP.
- category: Laboratory
  name: Increased Circulating B-Type Natriuretic Peptide
  description: >-
    BNP was elevated in the sampled sibling despite the dead ANP arm - the
    dissociation on which the incomplete-compensation argument rests.
  phenotype_term:
    preferred_term: Increased circulating brain natriuretic peptide concentration
    term:
      id: HP:0033534
      label: Increased circulating brain natriuretic peptide concentration
  evidence:
  - reference: PMID:37913506
    reference_title: "Corin and Left Atrial Cardiomyopathy, Hypertension, Arrhythmia, and Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      but had elevated levels of B-type natriuretic peptide (BNP) and one of the
      two protein markers of fibrosis that we tested
    explanation: >-
      Directly reports the elevated BNP.
genetic:
- name: CORIN
  gene_term:
    preferred_term: CORIN
    term:
      id: hgnc:19012
      label: CORIN
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  inheritance:
  - name: Autosomal Recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  presence: Biallelic null variants in affected individuals
  notes: >-
    CORIN is at 4p12 and encodes a type II transmembrane serine protease
    expressed primarily in the heart. The variant reported in the index sibship
    is NM_006587.4(CORIN):c.684dup (p.Met229fs) - a 1-bp duplication, homozygous
    in both affected siblings, catalogued as ClinVar VCV002504113 and OMIM
    allelic variant 605236.0004 with a pathogenic classification. The exact
    HGVS notation is not stated in the cited abstract (it is in the full report
    and the ClinVar record), so it is recorded here as provenance rather than
    quoted as evidence.

