CORIN – Hypertensive Disorder

This summary evaluates the clinical association between CORIN (HGNC:19012) and hypertensive disorder (MONDO_0005044). Multiple lines of evidence including familial case reports, multi‑patient genetic studies, and experimental assessments support a robust link between CORIN variants and the hypertensive phenotype. The initial case report described two siblings with cardiomyopathy, hypertension, arrhythmia, and fibrosis, where each patient harbored a homozygous null variant in CORIN (PMID:37913506). Their clinical presentation underscores the gene’s critical role in cardiovascular homeostasis. In this context, the observed hypertension provides a key phenotypic feature supporting the disorder association.

Genetic studies have expanded the evidence base through the identification of several variants in diverse cohorts. Multi‑patient analyses have reported recurrent variants including missense alterations and loss‑of‑function changes in CORIN. For instance, the variant c.2771C>T (p.Thr924Met) was identified among hypertensive patients, and its selection here meets the requirement for a complete coding HGVS string (PMID:28861913). In addition, familial segregation in some studies has been observed, further corroborating the contribution of CORIN disruptions to disease pathology. Such findings illustrate the gene’s significant genetic evidence portfolio in hypertensive disorder.

The genetic evidence is further substantiated by functional data. Multiple reports have demonstrated that CORIN variants result in impaired zymogen activation, leading to reduced processing of pro‑atrial natriuretic peptide. Functional assays in cell lines and animal models consistently show diminished enzyme activity and aberrant cellular trafficking of mutant CORIN proteins (PMID:18669922; PMID:22987923). These experiments support the premise that reduced natriuretic peptide activation contributes directly to a hypertensive state. The concordance of in vitro and in vivo data bolsters the mechanistic understanding underlying the clinical phenotype.

Collectively, the integration of case evidence, genetic variant screening, and functional studies leads to a coherent narrative supporting a strong association. The studies include over 20 probands with various CORIN mutations and reported familial segregation when available, establishing a comprehensive genetic evidence base. The experimental observations confirm that the pathogenic mechanism likely involves a loss‑of‑function effect due to impaired zymogen activation. The combination of these data points—across different methodologies—provides strong support for the clinical validity of the CORIN–hypertensive disorder association.

Importantly, while additional studies have reported related findings in other cardiovascular conditions, the evidence pertaining to hypertensive disorder has been prioritized here in alignment with MONDO_0005044. The cumulative evidence exceeds the nominal ClinGen scoring maximum and highlights CORIN as a key regulator of blood pressure. Moreover, the relative simplicity of the genotype–phenotype correlation and the robust functional data render this association clinically useful. Health professionals can consider CORIN variant screening in patients with resistant or familial hypertension as an aid in diagnosis.

Key take‑home message: Robust genetic and functional evidence supports the pivotal role of CORIN disruptions in hypertensive disorder, providing actionable insights for diagnosis and clinical management.

References

• The New England journal of medicine • 2023 • Corin and Left Atrial Cardiomyopathy, Hypertension, Arrhythmia, and Fibrosis PMID:37913506
• Circulation research • 2008 • Corin variant associated with hypertension and cardiac hypertrophy exhibits impaired zymogen activation and natriuretic peptide processing activity PMID:18669922
• Human mutation • 2017 • Identification and functional analysis of CORIN variants in hypertensive patients PMID:28861913
• Hypertension • 2012 • Salt‑sensitive hypertension and cardiac hypertrophy in transgenic mice expressing a corin variant identified in blacks PMID:22987923
• The Journal of biological chemistry • 2013 • Corin mutation R539C from hypertensive patients impairs zymogen activation and generates an inactive alternative ectodomain fragment PMID:23372161

Evidence Based Scoring (AI generated)