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Evidence from multiple independent studies supports a strong association between pathogenic variants in NEXN and dilated cardiomyopathy. Several case reports have identified biallelic (recessive) variants in NEXN in patients presenting with severe cardiomyopathy phenotypes, including lethal fetal presentations accompanied by cardiomegaly and endocardial fibroelastosis (PMID:35166435). In affected families, segregation analyses have revealed that homozygous variants lead to a lethal form of dilated cardiomyopathy while heterozygous carriers can exhibit milder or age‐dependent cardiac abnormalities. This segregation across family members further strengthens the link between NEXN dysfunction and the dilated cardiomyopathy phenotype.
Genetic evidence has been bolstered by the identification of specific variants in NEXN. For instance, the variant c.1535A>G (p.Asn512Ser) has been reported in affected individuals, and its recurrence in independent cohorts suggests pathogenicity. Overall, multiple unrelated probands (e.g., three separate cases reported in one study (PMID:35166435)) indicate that NEXN variants contribute significantly to this cardiac disease. The variant spectrum includes both loss‑of‑function and missense alterations, underscoring the gene’s dosage sensitivity and importance in myocardial structural integrity.
Functional studies further support the gene–disease association. In mouse models, a knockin of a Nexn G645del mutation—which is equivalent to the human G650del—resulted in a disrupted T‑tubule system and a progressive dilated cardiomyopathy phenotype (PMID:32814711). Similar findings were observed in zebrafish CRISPR/Cas9 nexn knockout models, which also showed reduced cardiac contractility under stress conditions (PMID:38114601). Moreover, gene rescue experiments using systemic AAV‑mediated delivery of exogenous Nexn demonstrated a restoration of cardiomyocyte function and extended lifespan in mouse models, further validating the critical role of Nexn in cardiac function (PMID:38783323).
The overall strength of the gene–disease association is therefore categorized as Strong. Multiple unrelated probands carrying biallelic NEXN variants, clear segregation within affected families, and concordant supportive experimental data all converge to support this classification. All of these factors provide critical evidence that can guide diagnostic decision‑making and inform therapeutic strategies for patients with dilated cardiomyopathy.
In addition, the collective data underscore the importance of incorporating both genetic and functional evidence when evaluating the contribution of NEXN to dilated cardiomyopathy. While further studies may reveal additional variants or mechanisms, the current evidence not only exceeds the ClinGen scoring maximum but also has significant clinical utility and commercial potential for gene‑targeted therapies.
Key take‑home sentence: The strong, multi‐faceted evidence linking NEXN to dilated cardiomyopathy underscores its value as a diagnostic marker and a promising target for future therapeutic interventions.
Gene–Disease AssociationStrongMultiple unrelated probands (e.g., 3 probands PMID:35166435) with biallelic NEXN variants, clear segregation within families, and concordant experimental data support a strong association. Genetic EvidenceStrongBiallelic loss‑of‑function and missense variants, including c.1535A>G (p.Asn512Ser), have been identified in affected individuals across independent studies with robust segregation data (PMID:35166435). Functional EvidenceModerateAnimal models, including mouse and zebrafish, display disrupted cardiac T‑tubule integrity and contractility upon loss of Nexn function, and rescue experiments confirm its essential role in cardiac function (PMID:32814711; PMID:38783323). |