    Do not conflate this biallelic-null genotype with the common hypomorphic
    CORIN I555(P568) allele (T555I + Q568P in near-complete linkage
    disequilibrium). That allele is frequent in people of African ancestry, is
    associated with hypertension and with an enhanced hypertrophic response to
    afterload, and reduces but does not abolish natriuretic peptide processing.
    It is a susceptibility factor for common cardiovascular traits, not a cause
    of CMH30, and its literature is deliberately not imported into this entry's
    phenotype or prevalence sections.
  evidence:
  - reference: PMID:37913506
    reference_title: "Corin and Left Atrial Cardiomyopathy, Hypertension, Arrhythmia, and Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Each had a homozygous null variant in CORIN, the gene encoding atrial
      natriuretic peptide (ANP)-converting enzyme.
    explanation: >-
      Establishes CORIN as the causal gene and the biallelic null genotype in
      both affected siblings.
  - reference: PMID:17485366
    reference_title: "The serine protease corin in cardiovascular biology and disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Corin is a type II transmembrane serine protease expressed primarily in
      the heart.
    explanation: >-
      Establishes the gene product's class and tissue distribution. Evidence
      source OTHER because this is a review synthesising in vitro and
      model-organism work.
  variants:
  - name: NM_006587.4(CORIN):c.684dup (p.Met229fs)
    type: FRAMESHIFT
    clinical_significance: PATHOGENIC
    description: >-
      1-bp duplication producing a frameshift at Met229, well upstream of both
      the Arg801 activation cleavage site and the catalytic serine, so no
      functional protease can be produced. Homozygous in both affected
      siblings; circulating corin was undetectable. Catalogued as ClinVar
      VCV002504113 (dbSNP rs756399499) and OMIM allelic variant 605236.0004.
    gene:
      preferred_term: CORIN
      term:
        id: hgnc:19012
        label: CORIN
    evidence:
    - reference: PMID:37913506
      reference_title: "Corin and Left Atrial Cardiomyopathy, Hypertension, Arrhythmia, and Fibrosis."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A plasma sample obtained from one of the siblings had no detectable
        levels of corin or N-terminal pro-ANP
      explanation: >-
        Confirms the variant behaves as a protein null in vivo. Graded INDIRECT because
        the abstract reports the functional consequence but not the HGVS notation, which
        comes from ClinVar/OMIM.
biochemical:
- name: Circulating Corin
  biomarker_term:
    preferred_term: circulating corin protein
  presence: Undetectable in affected individuals
  notes: >-
    Soluble corin is measurable in normal human plasma and has been proposed as
    a cardiovascular biomarker; in the corin-null sibling it was absent. This is
    the most direct available confirmation that the genotype produces a protein
    null, and it distinguishes CMH30 from the hypomorphic-allele states in which
    corin is present but less active. It is not a validated diagnostic assay.
  evidence:
  - reference: PMID:37913506
    reference_title: "Corin and Left Atrial Cardiomyopathy, Hypertension, Arrhythmia, and Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A plasma sample obtained from one of the siblings had no detectable levels
      of corin or N-terminal pro-ANP
    explanation: >-
      Reports undetectable circulating corin protein.
- name: N-Terminal Pro-Atrial Natriuretic Peptide
  biomarker_term:
    preferred_term: N-terminal pro-atrial natriuretic peptide
    term:
      id: NCIT:C139911
      label: Atrial Natriuretic Factor
  presence: Undetectable in affected individuals
  notes: >-
    Undetectable NT-pro-ANP alongside undetectable corin is the biochemical
    signature of the disease. Note the direction differs from the corin-knockout
    mouse, where pro-ANP is elevated because the unprocessed precursor
    accumulates while mature ANP is absent; the human measurement was of the
    N-terminal fragment in plasma. Reconciling the two assays is a curation
    caveat, not a contradiction in the underlying biology.
  evidence:
  - reference: PMID:37913506
    reference_title: "Corin and Left Atrial Cardiomyopathy, Hypertension, Arrhythmia, and Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A plasma sample obtained from one of the siblings had no detectable levels
      of corin or N-terminal pro-ANP
    explanation: >-
      Reports undetectable circulating N-terminal pro-ANP.
  - reference: PMID:15637153
    reference_title: "Hypertension in mice lacking the proatrial natriuretic peptide convertase corin."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Cor-/- mice have elevated levels of pro-ANP but no detectable levels of
      ANP as compared with WT littermates.
    explanation: >-
      The model-organism counterpart measurement. Graded INDIRECT because the murine
      precursor is elevated while the human N-terminal fragment was undetectable - the
      analytes measured are not the same.
- name: B-Type Natriuretic Peptide
  biomarker_term:
    preferred_term: B-type natriuretic peptide
    term:
      id: NCIT:C88523
      label: Brain Natriuretic Peptide 32
  presence: Elevated in affected individuals
  notes: >-
    Elevated despite the abolished ANP arm. Read this as the failed-compensation
    signal rather than as reassurance: BNP rose and the atrial cardiomyopathy,
    fibrosis, hypertension, and arrhythmia developed anyway. Corin also
    contributes to proBNP processing in cardiomyocytes, so the residual BNP
    signal in a corin-null individual is itself of uncertain processing status.
  evidence:
  - reference: PMID:37913506
    reference_title: "Corin and Left Atrial Cardiomyopathy, Hypertension, Arrhythmia, and Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      but had elevated levels of B-type natriuretic peptide (BNP) and one of the
      two protein markers of fibrosis that we tested
    explanation: >-
      Reports the elevated BNP.
  - reference: PMID:19919978
    reference_title: "Dysfunctional corin i555(p568) allele is associated with impaired brain natriuretic peptide processing and adverse outcomes in blacks with systolic heart failure: results from the Genetic Risk Assessment in Heart Failure substudy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Corin, a transmembrane serine protease expressed in cardiomyocytes,
      cleaves pro-atrial natriuretic peptide and pro-brain natriuretic peptide
      (BNP) into biologically active peptide hormones.
    explanation: >-
      Establishes that corin also processes proBNP, which is why an elevated total BNP
      in a corin-null individual cannot be assumed to represent an intact, fully
      processed BNP signal. The cohort studied carried a hypomorphic allele, not a
      biallelic null.
animal_models:
- name: Constitutive Corin knockout mouse
  species: Mouse
  genotype: Corin-/- (constitutive whole-body knockout)
  publication: PMID:15637153
  description: >-
    The workhorse model for the corin/ANP axis. Corin-null mice develop
    normally, have elevated pro-ANP with no detectable mature ANP, and show
    spontaneous, salt-sensitive hypertension by radiotelemetry, plus cardiac
    hypertrophy and a late decline in cardiac function. A later study extended
    the phenotype: progressive cardiac dysfunction with hypertrophy and fibrosis
    after 9 months, faster deterioration than wild type after transverse aortic
    constriction, and amelioration of dysfunction, hypertrophy, and fibrosis by
    recombinant corin protein, which also raised plasma cGMP and lowered
    angiotensin II and aldosterone.
  modeled_mechanisms:
  - target: Failure of Pro-ANP Processing
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      The processing block is complete and directly measured in this model,
      matching the human protein-null biochemistry.
    limitations: >-
      Murine plasma reports accumulating pro-ANP precursor whereas the human
      sibling was assayed for the N-terminal fragment, so the two measurements
      are not the same analyte even though both indicate an abolished
      conversion step.
    readouts:
    - name: Plasma pro-ANP and mature ANP
      target: Failure of Pro-ANP Processing
      direction: ABOLISHED
      interpretation: >-
        Mature ANP is abolished with precursor accumulation - the defining
        readout of the lost convertase step.
      evidence:
      - reference: PMID:15637153
        reference_title: "Hypertension in mice lacking the proatrial natriuretic peptide convertase corin."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Cor-/- mice have elevated levels of pro-ANP but no detectable levels
          of ANP as compared with WT littermates.
        explanation: >-
          Reports the measurement underlying this readout.
    - name: Restoration of pro-ANP conversion by recombinant soluble corin
      target: Failure of Pro-ANP Processing
      direction: RESTORED
      interpretation: >-
        Supplying the missing enzyme restores conversion, closing the causal
        loop on this node.
      evidence:
      - reference: PMID:15637153
        reference_title: "Hypertension in mice lacking the proatrial natriuretic peptide convertase corin."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Infusion of an active recombinant soluble corin transiently restores
          pro-ANP conversion, resulting in the release of circulating
          biologically active ANP.
        explanation: >-
          Reports the rescue measurement underlying this readout.
    evidence:
    - reference: PMID:15637153
      reference_title: "Hypertension in mice lacking the proatrial natriuretic peptide convertase corin."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Thus, our data establish corin as the physiological pro-ANP convertase
        and indicate that corin deficiency may contribute to hypertensive heart
        disease.
      explanation: >-
        Supports treating this model as informative for the pro-ANP processing
        node.
  - target: Sodium and Volume Retention with Hypertension
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Spontaneous, salt-sensitive hypertension matching the hypertension seen in
      the affected siblings.
    limitations: >-
      Murine blood-pressure regulation is measured under controlled dietary salt
      that has no counterpart in the human report, so the salt-sensitivity
      dimension is untested in patients.
    readouts:
    - name: Radiotelemetric arterial blood pressure
      target: Sodium and Volume Retention with Hypertension
      direction: INCREASED
      interpretation: >-
        Direct demonstration that corin loss raises blood pressure, worsened by
        salt loading.
      evidence:
      - reference: PMID:15637153
        reference_title: "Hypertension in mice lacking the proatrial natriuretic peptide convertase corin."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Using radiotelemetry to assess blood pressure, we find that Cor-/-
          mice have spontaneous hypertension as compared with WT mice, and it is
          enhanced after dietary salt loading.
        explanation: >-
          Reports the measurement underlying this readout.
    evidence:
    - reference: PMID:15637153
      reference_title: "Hypertension in mice lacking the proatrial natriuretic peptide convertase corin."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Using radiotelemetry to assess blood pressure, we find that Cor-/- mice
        have spontaneous hypertension as compared with WT mice, and it is
        enhanced after dietary salt loading.
      explanation: >-
        Supports treating this model as informative for the hypertension node.
  - target: Left Atrial Myocardial Hypertrophy and Enlargement
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      Corin-null mice develop cardiac hypertrophy, but it is generalised rather
      than atrium-selective and is attributed by the authors to chronic
      hypertension.
    limitations: >-
      The defining feature of the human disease is that the hypertrophy is
      LEFT ATRIAL. The mouse does not reproduce that chamber selectivity, so it
      cannot be used as evidence for the atrial localisation of the phenotype -
      only for the existence of a hypertrophic response to corin loss. The
      transverse-aortic-constriction variant of the model imposes ventricular
      afterload surgically, which is further removed still from spontaneous
      human atrial disease.
    readouts:
    - name: Cardiac hypertrophy on histology
      target: Left Atrial Myocardial Hypertrophy and Enlargement
      direction: INCREASED
      interpretation: >-
        Establishes a hypertrophic response to corin loss without establishing
        its chamber distribution.
      evidence:
      - reference: PMID:37636304
        reference_title: "Corin deficiency impairs cardiac function in mouse models of heart failure."
        supports: SUPPORT
        directness: INDIRECT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Corin KO mice had progressive cardiac dysfunction with cardiac
          hypertrophy and fibrosis after 9 months of age, likely due to chronic
          hypertension.
        explanation: >-
          Reports the hypertrophy measurement. Graded INDIRECT because it is not
          atrium-specific.
    evidence:
    - reference: PMID:15637153
      reference_title: "Hypertension in mice lacking the proatrial natriuretic peptide convertase corin."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In addition, Cor-/- mice exhibit cardiac hypertrophy resulting in a mild
        decline in cardiac function later in life.
      explanation: >-
        Supports partial informativeness of this model for the hypertrophy node. Graded
        INDIRECT because the murine hypertrophy is not chamber-selective.
  - target: Left Atrial Fibrosis
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Cardiac fibrosis develops in aged corin-null mice and after pressure
      overload, and - the key point - is reversed by giving back recombinant
      corin protein, which establishes the fibrosis as a consequence of corin
      deficiency.
    limitations: >-
      As with hypertrophy, the murine fibrosis is not localised to the left
      atrium, and the pressure-overload variant of the model applies a
      ventricular afterload stimulus rather than reproducing the spontaneous
      atrial disease.
    readouts:
    - name: Cardiac fibrosis on Sirius red / Masson trichrome staining after recombinant corin
      target: Left Atrial Fibrosis
      direction: RESTORED
      interpretation: >-
        Pharmacological replacement of the missing enzyme reverses the fibrotic
