NEBL

Inheritance Pattern: AD

Disease ID:MONDO:0016333

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0005021

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0005045

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0005021

Submitter: ClinGen

NEBL was originally evaluated for DCM by the ClinGen GCEP on 09/25/2020. Evidence of the association of this gene with DCM was re-evaluated using SOP v10 on 10/18/2024, resulting in a decrease in genetic evidence points at the time of recuration. As a result, the classification did not change. A summary of the information contributing to the classification of this gene at the time of re-evaluation is summarized herein. NEBL was evaluated for autosomal dominant dilated cardiomyopathy (DCM). Human genetic evidence supporting this gene-disease relationship includes case-level data. Arimura and colleagues (2000, PMID: 11140941) analyzed 83 DCM patients and 311 healthy controls, identifying 4 missense variants of unknown significance (VUSs) in 4 DCM cases. High minor allele frequencies (MAFs) and lack of segregation excluded these variants as evidence. Purevjav and colleagues (2010, PMID: 20951326) investigated a total of 260 DCM patients and 300 unrelated ethnic matched controls by direct DNA sequencing. Authors identified 4 missense VUSs. One of these variants (Q128R) was downgraded in level of evidence due to the lack of segregation. The other 3 variants were not scored because of their MAF. Perrot and colleagues (2016, PMID: 27186169) investigated a total of 389 patients with DCM, HCM, or LVNC, 320 Caucasian sex-matched controls and 192 Caucasian sex-matched blood donors and identified 3 missense VUSs in 4 families. One of these variants was also carried by healthy relatives and therefore was excluded, however this may be explained by reduced penetrance. The 2 other variants lacked segregation as well and therefore were also excluded. In addition, this gene-disease association is supported by animal models. Mastronotaro and colleagues (2015, PMID: 25987543) created a NEBL knockout mice that exhibited normal cardiac function up to 9 months of age but after 2 weeks of transaortic constriction (TAC), these mice showed Z-line widening since the age of 5 months and upregulation of cardiac stress genes (basal and after TAC) However, absence of clinical DCM features in KO-NEBL mice as well as Western Blot analysis which contradicted previous findings by showing a similar protein expression between knockout and wild-type mice, excluding it as evidence. Purevjav and colleagues (2010, PMID: 20951326) generated a transgenic mouse overexpressing WT or mutant NEBL under the control of the α-MyHC promoter (4 variants were tested). Mice overexpressing p.K60N or p.Q128R variants died within 1 year because of severe heart enlargement and heart failure. Mice overexpressing p.G202R or p.A592E were born and developed normally but after 6 months displayed reduced stress tolerance, cardiac enlargement due to left ventricle dilation, myocyte disarray, and interstitial cell infiltration. No further scorable variants or experimental evidences were identified during the re-curation process. In summary, there is limited evidence supporting the relationship between NEBL and DCM. More evidence is needed to support the relationship of NEBL and DCM. This classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on 10/18/2024 (SOP Version 10).