LAUSR

Monogenic hypertension describes a series of hypertension syndromes inherited by Mendelian law and present with complex phenotypes. 1179 cases with monogenic hypertension potential were evaluated by sequencing 37 causative genes. Pathogenic variants were classified by using American College of Medical Genetics guidelines. Additionally, 49 variants of unknown significance were selected to receive functional analysis. The yield of combined genetic and functional analysis was evaluated. 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. Overall, combining genetic screening 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). Sequencing Results Summary Number of variants Number of individuals* Percentage† Individuals with no variant 0 524 44.44% Individuals with variants identified 592 655 55.56% Individuals with single contributing variant 297 480 40.71% Individuals with two or multiple contributing variants 295 175 14.84% Number of variants identified   Pathogenic and likely pathogenic variants 21 33 2.80%   Variants of unknown significance 570 634 53.77%   Benign or likely benign variants 1 1 0.08% Type of variant   Frameshift deletion 8 15 1.27%   Frameshift insertion 5 5 0.42%   Nonframeshift deletion 10 10 0.85%   Nonframeshift insertion 6 12 1.02%   Nonsynonymous SNV 546 607 51.48%   Stopgain SNV 18 30 2.54% WES, whole-exome sequencing. *The statistics in this table was based on 1179 individuals. †The percentage was calculated by the number of individuals in each category. A flow chart of this study. Our findings demonstrate an enhanced diagnostic ability by combining genetic analysis with functional evaluation and enables targeted treatment and prevention of hypertension. This work was supported by National Basic Research Program of China (973 Program, 2014CB542300, 2014CB542302).