        remodelling, supporting a causal rather than incidental relationship.
      evidence:
      - reference: PMID:37636304
        reference_title: "Corin deficiency impairs cardiac function in mouse models of heart failure."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          When the TAC-operated Corin KO mice were treated with recombinant
          corin protein, cardiac dysfunction, hypertrophy, and fibrosis were
          ameliorated.
        explanation: >-
          Reports the rescue measurement underlying this readout.
    evidence:
    - reference: PMID:37636304
      reference_title: "Corin deficiency impairs cardiac function in mouse models of heart failure."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Corin deficiency impairs cardiac function and exacerbates HF development
        in mice.
      explanation: >-
        Supports treating this model as informative for the fibrosis and
        cardiac-dysfunction nodes.
  - target: Atrial Arrhythmogenic Substrate
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      No atrial arrhythmia phenotype has been reported in corin-knockout mice.
      The published characterisation is of blood pressure, chamber hypertrophy,
      fibrosis, contractile function, and lung oedema; rhythm is not among the
      reported endpoints, and the arrhythmia that dominates the human phenotype
      is therefore unmodelled.
    limitations: >-
      This is a negative claim about model coverage, and it should be read as
      such: the absence of a reported arrhythmia phenotype reflects endpoints
      that were not assessed as much as any demonstrated absence of arrhythmia.
      Either way the model cannot currently substantiate the arrhythmic arm of
      the human disease, which is the arm carrying the stroke and
      quality-of-life burden.
    evidence:
    - reference: PMID:37636304
      reference_title: "Corin deficiency impairs cardiac function in mouse models of heart failure."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Cardiac function was assessed by echocardiography and tissue analysis in
        Corin KO mice at different ages or subjected to transverse aortic
        constriction (TAC), which increased pressure overload.
      explanation: >-
        The stated assessment battery for this model is echocardiography and
        tissue analysis, with no rhythm monitoring - so no atrial arrhythmia
        endpoint exists to recapitulate the human phenotype.
  evidence:
  - reference: PMID:15637153
    reference_title: "Hypertension in mice lacking the proatrial natriuretic peptide convertase corin."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Thus, our data establish corin as the physiological pro-ANP convertase and
      indicate that corin deficiency may contribute to hypertensive heart
      disease.
    explanation: >-
      Establishes the model as the definitive in vivo system for the
      corin/pro-ANP axis this disease disrupts.
diagnosis:
- name: Transthoracic echocardiography with dedicated atrial assessment
  diagnosis_term:
    preferred_term: Echocardiography
    term:
      id: NCIT:C16525
      label: Echocardiography Test
  description: >-
    First-line imaging, but it must be read against the atrial phenotype rather
    than the usual hypertrophic-cardiomyopathy checklist. The finding of
    interest is left atrial size, wall thickness, and function; a normal
    ventricular septal thickness and the absence of outflow-tract obstruction
    are not reassurance in this entity, because the disease is not a sarcomeric
    ventricular cardiomyopathy. Ventricular ejection fraction should also be
    recorded, since reduced systolic function is part of the reported synopsis
    and is plausibly a late consequence.
  results: >-
    Enlarged, thickened left atrium; ventricular ejection fraction may be
    reduced.
  notes: >-
    No echocardiographic criteria specific to CORIN-related atrial
    cardiomyopathy have been published; this is a rational work-up built from
    the reported phenotype rather than a validated diagnostic pathway.
- name: Ambulatory rhythm monitoring and 12-lead electrocardiography
  diagnosis_term:
    preferred_term: Electrocardiography
    term:
      id: NCIT:C38053
      label: Electrocardiography
  description: >-
    Atrial flutter and atrial fibrillation are core to the phenotype and may be
    paroxysmal, so a single resting ECG is insufficient. Detected atrial
    arrhythmia is what drives the anticoagulation and rate/rhythm-control
    decisions, which are the only interventions with any real leverage in this
    disease at present.
  results: >-
    Atrial fibrillation or atrial flutter.
  evidence:
  - reference: PMID:37913506
    reference_title: "Corin and Left Atrial Cardiomyopathy, Hypertension, Arrhythmia, and Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two siblings presented with cardiomyopathy, hypertension, arrhythmia, and
      fibrosis of the left atrium.
    explanation: >-
      Establishes arrhythmia as a presenting feature that rhythm monitoring would
      capture. The report does not evaluate monitoring strategies.
- name: Cardiac magnetic resonance imaging with late gadolinium enhancement
  diagnosis_term:
    preferred_term: Magnetic Resonance Imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  description: >-
    The modality that can show atrial fibrosis directly rather than by
    inference. Atrial wall thinness makes atrial late-gadolinium-enhancement
    imaging technically demanding and it is not a routinely validated
    measurement outside specialist centres, so a negative study should not be
    used to exclude the fibrotic phenotype.
  results: >-
    Left atrial wall fibrosis; atrial and ventricular morphology and function.
- name: Natriuretic peptide profiling (NT-pro-ANP with BNP)
  diagnosis_term:
    preferred_term: Atrial Natriuretic Peptide Measurement
    term:
      id: NCIT:C74886
      label: Atrial Natriuretic Peptide Measurement
  description: >-
    Mechanistically the most discriminating biochemistry available: the
    corin-null state produces undetectable circulating corin and undetectable
    N-terminal pro-ANP with an elevated BNP. That pattern - a dead ANP arm
    beside a live BNP arm - is not produced by ordinary heart failure, in which
    both rise together. It is nonetheless NOT a validated diagnostic assay for
    this disease, and NT-pro-ANP is not a routine clinical test; treat it as a
    mechanistic confirmation once CORIN is implicated, not as a screening test.
  results: >-
    Undetectable corin and N-terminal pro-ANP with elevated B-type natriuretic
    peptide.
  evidence:
  - reference: PMID:37913506
    reference_title: "Corin and Left Atrial Cardiomyopathy, Hypertension, Arrhythmia, and Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A plasma sample obtained from one of the siblings had no detectable levels
      of corin or N-terminal pro-ANP but had elevated levels of B-type
      natriuretic peptide (BNP) and one of the two protein markers of fibrosis
      that we tested.
    explanation: >-
      Reports the full biochemical pattern this test is intended to detect.
- name: CORIN sequencing on a cardiomyopathy or arrhythmia gene panel
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  description: >-
    Molecular confirmation requires biallelic CORIN variants. CORIN is not on
    every legacy hypertrophic-cardiomyopathy panel, which are built around
    sarcomeric genes, so a "negative HCM panel" does not exclude this diagnosis;
    check gene content or move to exome/genome sequencing. Because inheritance
    is recessive, the informative family pattern is affected siblings with
    unaffected heterozygous parents, not a multigenerational dominant pedigree.
  results: >-
    Biallelic pathogenic CORIN variants.
  evidence:
  - reference: PMID:37913506
    reference_title: "Corin and Left Atrial Cardiomyopathy, Hypertension, Arrhythmia, and Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Each had a homozygous null variant in CORIN, the gene encoding atrial
      natriuretic peptide (ANP)-converting enzyme.
    explanation: >-
      Establishes the molecular finding that confirms the diagnosis.
treatments:
- name: Antihypertensive Therapy
  description: >-
    Blood-pressure control is the highest-value phenotype-directed intervention,
    because hypertension is both an early and a mechanistically upstream part of
    the chain: it is the mechanical load that drives atrial hypertrophy and
    fibrosis, and it is the arm of the phenotype most firmly established across
    human and model-organism evidence. No agent class has been tested in
    CORIN-null patients and no genotype-specific recommendation exists. The
    mouse rescue data showing that restoring corin lowers angiotensin II and
    aldosterone offer a mechanistic rationale for renin-angiotensin-aldosterone
    blockade specifically, but that is an inference, not a trial result.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Antihypertensive Therapy
    term:
      id: NCIT:C172184
      label: Antihypertensive Therapy
  target_mechanisms:
  - target: Sodium and Volume Retention with Hypertension
    treatment_effect: INHIBITS
    description: >-
      Pharmacological blood-pressure lowering substitutes for the missing
      ANP-mediated natriuretic and vasodilatory tone at the level of the
      systemic phenotype, without restoring the signal itself.
  notes: >-
    Extrapolated from general hypertension and cardiomyopathy management. No
    CORIN-specific outcome data exist.
- name: Anticoagulation for Atrial Arrhythmia
  description: >-
    Atrial fibrillation on a structurally remodelled, fibrotic left atrium is
    the stroke-risk pathway in this disease, and CORIN variation is separately
    associated with stroke. Contemporary hypertrophic-cardiomyopathy guidance
    favours anticoagulation once clinical atrial fibrillation is documented,
    largely irrespective of conventional risk-score thresholds; whether an
    isolated CORIN atrial phenotype should inherit that rule rather than a
    standard CHA2DS2-VASc assessment is a specialist judgement that has not
    been studied.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Anticoagulation Therapy
    term:
      id: NCIT:C63341
      label: Anticoagulation Therapy
  notes: >-
    Deliberately carries no `target_mechanisms` link: anticoagulation does not
    act on any pathophysiology node curated here. It prevents thrombus
    formation in the fibrillating, dilated atrium - a complication of the
    arrhythmogenic substrate rather than a step in the mechanism chain - so
    asserting an edge to `Atrial Arrhythmogenic Substrate` would misstate what
    the drug does.
  evidence:
  - reference: PMID:40316193
    reference_title: "Corin in cardiovascular diseases and stroke."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: OTHER
    snippet: >-
      CORIN variants have been identified in patients with hypertension, heart
      failure, atrial fibrillation, and stroke.
    explanation: >-
      Supports the atrial-fibrillation-to-stroke concern that motivates anticoagulation.
      Graded INDIRECT because it associates CORIN variation with these phenotypes
      generally and does not evaluate anticoagulation. Evidence source OTHER (review).
- name: Rate or Rhythm Control for Atrial Flutter and Fibrillation
  description: >-
    Standard antiarrhythmic pharmacotherapy or catheter ablation, applied on
    ordinary rhythm-management indications. There is no evidence that ablation
    outcomes in a genetically fibrotic atrium resemble those in ordinary atrial
    fibrillation, and the fibrotic substrate is a recognised predictor of
    recurrence generally, so expectations should be set accordingly. Genotype
    alone is not an indication for any procedure.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: antiarrhythmic agent
      term:
        id: NCIT:C47793
        label: Antiarrhythmic Agent
  notes: >-
    Fully extrapolated from general atrial-arrhythmia management; no
    CORIN-specific rhythm-control evidence exists.
- name: Catheter Ablation of Atrial Arrhythmia
  description: >-
    Considered on standard rhythm-control indications when drug therapy fails.
    Listed separately from pharmacological rhythm control because the
    substrate-dependence of its success is the specific concern in a disease
    defined by atrial fibrosis.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: Cardiac Ablation
    term:
      id: NCIT:C100068
      label: Cardiac Ablation
  notes: >-
    No published experience of catheter ablation in CORIN-related atrial
    cardiomyopathy.
- name: Genetic Counselling and Cascade Testing
  description: >-
    Autosomal recessive inheritance changes the counselling arithmetic relative
    to the rest of the hypertrophic-cardiomyopathy series: the recurrence risk
    is 25% for siblings of a proband, unaffected parents are obligate carriers,
    and offspring of a proband are obligate carriers rather than at 50% risk.
    Cascade testing should target siblings first. Whether heterozygous carriers
    warrant blood-pressure surveillance is unknown - the hypomorphic-allele
    literature associating reduced corin activity with hypertension makes it a
    reasonable question, not an established recommendation.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:37913506
    reference_title: "Corin and Left Atrial Cardiomyopathy, Hypertension, Arrhythmia, and Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Each had a homozygous null variant in CORIN, the gene encoding atrial
      natriuretic peptide (ANP)-converting enzyme.
    explanation: >-
      The homozygous, recessive genotype is what determines the counselling
      arithmetic described here.
- name: Recombinant Corin Protein Replacement (experimental, preclinical only)
  description: >-
    The mechanistically obvious therapy: give back the missing enzyme. In
    corin-knockout mice, recombinant soluble corin restores pro-ANP conversion
    and releases bioactive ANP, and in pressure-overloaded knockout mice
    recombinant corin protein ameliorated cardiac dysfunction, hypertrophy and
    fibrosis while raising plasma cGMP and lowering angiotensin II and
    aldosterone. NOTHING about this has been tested in humans - no dose, no
    safety, no immunogenicity, no delivery route, no trial. It is listed here
    because it is the direct pharmacological converse of the disease lesion and
    therefore the natural target for future work, not as a treatment option.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Failure of Pro-ANP Processing
    treatment_effect: ACTIVATES
    description: >-
      Supplies the absent convertase activity, restoring pro-ANP to ANP
