9287 CASZ1 gene: From a Promising GWAS Risk Locus To a Possible New Monogenic Etiology For Primary Aldosteronism
Authors: Santos Santana Lucas , Guimaraes Augusto G , Freitas-Castro Felipe , Maciel Ana Alice W , Cardoso Fagundes Gustavo Freitas , Pereira Maria Adelaide A , Drager Luciano F , Bortolotto Luiz A , Barisson Villares Fragoso Maria Candida , Bilharinho Mendonca Berenice , Claudia Latronico Ana , Almeida Madson Q 
Published: October 2024

Disclosure: L.S. Santana: None. A.G. Guimaraes: None. F. Freitas-Castro: None. A.W. Maciel: None. G.F. Fagundes: None. M.A. Pereira: None. L.F. Drager: None. L.A. Bortolotto: None. M.C. Fragoso: None. B.B. Mendonca: None. A. Latronico: None. M.Q. Almeida: None.

Primary aldosteronism (PA) is the most common cause of endocrine hypertension, with an estimated prevalence of 10-20% in patients referred to tertiary hospitals. The most common causes of PA are bilateral adrenal hyperplasia (BAH) and aldosteronomas. Significant advances in elucidating the pathogenesis of PA have been made over the past decade. Pathogenic/likely pathogenic germline allelic variants in KCNJ5, CACNA1D, CACNA1H, CLCN2, PDE2A, and PDE3B genes have already been documented in individuals diagnosed with PA. However, most of the cases still lack a defined genetic etiology. Genomic investigation of these individuals through whole-exome sequencing (WES) would enable the identification of causal monogenic genotype-phenotype associations in genes not yet linked to bilateral PA. In our study, thirty-one patients were selected, including 29 probands and 2 relatives, with a confirmed diagnosis of bilateral PA by adrenal venous sampling. All probands were previously investigated for KCNJ5 pathogenic/likely pathogenic germline variants. Additionally, all cases also had negative genetic screening for glucocorticoid-remediable PA. WES was performed using BGI Genomics technology, DNA nanoball sequencing, on the DNBSEQ platform. Raw data were processed (bioinformatics) using in-house pipelines. The 31 sequenced samples showed excellent coverage metrics, with coverage ranging from 200-467X and %&gt;10X at 99%. Each patient presented an average of 150,000 variants. After the gene/allelic prioritization workflow, 4 heterozygous SNVs were listed as candidates in 3 out of 29 patients (10.34%). Two of the variants were identified in rare but previously documented germline causes of PA: CACNA1H and CACNA1D (patients 13 and 29, respectively). Patient 4 (hypertension diagnosed at 36 years of age) presented 2 variants in possible new candidate genes, CASZ1 and STRN. The NM_001079843.3(CASZ1):c.1912G&gt;C/p.(Asp638His) variant caught our attention not only for its absence in population genomic databases (gnomAD v.4), but also due to the association between CASZ1 locus and PA. The zinc finger transcription factor CASZ1 has CACNA1D as one of its targets and participates in key biological processes for PA pathogenesis, such as: co-repression of mineralocorticoid receptor transcriptional activity; mediation of tissue response to aldosterone and differential expression in aldosterone-producing cell clusters (APCC) and in zona glomerulosa; its hypoexpression promotes aldosterone-dependent mineralocorticoid receptor transcriptional activity and hyperexpression suppresses aldosterone biosynthesis by adrenal cells. In conclusion, an extremely rare CASZ1 variant was identified in a woman with bilateral PA. The functional characterization of the CASZ1 p.(Asp638His) variant might reinforce its role as a new monogenic cause of PA.

Presentation: 6/3/2024