The genetic analysis of mendelian form of human hypertension among Thai hypertensives

Abstract

Certain Mendelian disorders have been found to be a cause of hypertension (HT). A growing number of hypertensive subjects with clinical phenotype compatible with genetic disorders; including glucocorticoid remediable aldosteronism (GRA) caused by CYP11B1/CYP11B2 chimeric gene, Liddle's syndrome caused by mutations in SCNN1B and SCNN1G genes, a syndrome of apparent mineralocorticoid excess (SAME) caused by mutations in HSD11B2, and HT exacerbated in pregnancy caused by mutations in NR3C2 gene have been found in Siriraj Hospital. These mutated genes lead to increased sodium reabsorption, volume expansion, and HT. The aims of this study were 1) to screen for the mutations in hypertensive causing genes, which are the CYP11B1/CYP11B2 chimeric gene, SCNN1B, SCNN1G, HSD11B2, and NR3C2 genes, and 2) to optimize methods for mutation detection in hypertensive causing genes. A total of 225 hypertensive subjects were recruited in this study. The subjects were classified into 3 groups: 1) 93 cases with low plasma renin activity (PRA) and high serum aldosterone were screened for GRA by multiplex long polymerase chain reaction (PCR); 2) 101 cases with low PRA and low serum aldosterone were screened for Liddle's syndrome and SAME; and 3) 50 cases with HT at age of onset less than 25 years old, HT exacerbated during pregnancy, or a history of heart failure were screened for HT exacerbated in pregnancy. Denaturing high performance liquid chromatography (DHPLC) was utilized for the identification of mutation in groups 2 and 3. Only two mutations in exon 13 of SCNN1G gene causing Liddle's syndrome were identified. The study in the other hypertensive causing genes did not show any mutations. The novel nonsense mutation, W572X, was identified in one subject and a previously reported missense mutation, L609F, was found in another subject. Both mutations were found in heterozygous form. Certain genetic disorders causing HT can be found among Thai hypertensives. The identification of GRA, SAME, and HT exacerbated in pregnancy cases in the Thai population may be possible if studied in a larger group of subjects. The two mutations of SCNN1G gene found here provide useful information for the clinician in giving specific treatment, genetic counseling, and presymptomatic diagnosis in the siblings of the probands.