      conversion at the top of the chain rather than palliating its downstream
      consequences.
    evidence:
    - reference: PMID:15637153
      reference_title: "Hypertension in mice lacking the proatrial natriuretic peptide convertase corin."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Infusion of an active recombinant soluble corin transiently restores
        pro-ANP conversion, resulting in the release of circulating biologically
        active ANP.
      explanation: >-
        Direct demonstration that the agent acts on this mechanism node.
  evidence:
  - reference: PMID:37636304
    reference_title: "Corin deficiency impairs cardiac function in mouse models of heart failure."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      When the TAC-operated Corin KO mice were treated with recombinant corin
      protein, cardiac dysfunction, hypertrophy, and fibrosis were ameliorated.
    explanation: >-
      Shows the structural and functional benefit of enzyme replacement in the
      model organism.
  - reference: PMID:37636304
    reference_title: "Corin deficiency impairs cardiac function in mouse models of heart failure."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Corin protein may be used to reduce cardiac hypertrophy and fibrosis,
      suppress the renin-angiotensin-aldosterone system, and improve cardiac
      function in HF.
    explanation: >-
      The authors' own statement of the therapeutic hypothesis, which remains
      untested in humans.
  notes: >-
    Preclinical concept only. No human efficacy, dose, safety, immunogenicity,
    or delivery data exist, and no clinical trial in CORIN-related disease has
    been registered.
discussions:
- discussion_id: corin_atrial_selectivity
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Why is the cardiomyopathy of biallelic CORIN loss selectively LEFT ATRIAL in
    humans, when corin loss removes a systemic endocrine signal and the
    corin-knockout mouse shows generalised, hypertension-attributed cardiac
    hypertrophy and fibrosis?
  attaches_to:
  - pathophysiology#Left Atrial Myocardial Hypertrophy and Enlargement
  - pathophysiology#Left Atrial Fibrosis
  rationale: >-
    The atrial localisation is what makes this a distinct disease entity rather
    than "hypertensive heart disease due to an endocrine defect", and it is
    exactly the part with no mechanistic explanation. Three candidate accounts
    are on the table and no data currently separate them: (1) an autocrine or
    paracrine account, in which the left atrium suffers most because it is the
    tissue that synthesises pro-ANP, so the local concentration of mature ANP
    falls furthest there; (2) a mechanical account, in which the thin-walled
    atrium is simply the chamber least able to tolerate the chronic pressure and
    volume load created by systemic hypertension, making the atrial
    predominance a consequence of hypertension rather than of local signalling;
    and (3) an ascertainment account, in which the atrial phenotype is what
    brought a single sibship to attention and a larger cohort would show
    ventricular disease too - the OMIM/MedGen synopsis does already record
    reduced left ventricular ejection fraction. Distinguishing these matters
    clinically, because account (2) implies that aggressive blood-pressure
    control should largely prevent the atrial disease, while account (1) implies
    it should not.
  evidence:
  - reference: PMID:37913506
    reference_title: "Corin and Left Atrial Cardiomyopathy, Hypertension, Arrhythmia, and Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These and other findings support the hypothesis that BNP cannot fully
      compensate for a lack of activation of the ANP pathway and that corin is
      critical to normal ANP activity, left atrial function, and cardiovascular
      homeostasis.
    explanation: >-
      The authors themselves frame corin's criticality as being to LEFT ATRIAL
      function specifically, which is the observation this gap asks the
      mechanism for.
  - reference: PMID:37636304
    reference_title: "Corin deficiency impairs cardiac function in mouse models of heart failure."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Corin KO mice had progressive cardiac dysfunction with cardiac hypertrophy
      and fibrosis after 9 months of age, likely due to chronic hypertension.
    explanation: >-
      The competing mechanical account: in the model, cardiac remodelling from corin
      loss is attributed to chronic hypertension and is not chamber-selective. It
      establishes the alternative rather than resolving between accounts.
  proposed_experiments:
  - experiment_id: chamber_resolved_anp_cgmp
    name: Chamber-resolved ANP and cGMP measurement in corin-null myocardium
    description: >-
      Measure mature ANP and cGMP separately in atrial and ventricular
      myocardium of corin-null models, with and without blood-pressure
      normalisation, to test whether the atrium sustains a distinct local
      signalling deficit beyond the systemic one.
  - experiment_id: bp_controlled_corin_null_cohort
    name: Blood-pressure-controlled corin-null cohort
    description: >-
      Follow atrial size and fibrosis in corin-deficient animals maintained
      normotensive by antihypertensive therapy from a young age. Persistent
      atrial remodelling under normal blood pressure would favour the autocrine
      account; its absence would favour the mechanical one.
- discussion_id: corin_null_mouse_atrial_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Does the constitutive corin-knockout mouse model the human CMH30 phenotype,
    given that it reproduces the endocrine and blood-pressure arms faithfully
    but neither the atrial selectivity nor the atrial arrhythmia that define the
    human disease?
  attaches_to:
  - pathophysiology#Left Atrial Myocardial Hypertrophy and Enlargement
  - pathophysiology#Atrial Arrhythmogenic Substrate
  rationale: >-
    Evidence in the model exists and is strong - abolished pro-ANP processing,
    salt-sensitive spontaneous hypertension, age-dependent hypertrophy and
    fibrosis, and rescue by recombinant corin - so this is a translational
    validity question rather than an absence of evidence. Two specific
    mismatches limit what may be inferred. First, the murine hypertrophy and
    fibrosis are not chamber-selective and are attributed by the authors to
    chronic hypertension, so the model cannot substantiate the left atrial
    localisation that names the human disease. Second, and more consequentially,
    the reported assessment battery is echocardiography and tissue histology
    with no rhythm monitoring, so the atrial flutter and fibrillation that carry
    the human stroke and symptom burden have no counterpart endpoint at all -
    the model is silent on them rather than negative. The
    transverse-aortic-constriction variant compounds this by imposing surgical
    VENTRICULAR afterload, a stimulus with no equivalent in the spontaneous
    human disease.
    Consequently the mouse should be cited for the corin/ANP/blood-pressure
    axis and for the corin-replacement rescue, and NOT as support for the
    atrial phenotype.
  evidence:
  - reference: PMID:37636304
    reference_title: "Corin deficiency impairs cardiac function in mouse models of heart failure."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Cardiac function was assessed by echocardiography and tissue analysis in
      Corin KO mice at different ages or subjected to transverse aortic
      constriction (TAC), which increased pressure overload.
    explanation: >-
      Documents the model's assessment battery - imaging and histology, with no
      rhythm monitoring - which is the specific reason the atrial arrhythmia arm
      of the human phenotype has no counterpart endpoint in the model.
  - reference: PMID:15637153
    reference_title: "Hypertension in mice lacking the proatrial natriuretic peptide convertase corin."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In addition, Cor-/- mice exhibit cardiac hypertrophy resulting in a mild
      decline in cardiac function later in life.
    explanation: >-
      The murine hypertrophy is reported at whole-heart level with no atrial
      localisation, establishing the chamber-selectivity mismatch this
      discussion records.
  proposed_experiments:
  - experiment_id: atrial_ep_aged_corin_null
    name: Atrial electrophysiology in aged corin-null mice
    description: >-
      Implanted telemetry or programmed atrial stimulation in aged corin-null
      mice to determine whether atrial arrhythmia occurs at all in the model,
      converting a silent endpoint into a positive or negative result.
  - experiment_id: atrium_restricted_corin_deletion
    name: Atrium-restricted conditional Corin deletion
    description: >-
      Delete Corin selectively in atrial cardiomyocytes to test whether atrial
      disease can be produced without systemic hypertension - the cleanest
      discriminator between the autocrine and mechanical accounts of atrial
      selectivity.
  - experiment_id: ipsc_atrial_cardiomyocytes
    name: Patient-derived iPSC atrial cardiomyocytes and engineered atrial tissue
    description: >-
      Isogenic CRISPR-corrected patient lines differentiated to atrial
      cardiomyocytes, with pro-ANP cleavage, cGMP, conduction, and matrix
      production as readouts, to establish the human atrial cell-autonomous
      consequence of the null genotype.
- discussion_id: corin_cmh30_evidence_base
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What are the penetrance, natural history, arrhythmic burden, stroke rate,
    and prognosis of biallelic CORIN loss of function?
  attaches_to:
  - pathophysiology#Biallelic CORIN Null Variant
  - phenotypes#Atrial Cardiomyopathy
  rationale: >-
    Every quantitative dimension of this entity is unmeasured because the human
    evidence base is a single sibship of two. There is no second family, no
    cohort, no prevalence estimate, no age-of-onset distribution, no penetrance
    figure for biallelic carriers, no arrhythmia incidence, no stroke rate, and
    no survival data. Nothing in this entry's treatment section rests on
    CORIN-specific outcome evidence; all of it is extrapolated from general
    hypertension, atrial-fibrillation, and cardiomyopathy management. Curators
    should resist the temptation to borrow numbers from the sarcomeric
    hypertrophic cardiomyopathy series that shares the CMH naming - those
    figures describe a mechanistically unrelated ventricular disease. A second
    reported family with an independent CORIN null genotype would be the single
    most valuable addition to this entry.
  evidence:
  - reference: PMID:37913506
    reference_title: "Corin and Left Atrial Cardiomyopathy, Hypertension, Arrhythmia, and Fibrosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two siblings presented with cardiomyopathy, hypertension, arrhythmia, and
      fibrosis of the left atrium.
    explanation: >-
      The entire human evidence base for this entity is the two individuals
      named here, which is what makes every quantitative dimension unmeasured.
- discussion_id: corin_hypomorphic_allele_boundary
  kind: INTERPRETATION
  status: RESOLVED
  prompt: >-
    Should the common CORIN I555(P568) hypomorphic allele, and the CORIN-low
    fibrotic cardiomyopathy transcriptomic cluster, be curated as part of this
    disease entry?
  attaches_to:
  - genetic#CORIN
  - pathophysiology#Cardiac Fibroblast Activation
  rationale: >-
    Resolved as NO for the phenotype and prevalence sections, YES as
    mechanistic corroboration only. The I555(P568) allele (T555I + Q568P) is
    common in people of African ancestry, reduces rather than abolishes
    natriuretic peptide processing, and is associated with hypertension, an
    enhanced hypertrophic response to afterload, and impaired BNP processing in
    heart failure. Those are common complex traits attributable to a hypomorph
    in the heterozygous state, not the recessive null disease described here,
    and importing their frequencies or outcomes would inflate this entry with
    numbers that do not describe it. The same boundary applies to the
    transcriptomic finding that a low-CORIN, fibroblast-activated cluster of
    sporadic cardiomyopathy has worse ejection fraction and prognosis: that
    cohort is not CORIN-null. Both bodies of work are retained where they speak
    to MECHANISM - that reduced corin activity is sufficient to raise blood
    pressure and to dis-inhibit cardiac fibroblast activation - and the
    corresponding evidence items record exactly that distinction in their
    explanations.
  evidence:
  - reference: PMID:16216958
    reference_title: "Corin gene minor allele defined by 2 missense mutations is common in blacks and associated with high blood pressure and hypertension."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The corin I555 (P568) allele is common in blacks and is associated with
      higher blood pressure and an increased risk for prevalent hypertension.
    explanation: >-
      Defines the hypomorphic-allele literature this boundary excludes from the
      phenotype and prevalence sections: a common allele producing a common complex
      trait, not the recessive null disease. It concerns a different genotype from
      CMH30.
  - reference: PMID:17296875
    reference_title: "Corin I555(P568) allele is associated with enhanced cardiac hypertrophic response to increased systemic afterload."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These data suggest that the corin I555(P568) allele represents a cardiac
      hypertrophy-sensitizing genetic locus in systemic hypertension.
    explanation: >-
      Retained as mechanistic corroboration that reduced corin activity sensitises the
      heart to hypertrophy under afterload. The genotype is a common hypomorph in the
      heterozygous state, so neither its effect sizes nor its frequencies transfer to
      CMH30.
  - reference: PMID:39315128
    reference_title: "Progression from cardiomyopathy to heart failure with reduced ejection fraction: A CORIN deficient course."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      This cluster also exhibited lower left ventricular ejection fraction
      (LVEF) and worse prognostic outcomes, establishing the significance of
      this molecular subclassification.
    explanation: >-
      The transcriptomic prognostic association this boundary declines to import as
      prognosis for CMH30. The cohort is sporadic cardiomyopathy stratified by CORIN
      expression, not CORIN-null patients.
classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
  - classification_value: GENETICS_ENVIRONMENT_DISEASE

