Genetic screening for monogenic hypertension in hypertensive individuals in a clinical setting

Abstract

BackgroundMonogenic hypertension describe a series of hypertensive syndromes that are inherited by Mendelian laws. Sometimes genetic testing is required to provide evidence for their diagnoses, precise classification and targeted treatment. This study is the first to investigate the clinical utility of a causative gene screening and the combined yield of gene product expression analyses in cases with suspected monogenic hypertension.MethodsWe performed a large-scale multi-centre clinical genetic research of 1179 expertly selected hypertensive individuals from the Chinese Han population. Targeted sequencing were performed to evaluate 37 causative genes of potential cases of monogenic hypertension. Pathogenic and likely pathogenic variants were classified using the American College of Medical Genetics guidelines. Additionally, 49 variants of unknown significance (VUS) that had relatively high pathogenicity were selected and analysed using immunoblot protein expression assays.Results21 pathogenic or likely pathogenic variants were identified in 33 of 1179 cases (2.80%). Gene product expression analyses showed 27 VUSs harboured by 49 individuals (4.16%) could lead to abnormally expressed protein levels. Consequently, combining genetic screening with gene product expression analyses increased the diagnostic yield from 2.80% to 6.79%. The main aetiologies established were primary aldosteronism (PA; 27, 2.29%) and pheochromocytoma and paraganglioma (PPGL; 10, 0.85%).ConclusionMolecular diagnoses obtained using causative gene screening combined with gene product expression analyses initially achieved a modest diagnostic yield. Our data highlight the predominant roles of PA and PPGL. Furthermore, we provide evidence indicating the enhanced diagnostic ability of combined genetic and functional evaluation.

CACNA1D Gene Polymorphisms Associate With Increased Blood Pressure and Salt Sensitivity of Blood Pressure in White Individuals

“…26,27 Follow-up studies identified 7 CACNA1D exon locus mutations that correlated with hypertension. 28 Wang et al 29 selected 3 of these mutations and utilized CRISPR-Cas9 technology to generate Sprague-Dawley rats carrying mutations of the CACNA1D gene. Higher BP was observed in rats with double-site mutants versus those with single-site mutant and in rats with single-site mutations versus wild-type rats.…”

Dominant role of CACNA1D exon mutations for blood pressure regulation

“…These findings imply the importance of intron polymorphisms in CACNA1D play an important role in BP regulation and are targets of antihypertensive drug calcium-channel blockers. We took part in a large-scale multicentric clinical genetic research [9], and found seven CACNA1D exon locus variation [10]. They were c.G2689A, c.A1697G, c.G2242A, c.C3914T, c.A920G, c.G4475A and c.G1345A.…”

The association between Alu hypomethylation and the severity of hypertension

“…There is increasing empirical evidence that hypertension is one of the most serious health problems worldwide [4][5][6]. A previous study demonstrated that hypertension often has epigenetic alterations, and genome instability is believed to be a contributing factor to hypertension [7][8][9][10]. Several studies have reported changes in epigenomic marks and DNA methylation in hypertension and a poor health status in humans [11][12][13][14][15][16].…”