Submission Details

Natriuretic Peptide Precursor A (NPPA) was originally evaluated for autosomal recessive dilated cardiomyopathy (DCM) on October 25th, 2019. Evidence of the association of this gene with DCM was re-evaluated using SOP v10 on September 6th 2024. As a result, the classification did not change. A summary of the information contributing to the classification of the gene at the time of re-evaluation is summarized herein.

NPPA encodes ANP (atrial natriuretic peptide) a cardiac hormone produced in the atria and released in pathological conditions (e.g. heart failure, hypertrophy) associated with increased atrial wall stress (Lekanne Deprez et al, 1998, PMID: 9769242). There is no supporting human genetic evidence demonstrating this gene-disease relationship in the literature at the time of curation. Variants in this gene have been found to be associated with autosomal dominant atrial fibrillation and autosomal recessive Atrial Dilated Cardiomyopathy with Standstill Evolution (OMIM 108780; Disertori et al, 2013, PMID: 23275345). The 13 patients with autosomal recessive Atrial Dilated Cardiomyopathy with Standstill Evolution were followed up to 37 years and showed normal left ventricular function and stable New York Heart Association functional class during the long-term course of the disease. No signs of a dilated (ventricular) cardiomyopathy. So far no disease association with DCM has been published. However, this gene-disease association is supported by expression studies. Using human iPS cell derived cardiomyocytes and mouse models to analyze transcription factors involved in DCM pathogenesis, NPPA was identified to have been expressed in heart tissue, and upregulated in heart tissue derived from DCM patients (Feng et. al, 2022, PMID: 35400201). Additionally, in a study to assess underlying genes that could be utilized as diagnostic biomarkers for DCM in heart failure patients, single-cell RNA-sequencing analysis of NPPA in DCM patient derived cardiomyocytes identified increased expression of NPPA (Zhu et. al, 2022, PMID: 36544902). Finally, a study assessing expression in left vertical myocardial tissues obtained from explanted hearts noted that NPPA is expressed in the heart and positively correlated with LVESD (Schiana et. al, 2021, PMID: 34946895).

No convincing evidence for a casual role for NPPA and autosomal dominant DCM has been reported. Although this gene-disease assertion is supported by expression studies, no reports have directly implicated the gene in humans. This re-classification was approved by the ClinGen Dilated Cardiomyopathy Working Group on September 6th, 2024 (SOP Version 10).