📚

References & Deep Research

Deep Research

1

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Hypertrophic Cardiomyopathy 30, Atrial: Disease-Characteristics Report

Edison Scientific Literature 13 citations 2026-08-19T09:13:43.178911

Hypertrophic Cardiomyopathy 30, Atrial: Disease-Characteristics Report

Executive summary and evidence boundary

Hypertrophic cardiomyopathy 30, atrial is an exceptionally rare, recently delineated Mendelian cardiomyopathy associated with CORIN, the gene encoding the cardiac transmembrane serine protease corin. Its defining clinical spectrum is better described as left-atrial cardiomyopathy with hypertension, atrial arrhythmia, and fibrosis than as conventional sarcomeric, left-ventricular hypertrophic cardiomyopathy. Open Targets maps the entity to MONDO:0958241, CORIN/ENSG00000145244, PMID 37913506, and ClinVar records RCV003882741 and RCV005234881. (OpenTargets Search: Hypertrophic cardiomyopathy 30, atrial)

The evidence base is extremely small. The pivotal human report is Feldman et al., New England Journal of Medicine, published 2 November 2023, PMID 37913506, DOI: 10.1056/NEJMoa2301908. Its full text and detailed pedigree tables were not retrievable through the available tools. Consequently, exact family size, nucleotide/protein variant, allele frequency, segregation, penetrance, and patient-level frequencies should be curated directly from that article and its ClinVar submissions rather than inferred. The strongest accessible mechanistic evidence comes from CORIN-null mice, pressure-overload models, fibroblast experiments, and human cardiomyopathy transcriptomic analyses. (OpenTargets Search: Hypertrophic cardiomyopathy 30, atrial, niu2023corindeficiencyimpairs pages 12-13, kan2024progressionfromcardiomyopathy pages 1-2)

The following table distinguishes disease-specific observations from broader CORIN biology and general-HCM extrapolation.

Field	Disease-specific / extrapolated	Knowledge-base-ready summary	Suggested ontology terms	Evidence
Canonical name	Disease-specific	Hypertrophic cardiomyopathy 30, atrial; also represented as cardiomyopathy, familial hypertrophic, 30, atrial	MONDO:0958241	(OpenTargets Search: Hypertrophic cardiomyopathy 30, atrial)
MONDO ID	Disease-specific	MONDO:0958241	MONDO:0958241	(OpenTargets Search: Hypertrophic cardiomyopathy 30, atrial)
Causal gene / protein	Disease-specific	CORIN encodes corin, a cardiac transmembrane serine protease involved in natriuretic peptide activation	Gene: CORIN; Protein: corin, serine peptidase	(OpenTargets Search: Hypertrophic cardiomyopathy 30, atrial, niu2023corindeficiencyimpairs pages 1-2)
Key disease-specific evidence	Disease-specific	Open Targets links MONDO:0958241 to CORIN with literature support including PMID 37913506 and ClinVar submissions; exact family-level variant and pedigree details were not accessible in the retrieved text and should be curated directly from the primary report/ClinVar before database finalization	Disease entity to gene association	(OpenTargets Search: Hypertrophic cardiomyopathy 30, atrial)
Inheritance / penetrance	Disease-specific	Familial/inherited disease label supports Mendelian inheritance, but exact mode of inheritance, penetrance, and expressivity could not be verified from accessible full-text evidence; record as unknown pending direct review of PMID 37913506/ClinVar	Inheritance: unknown; Penetrance: unknown; Expressivity: unknown	(OpenTargets Search: Hypertrophic cardiomyopathy 30, atrial)
Core phenotypes	Disease-specific	Left atrial cardiomyopathy/atrial remodeling with arrhythmia, hypertension, and fibrosis are implicated by the disease association and title-level evidence; exact frequencies and ventricular involvement remain incompletely accessible	HPO label suggestions: atrial arrhythmia, atrial fibrillation, cardiac fibrosis, hypertension, cardiomyopathy, abnormality of the left atrium	(OpenTargets Search: Hypertrophic cardiomyopathy 30, atrial)
Mechanism	Disease-specific with strong support from related CORIN biology	CORIN deficiency impairs conversion of pro-ANP to ANP, lowering downstream cGMP signaling and permitting maladaptive RAAS activation, sodium-retention/pressure-load effects, hypertrophy, fibrosis, and heart failure progression; direct atrial-human mechanism is plausible but incompletely resolved for this named disease	GO label suggestions: atrial natriuretic peptide processing, cGMP-mediated signaling, regulation of blood pressure, negative regulation of cardiac muscle hypertrophy, extracellular matrix organization, cardiac muscle fibrosis	(kan2024progressionfromcardiomyopathy pages 17-17, niu2023corindeficiencyimpairs pages 12-13, niu2023corindeficiencyimpairs pages 1-2)
Anatomy / cell types / subcellular localization	Mixed: disease-specific cardiac focus; mechanistic details from related CORIN studies	Primary anatomy: heart, especially left atrium; likely secondary involvement via hypertension/heart failure. Cell types: cardiomyocytes, cardiac fibroblasts. Subcellular/localization: plasma membrane/cell surface for corin; extracellular space for ANP signaling	UBERON label suggestions: heart, left atrium, myocardium; CL label suggestions: cardiomyocyte, cardiac fibroblast; GO-CC label suggestions: plasma membrane, cell surface, extracellular region	(kan2024progressionfromcardiomyopathy pages 1-2, niu2023corindeficiencyimpairs pages 1-2)
Diagnostic approach	Mostly extrapolated from general HCM/cardiomyopathy practice; gene-specific confirmation is disease-specific	For suspected cases: cardiac phenotyping with ECG/rhythm monitoring, echocardiography, consider CMR, blood pressure assessment, family history, and molecular testing including CORIN within cardiomyopathy/arrhythmia panels or exome/genome approaches if panel-negative; cascade testing depends on confirmation of a pathogenic familial variant	HPO label suggestions relevant to workup: atrial fibrillation, cardiomyopathy, hypertension	(OpenTargets Search: Hypertrophic cardiomyopathy 30, atrial)
Management evidence status	Mostly extrapolated from general HCM/atrial cardiomyopathy; no disease-specific treatment trials identified	No disease-specific therapy established from accessible evidence. Management should currently follow phenotype-directed care for HCM/atrial arrhythmia/hypertension/heart failure, while noting experimental rationale for restoring corin/ANP signaling from animal studies. Emerging general HCM therapies such as myosin inhibitors are not validated for CORIN-mediated atrial disease specifically	NCIT label suggestions: genetic counseling, electrocardiographic monitoring, echocardiography, cardiac MRI, antiarrhythmic therapy, anticoagulation, antihypertensive therapy	(niu2023corindeficiencyimpairs pages 12-13, niu2023corindeficiencyimpairs pages 1-2)
Epidemiology	Disease-specific	Ultra-rare; no prevalence or incidence estimates were recovered for this named entity from accessible evidence	Rare disease	(OpenTargets Search: Hypertrophic cardiomyopathy 30, atrial)
Animal / experimental models	Related CORIN biology, not exact human atrial disease replica	Corin knockout mice develop salt-sensitive hypertension and progressive cardiac dysfunction, hypertrophy, and fibrosis after aging; pressure-overload (TAC) accelerates dysfunction in young KO mice; recombinant soluble corin ameliorates dysfunction, fibrosis, hypertrophy markers, RAAS activation, and lung edema. Fibroblast studies show CORIN overexpression can blunt profibrotic activation	GO label suggestions: response to pressure overload, regulation of cardiac muscle hypertrophy, fibrosis, fibroblast activation; CL: cardiac fibroblast	(niu2023corindeficiencyimpairs pages 12-13, kan2024progressionfromcardiomyopathy pages 1-2, niu2023corindeficiencyimpairs pages 1-2)
Major evidence gaps	Disease-specific	Missing or inaccessible in retrieved evidence: exact pathogenic variant(s), ACMG classification, segregation data, patient counts, age/sex distribution, penetrance, quantitative phenotype frequencies, natural history, prognosis, and whether ventricular hypertrophy is obligatory or secondary. These should be abstracted directly from PMID 37913506, ClinVar records, and any follow-up correspondence before structured curation	Evidence gap annotation	(OpenTargets Search: Hypertrophic cardiomyopathy 30, atrial)

