NEXN

Inheritance Pattern: SD

Disease ID:MONDO:0013147

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0024573

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0005045

Submitter: ClinGen

*NEXN* was first reported in relation to hypertrophic cardiomyopathy (HCM) in 2 probands in a single 2010 publication (Wang et al, PMID 20970104). Two unique missense variants were reported in this publication. The pathogenicity of one variant was supported by functional studies in a cell culture model system that showed mutant protein fragments accumulated in the cytoplasm and failed to bind to actin filaments. This variant also segregated with disease in 2 additional family members. The second variant reported by Wang et al. was found at a high frequency in the gnomAD database, which is consistent with benign variation. The mechanism for disease is unknown. This gene-disease relationship is supported by expression studies (Hassel et al, 2009, PMID 1988149; Fagerberg et al, 2013, PMID 24309898) and localization of NEXN to the intercalated disk (Hassel et al, 2009, PMID 1988149), and interaction with alpha actin (Wang et al, PMID 20970104). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. The relationship between *NEXN *and autosomal dominant hypertrophic cardiomyopathy was originally evaluated by the ClinGen Hypertrophic Cardiomyopathy Gene Curation Expert Panel (GCEP) on October 28, 2016 and found to have a limited classification. It was re-evaluated on March 23, 2023 by the Hereditary Cardiovascular Disease GCEP. As a result of this recuration, the classification has not changed, and remains limited.

Inheritance Pattern: AD

Disease ID:MONDO:0015470

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0013477

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0013147

Submitter: ClinGen

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 Although independent reports over a 3 year period contributed to this curation, the panel elected to classify as Strong to allow additional experimental evidence to accumulate before upgrading to a final Definitive classification. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on November 15 2024

Inheritance Pattern: AD

Disease ID:MONDO:0013147

Submitter: Labcorp Genetics (formerly Invitae)