Abstract
Objectives: Monogenic hypertension describes a series of hypertension syndromes inherited by Mendelian law and present with complex phenotypes. Genetic screening in a clinical setting substantially facilitates diagnosis and increases the diagnostic yield of this setting of disease. Methods: 1179 expertly selected cases with monogenic hypertension potential were evaluated by sequencing 37 causative genes of monogenic hypertension. Pathogenic and likely pathogenic variants were classified by using American College of Medical Genetics guidelines. In addition, 49 variants of unknown significance were selected to receive functional analysis. The yield of combined genetic and functional analysis was evaluated. Results: 21 deleterious variants were identified in 33 of 1179 (2.80%). Functional analysis for 49 unknown significant variants showed 32 variants harbored by 61 individuals led to abnormally expressed protein levels. 9 of the 524 panel negative individuals had adrenal tumors and their pathogenic somatic mutations gave additional yield. Overall, combining genetic screening of germline and somatic mutations with functional analysis promoted diagnostic yield to 8.73%. The main etiology established was primary aldosteronism, with CACNA1H harboring the greatest mutation burden. Logistic regression analysis showed hypertension complicated with special manifestations had the strongest correlation with disease causing variants detection (p = 0.03). Conclusion: Comprehensive genetic screening was firstly performed among hypertensive cases and a diagnostic yield of 8.73% was identified by molecular diagnoses combined with functional analysis. Our findings demonstrate an enhanced diagnostic ability by combining genetic analysis with functional evaluation and enables targeted treatment and prevention of hypertension.
Published Version
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