Table: This table condenses the currently recoverable knowledge-base-ready facts for Hypertrophic Cardiomyopathy 30, Atrial and clearly separates disease-specific evidence from inferences based on broader CORIN biology and general HCM practice.

1. Disease information

Definition

This is a familial cardiac disorder attributed to impaired CORIN function and characterized principally by structural and electrical disease of the atrium, including atrial remodeling/fibrosis, atrial arrhythmia, and associated hypertension. The nomenclature “hypertrophic cardiomyopathy 30, atrial” should not be assumed to mean that conventional unexplained left-ventricular hypertrophy is obligatory; the accessible disease-specific evidence instead emphasizes a left-atrial phenotype. (OpenTargets Search: Hypertrophic cardiomyopathy 30, atrial)

Identifiers and synonyms

MONDO: MONDO:0958241.
Preferred database label: cardiomyopathy, familial hypertrophic, 30, atrial.
Synonyms: hypertrophic cardiomyopathy 30, atrial; HCM30, atrial; CORIN-related atrial cardiomyopathy; familial left-atrial cardiomyopathy associated with CORIN.
Gene: CORIN; Ensembl ENSG00000145244; approved protein name “corin, serine peptidase.”
ClinVar disease records surfaced: RCV003882741 and RCV005234881.
OMIM, Orphanet, MeSH, ICD-10/ICD-11: a distinct code could not be verified from retrieved evidence. Until confirmed, use broader cardiomyopathy/atrial-cardiomyopathy codes and preserve MONDO:0958241 as the specific computational identifier. (OpenTargets Search: Hypertrophic cardiomyopathy 30, atrial)

The source is an aggregated disease-level entity built from a family report and variant databases, not an EHR-derived population phenotype.

2. Etiology

Causal factor

The nominated cause is a germline CORIN defect. Corin normally converts pro-atrial natriuretic peptide (pro-ANP) to active ANP. Reduced activity therefore weakens natriuretic-peptide signaling, favors sodium retention and hypertension, and removes anti-hypertrophic and anti-fibrotic restraint. (kan2024progressionfromcardiomyopathy pages 17-17, niu2023corindeficiencyimpairs pages 1-2)

Risk factors and modifiers

Genetic: a disease-associated CORIN variant is the primary risk factor. Exact HGVS nomenclature, ACMG/AMP classification, zygosity, population frequency, and segregation require direct ClinVar/PMID 37913506 review.
Family history: relevant because the disorder is familial, but penetrance and age dependence are not yet quantifiable.
Environmental/physiologic: high sodium intake, uncontrolled blood pressure, and chronic pressure load are biologically plausible aggravators, not proven human modifiers of this exact subtype. In mice, Corin loss produces salt-sensitive hypertension, while transverse aortic constriction markedly accelerates dysfunction. (niu2023corindeficiencyimpairs pages 12-13, niu2023corindeficiencyimpairs pages 1-2)
Age: aging unmasks disease in CORIN-null mice; hypertrophy and fibrosis become evident after approximately nine months, with dysfunction prominent by 12 months. Human age-specific risk is unknown. (niu2023corindeficiencyimpairs pages 12-13, niu2023corindeficiencyimpairs pages 1-2)

No validated protective allele, modifier gene, sex-specific risk, occupational exposure, toxin, infection, diet, or pharmacogenomic association has been established for the named disorder. Blood-pressure control and avoidance of excessive sodium are reasonable phenotype-directed precautions, not demonstrated primary prevention.

3. Phenotypes

Disease-specific quantitative frequencies are unavailable. Suggested phenotypes are therefore separated into reported/core, mechanistically supported, and possible complications.

Left-atrial cardiomyopathy/remodeling: core structural manifestation; likely chronic and progressive. Suggested HPO labels: abnormality of the left atrium, left atrial enlargement, and cardiomyopathy.
Atrial arrhythmia, particularly atrial fibrillation: core electrical manifestation; potentially episodic initially and persistent later. HPO: atrial arrhythmia, atrial fibrillation.
Cardiac fibrosis: core tissue manifestation and probable arrhythmogenic substrate. HPO: myocardial fibrosis/cardiac fibrosis.
Hypertension: prominent associated systemic sign. HPO: systemic arterial hypertension.
Cardiac hypertrophy: supported by the disease name and CORIN-deficiency models, but the relative atrial versus ventricular distribution in human carriers must not be inferred without the primary report. HPO: cardiac hypertrophy or left ventricular hypertrophy only if documented in the individual.
Heart failure, pulmonary edema, reduced ejection fraction: plausible advanced consequences supported by models and broader cardiomyopathy data, but not established as universal disease-specific findings. (OpenTargets Search: Hypertrophic cardiomyopathy 30, atrial, niu2023corindeficiencyimpairs pages 12-13, kan2024progressionfromcardiomyopathy pages 1-2)

Potential quality-of-life effects include palpitations, exertional intolerance, anxiety concerning arrhythmia/stroke, medication burden, and limitations from heart failure. No disease-specific EQ-5D, SF-36, PROMIS, or functional-outcome study is available.

4. Genetic and molecular information

Gene and protein

CORIN encodes a type-II transmembrane serine protease expressed predominantly on cardiomyocyte surfaces. It activates pro-ANP; related literature also implicates corin in pro-BNP processing, sodium homeostasis, vascular remodeling, and blood-pressure regulation. (kan2024progressionfromcardiomyopathy pages 17-17, niu2023corindeficiencyimpairs pages 13-13, niu2023corindeficiencyimpairs pages 1-2)

Variant evidence

Open Targets links CORIN to the disease through PMID 37913506 and two ClinVar records. However, the accessible evidence does not safely establish the exact variant, transcript, HGVS expression, ACMG class, molecular consequence, or gnomAD/TOPMed frequency. Those fields should be marked pending primary-source verification, not populated from secondary inference. The disorder should be treated as germline/familial; no somatic etiology is implicated. (OpenTargets Search: Hypertrophic cardiomyopathy 30, atrial)

No validated modifier genes, epigenetic signature, recurrent structural variant, chromosomal rearrangement, anticipation, germline mosaicism, founder effect, or consanguinity association is known.

5. Environmental and lifestyle information

No environmental agent or infection causes this Mendelian disease. Physiologic stressors could nevertheless alter expression:

Increased sodium/volume burden may amplify hypertension when ANP activation is impaired.
Chronic hypertension raises atrial and ventricular wall stress.
Pressure overload promotes hypertrophy, fibroblast activation, and fibrosis.
Fibrosis creates an arrhythmogenic substrate and may impair filling and pump function.

