Submission Details

NEXN was originally evaluated for DCM by the ClinGen DCM GCEP on February 14 2020. Evidence of the association of this gene with DCM was re-evaluated using SOP v10 on November 15 2024. As a result, the classification changed. A summary of the information contributing to the classification of this gene at the time of re-evaluation is summarized herein:

NEXN was evaluated for autosomal dominant dilated cardiomyopathy (DCM). NEXN encodes a filamentous actin (F-actin)-binding protein that also binds to RyR2 and Jph2, is a pivotal component of the junctional membrane complex, is required for initiation and formation of T-tubules and is important Ca2+ homeostasis in the heart (Liu et al 2019, PMID: 30982350; Spinozzi et al 2020, PMID: 32635769). Human genetic evidence supporting this gene-disease relationship includes case-level data and case-control data. At least 30 heterozygous rare variants (both truncating and non-truncating) have been described in patients with DCM. Rare NEXN variants (truncating and non-truncating jointly) are significantly enriched in DCM compared to controls (Mazzarotto et al, 2020, PMID: 31983221). The heterozygous variant NM_144573.3(NEXN): c.1949_1951del p.(Gly650del) was found in 6/1000 DCM patients analyzed in Germany. All 6 shared an identical haplotype over a large genomic region surrounding the NEXN gene suggesting a founder effect. The variant occurred in 155/1461510 gnomAD (v4.1) alleles, and overexpression of the variant in zebrafish and mouse models results in DCM (Hassel et al 2009, PMID: 19881492; Liu et al 2020, PMID: 32814711). This gene-disease relationship is supported by experimental evidence. NEXN RNA and protein are highly expressed in the myocardium (Zhao et al, 2001, PMID: 12053183, Hassel et al, 2009, PMID: 19881492). Nexn knock-out (KO) zebrafish (using morpholino-modified antisense oligonucleotides) and mouse models (using cre-loxP) show severe, progressive DCM (Hassel et al, 2009, PMID: 19881492; Aherrahrou et al, 2016, PMID: 26659360; Liu et al, 2019, PMID: 30982350). A in vivo mouse rescue model has also demonstrated restoration of cardiomyocyte function in Nexn KO and G645del (equivalent to human G650del) mice following AAV-mediated Nexn gene replacement (Shao et al 2024, PMID: 38783323). Western blot analyses and pull-down results showed that NEXN was coimmunoprecipitated with both Jph2 and RyR2 (proteins from the T tubule) (Liu et al, 2019, PMID: 30982350). Confocal analysis of postnatal control and Nexn KO cardiomyocytes showed that organized T-tubules were completely absent in KO cells (Liu et al, 2019, PMID: 30982350).

In summary, there is strong evidence to support this gene-disease relationship Three years must elapse from the first proposal of the relationship definitively, with no convincing contradictory evidence emerging. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on November 15 2024