This gene–environment chain is strongly supported in CORIN-null mice but remains unquantified in affected humans. Corin-null mice have impaired sodium handling and a systolic pressure around 118 mmHg versus 107 mmHg in wild-type controls. (niu2023corindeficiencyimpairs pages 1-2)

Smoking, alcohol, obesity, sleep apnea, and extreme exercise should be assessed because they affect atrial fibrillation and cardiomyopathy generally, but they have not been demonstrated as CORIN-specific modifiers.

6. Mechanism and pathophysiology

Proposed causal chain

Upstream: deleterious CORIN variation → reduced cell-surface corin abundance, activation, or protease function → deficient pro-ANP cleavage.

Intermediate: reduced mature ANP → reduced natriuretic-peptide receptor-A/cGMP/PKG signaling → diminished natriuresis and vasodilation plus inadequate suppression of renin–angiotensin–aldosterone signaling.

Downstream: sodium/volume retention and hypertension → atrial wall stress and pressure loading → cardiomyocyte hypertrophy and cardiac-fibroblast activation → extracellular-matrix deposition/fibrosis → atrial electrical remodeling and arrhythmia; prolonged disease may progress to ventricular dysfunction, heart failure, and pulmonary edema. (kan2024progressionfromcardiomyopathy pages 17-17, niu2023corindeficiencyimpairs pages 12-13, niu2023corindeficiencyimpairs pages 1-2)

A direct experimental quote from the 2023 mouse study summarizes the rescue evidence: “Corin deficiency impairs cardiac function and exacerbates HF development in mice.” Recombinant soluble corin increased plasma cGMP, reduced N-terminal pro-ANP, angiotensin II, and aldosterone, and ameliorated hypertrophy, fibrosis, dysfunction, and lung edema after pressure overload. (niu2023corindeficiencyimpairs pages 12-13, niu2023corindeficiencyimpairs pages 1-2)

Molecular profiling

A 2024 analysis integrated bulk transcriptomic data from 106 HCM and 184 dilated-cardiomyopathy patients with single-nucleus RNA sequencing and Mendelian-randomization analyses. A low-CORIN/high-fibroblast-activation cluster was associated with lower ejection fraction and poorer prognosis. In neonatal-rat cardiac fibroblasts, CORIN overexpression reduced TGF-β1-induced COL1A1 and α-SMA expression. These results support an anti-fibrotic role but are not specific to MONDO:0958241; clinical covariates and independent subtype validation were limited. (kan2024progressionfromcardiomyopathy pages 1-2)

Suggested annotations:

GO biological processes: proteolytic activation of peptide hormone; natriuretic peptide signaling; cGMP-mediated signaling; regulation of systemic arterial blood pressure; sodium-ion homeostasis; negative regulation of cardiac-muscle hypertrophy; extracellular-matrix organization; cardiac fibrosis.
Cell Ontology: cardiomyocyte; atrial cardiomyocyte; cardiac fibroblast; vascular endothelial cell.
GO cellular components: plasma membrane; cell surface; extracellular region.
Chemical entities: ANP, cGMP, sodium ion, angiotensin II, aldosterone; CHEBI identifiers should be validated during ontology ingestion.

No disease-specific methylome, proteome, metabolome, lipidome, spatial-transcriptomic, CRISPR-screen, or patient-derived single-cell atlas was identified.

7. Anatomical structures affected

Primary organ: heart.
Principal site: left atrium/atrial myocardium; suggested UBERON labels: heart, left atrium, myocardium.
Cells: atrial cardiomyocytes and cardiac fibroblasts.
Subcellular site: cardiomyocyte plasma membrane/cell surface, where corin processes extracellular pro-ANP.
Secondary systems: systemic vasculature and kidney through blood-pressure, volume, and sodium regulation; lungs may be involved secondarily through heart-failure pulmonary edema.
Lateralization: not applicable beyond specific left-atrial predominance; unilateral/bilateral terminology is inappropriate. (kan2024progressionfromcardiomyopathy pages 17-17, niu2023corindeficiencyimpairs pages 12-13, niu2023corindeficiencyimpairs pages 1-2)

8. Temporal development

Human onset, median diagnostic age, and progression rate are unknown. The familial phenotype is most reasonably regarded as chronic, potentially age-dependent, and variably expressive pending longitudinal study.

The model-organism trajectory is clearer: CORIN-null mice develop hypertension first, then hypertrophy and fibrosis after about nine months, and progressive dysfunction by roughly 12 months. Pressure overload at 10–12 weeks precipitates more rapid deterioration than in wild-type mice. This suggests a latent compensated phase followed by stress- or age-associated decompensation, but mouse timing cannot be directly translated to patients. (niu2023corindeficiencyimpairs pages 12-13, niu2023corindeficiencyimpairs pages 1-2)

No spontaneous remission, treatment-induced molecular remission, or critical pediatric intervention window has been demonstrated.

9. Inheritance and population

The disease is familial and Mendelian, but the precise inheritance mode and penetrance could not be verified from accessible primary text. An autosomal-dominant model may be plausible for a multigenerational familial cardiomyopathy, but it should remain unconfirmed until the pedigree and ClinVar records are reviewed.

There are no reliable estimates of prevalence, incidence, carrier frequency, sex ratio, ethnic enrichment, geographic distribution, founder effect, or age distribution. It should be classified as ultra-rare rather than assigned a numerical prevalence. General HCM prevalence must not be substituted for CORIN-related atrial cardiomyopathy.

10. Diagnostics

Clinical evaluation

A rational work-up is:

Three-generation pedigree, blood-pressure history, symptoms, and medication/exposure review.
Resting 12-lead ECG and ambulatory rhythm monitoring to detect atrial fibrillation or other atrial arrhythmias.
Transthoracic echocardiography, emphasizing atrial size/function, ventricular wall thickness, diastolic function, ejection fraction, and outflow obstruction.
Cardiac MRI for atrial/ventricular morphology and late-gadolinium-enhancement fibrosis where technically appropriate.
Biomarkers such as NT-proBNP/BNP, renal function, electrolytes, and troponin when clinically indicated. Pro-ANP processing or soluble corin is mechanistically attractive but not a validated disease-specific diagnostic assay.
Exclude secondary hypertrophy/remodeling: long-standing hypertension, valve disease, athlete’s heart, infiltrative/storage disorders, sarcomeric HCM, congenital structural disease, and tachycardia-mediated remodeling.

Genetic testing

Use a validated cardiomyopathy/arrhythmia panel that includes CORIN, with deletion/duplication analysis as appropriate. If negative despite a compelling family phenotype, consider exome or genome sequencing and periodic reanalysis. A confirmed familial pathogenic/likely pathogenic variant enables cascade testing; relatives without definitive molecular clarification require longitudinal ECG and imaging surveillance.

General-HCM data indicate that targeted testing yields a causal variant in about 30% of sporadic cases and up to 60% of familial or younger, typical cases, but these figures cannot be applied to this CORIN entity. A 2024 review recommends disease-focused next-generation-sequencing panels and cascade testing when a decisively pathogenic familial variant is found. Abbas et al., 20 March 2024, DOI 10.3390/biomedicines12030682. No evidence supports routine karyotyping, FISH, mitochondrial sequencing, repeat-expansion testing, liquid biopsy, or diagnostic proteomics for this disorder.

11. Outcome and prognosis

No disease-specific survival curve, mortality rate, life-expectancy estimate, stroke rate, heart-failure rate, or quality-of-life dataset exists in accessible evidence. Plausible complications include persistent atrial fibrillation, thromboembolism/stroke, progressive fibrosis, hypertension-mediated organ damage, heart failure, and—if ventricular disease is present—ventricular arrhythmia or sudden cardiac death. These require individual risk assessment rather than assumed attribution.

In broader cardiomyopathy datasets, reduced CORIN expression is associated with lower ejection fraction and worse prognosis, while CORIN-null mice develop progressive dysfunction and fibrosis. These observations establish biological concern but not patient-level prognostic calibration for HCM30. (kan2024progressionfromcardiomyopathy pages 17-17, kan2024progressionfromcardiomyopathy pages 1-2)

Potential prognostic measurements include atrial size and strain, atrial-fibrillation burden, fibrosis on MRI, blood-pressure control, ventricular thickness/function, NT-proBNP, and clinical heart-failure status. None is yet validated specifically for CORIN-related disease.

12. Treatment

There is no approved CORIN-genotype-specific therapy and no disease-specific clinical trial identified. Current care should be phenotype-directed at a cardiomyopathy center.

Hypertension/volume control: individualized antihypertensive therapy and avoidance of excessive sodium; avoid abrupt preload reduction if significant obstructive ventricular physiology exists.
Atrial fibrillation: rhythm/rate control as appropriate and thromboembolic-risk management. In established HCM with clinical AF, contemporary guidelines generally favor anticoagulation irrespective of conventional CHA₂DS₂-VASc thresholds, but whether every isolated CORIN atrial phenotype meets that HCM rule requires specialist judgment.
Heart failure: guideline-directed therapy matched to ejection fraction and hemodynamics.
Obstructive ventricular HCM, if independently documented: non-vasodilating beta-blocker first; verapamil/diltiazem when appropriate; disopyramide, septal reduction, or a cardiac-myosin inhibitor in eligible patients. These interventions target ventricular sarcomeric hypercontractility and are not validated for isolated CORIN-mediated atrial disease.
Devices/ablation: catheter ablation, pacemaker, or ICD only for standard rhythm and sudden-death indications, not genotype alone.
Support: genetic counseling, family screening, exercise counseling, pregnancy planning, and management of obesity/sleep apnea and other AF-promoting conditions.

The authoritative current frameworks are the 2023 ESC cardiomyopathy guideline and 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR HCM guideline (published June 2024; DOI 10.1161/CIR.0000000000001250). A systematic comparison found broad agreement on echocardiography, genetic testing/family screening, medical and invasive management, exercise, and reproductive counseling, with differences in diagnostic definitions, MRI use, and sudden-death risk assessment.

Recombinant soluble corin is an experimental concept only. In pressure-overloaded knockout mice it increased cGMP and reduced RAAS activation, hypertrophy, fibrosis, and edema; no human efficacy, dose, safety, immunogenicity, or delivery data support clinical use. (niu2023corindeficiencyimpairs pages 12-13, niu2023corindeficiencyimpairs pages 1-2)

Suggested NCIT intervention labels: genetic counseling; electrocardiography; ambulatory ECG monitoring; echocardiography; cardiac MRI; antihypertensive therapy; anticoagulation therapy; antiarrhythmic therapy; catheter ablation; implantable cardioverter-defibrillator; septal myectomy. Validate exact NCIT codes during ingestion.

13. Prevention

Primary prevention: the inherited variant cannot currently be prevented. Reproductive options after molecular confirmation include prenatal diagnosis and preimplantation genetic testing with nondirective counseling.
Secondary prevention: cascade genetic testing, ECG/rhythm surveillance, echocardiography, MRI when indicated, and early detection/control of hypertension and atrial arrhythmia.
Tertiary prevention: blood-pressure control, stroke prevention in AF, heart-failure therapy, and individualized arrhythmic-risk management.
Behavioral measures: avoid smoking and stimulant misuse; maintain healthy weight; diagnose sleep apnea; use individualized exercise advice; avoid excessive sodium and alcohol where hypertension/AF is present.
Vaccination/public-health control: no disease-specific vaccine or infectious prophylaxis applies.

No intervention has been shown to prevent phenoconversion in genotype-positive CORIN carriers.

14. Other species and natural disease

No verified naturally occurring CORIN-associated counterpart in companion animals, livestock, or wildlife was identified. There is no zoonotic transmission. CORIN is evolutionarily conserved, and experimental mouse phenotypes demonstrate conservation of natriuretic-peptide activation and blood-pressure regulation, but engineered knockout disease should not be entered as naturally occurring veterinary HCM30.

Suggested taxonomy for the principal experimental species: Mus musculus (NCBI Taxon 10090). Exact mouse Corin and ortholog gene identifiers should be imported from NCBI Gene/Alliance rather than inferred here.

15. Model organisms and experimental systems

Mouse models

Constitutive Corin knockout: salt-sensitive hypertension, progressive cardiac hypertrophy and fibrosis after nine months, and later dysfunction. Strength: models systemic loss of corin. Limitation: the human variant may be hypomorphic or domain-specific, and the mouse phenotype is not selectively atrial. (niu2023corindeficiencyimpairs pages 12-13, niu2023corindeficiencyimpairs pages 1-2)
Corin knockout plus transverse aortic constriction: at 10–12 weeks, knockout mice deteriorate faster than similarly stressed wild types, modeling gene–pressure-load interaction. Recombinant soluble corin partially rescues function, morphology, cGMP signaling, RAAS activation, and pulmonary edema. Strength: causal perturbation and rescue. Limitation: surgically imposed ventricular afterload differs from spontaneous human atrial disease. (niu2023corindeficiencyimpairs pages 12-13, niu2023corindeficiencyimpairs pages 1-2)
Conditional cardiac/renal Corin models: useful for separating endocrine cardiac CORIN from renal or intestinal sodium-handling effects; these are mechanistic models rather than faithful replicas of HCM30.

Cellular and computational systems

Neonatal-rat cardiac fibroblasts exposed to TGF-β1 show reduced COL1A1 and α-SMA activation after CORIN overexpression. Human HCM/DCM bulk and single-nucleus transcriptomic analyses identify low-CORIN, fibroblast-rich disease clusters. These systems support anti-fibrotic activity but cannot establish variant-specific atrial causality. (kan2024progressionfromcardiomyopathy pages 1-2)

High-priority future models are patient-derived iPSC atrial cardiomyocytes and fibroblasts, isogenic CRISPR correction/knock-in lines, atrial engineered tissues, and variant-specific knock-in mice. Required readouts include pro-ANP cleavage, cell-surface CORIN abundance, cGMP/PKG activity, electrophysiology, conduction, extracellular-matrix production, and response to pressure/sodium stress.

Key evidence gaps and curation priorities

Retrieve PMID 37913506 and ClinVar RCV003882741/RCV005234881 to capture exact HGVS variant, transcript, zygosity, ACMG class, family size, segregation, and functional assays.
Determine whether inheritance is definitively autosomal dominant and quantify age-dependent penetrance.
Separate atrial hypertrophy/remodeling from ventricular HCM in the formal disease definition.
Obtain individual-level phenotype frequencies, onset, rhythm burden, fibrosis measurements, blood-pressure data, treatment responses, and outcomes.
Establish whether soluble corin, pro-ANP:mature-ANP ratio, or cGMP is diagnostically or prognostically useful.
Develop variant-specific human atrial models and a prospective international registry.

Overall, the association of CORIN with MONDO:0958241 is supported, and the CORIN–ANP–cGMP/RAAS axis provides a coherent causal mechanism. Nevertheless, most clinical implementation currently rests on phenotype-directed cardiomyopathy and atrial-arrhythmia practice, while exact molecular and natural-history annotations remain dependent on direct curation of the foundational 2023 family report. (OpenTargets Search: Hypertrophic cardiomyopathy 30, atrial, niu2023corindeficiencyimpairs pages 12-13, kan2024progressionfromcardiomyopathy pages 1-2, niu2023corindeficiencyimpairs pages 1-2)

References

(OpenTargets Search: Hypertrophic cardiomyopathy 30, atrial): Open Targets Query (Hypertrophic cardiomyopathy 30, atrial, 1 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(niu2023corindeficiencyimpairs pages 12-13): Yayan Niu, Tiantian Zhou, Shengnan Zhang, Wenguo Li, Kun Wang, Ningzheng Dong, and Qingyu Wu. Corin deficiency impairs cardiac function in mouse models of heart failure. Frontiers in Cardiovascular Medicine, Aug 2023. URL: https://doi.org/10.3389/fcvm.2023.1164524, doi:10.3389/fcvm.2023.1164524. This article has 11 citations and is from a peer-reviewed journal.
(kan2024progressionfromcardiomyopathy pages 1-2): Jun-yan Kan, Dong-chen Wang, Zi-hao Jiang, Li-da Wu, Ke Xu, and Yue Gu. Progression from cardiomyopathy to heart failure with reduced ejection fraction: a corin deficient course. Heliyon, 10:e37838, Sep 2024. URL: https://doi.org/10.1016/j.heliyon.2024.e37838, doi:10.1016/j.heliyon.2024.e37838. This article has 2 citations.
(niu2023corindeficiencyimpairs pages 1-2): Yayan Niu, Tiantian Zhou, Shengnan Zhang, Wenguo Li, Kun Wang, Ningzheng Dong, and Qingyu Wu. Corin deficiency impairs cardiac function in mouse models of heart failure. Frontiers in Cardiovascular Medicine, Aug 2023. URL: https://doi.org/10.3389/fcvm.2023.1164524, doi:10.3389/fcvm.2023.1164524. This article has 11 citations and is from a peer-reviewed journal.
(kan2024progressionfromcardiomyopathy pages 17-17): Jun-yan Kan, Dong-chen Wang, Zi-hao Jiang, Li-da Wu, Ke Xu, and Yue Gu. Progression from cardiomyopathy to heart failure with reduced ejection fraction: a corin deficient course. Heliyon, 10:e37838, Sep 2024. URL: https://doi.org/10.1016/j.heliyon.2024.e37838, doi:10.1016/j.heliyon.2024.e37838. This article has 2 citations.
(niu2023corindeficiencyimpairs pages 13-13): Yayan Niu, Tiantian Zhou, Shengnan Zhang, Wenguo Li, Kun Wang, Ningzheng Dong, and Qingyu Wu. Corin deficiency impairs cardiac function in mouse models of heart failure. Frontiers in Cardiovascular Medicine, Aug 2023. URL: https://doi.org/10.3389/fcvm.2023.1164524, doi:10.3389/fcvm.2023.1164524. This article has 11 citations and is from a peer-reviewed journal.

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Hypertrophic Cardiomyopathy 30, Atrial: Disease-Characteristics Report

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1. Disease information

Definition

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2. Etiology

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3. Phenotypes

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