R.GURUNG1, Y.M1, D.M.K.YONG1, S.K.TAN1, D.H.M.LEE1, S.DISSANAYAKE1, A.Y.L.LIU1, S.C.LIM1
Khoo Teck Puat Hospital1
Hypertension(HTN) is a major cause of morbidity and mortality. Monogenic hypertension (MGH) is caused by a single gene mutation, and an accurate diagnosis of MGH facilitates a better prognosis. We combined clinical criteria and genetic screening to identify causative mutations in patients with clinically suspected MGH.
We enrolled patients with at least one of the following criteria: 1) HTN onset age <30; 2) HTN onset age 30-40 with a strong family history of HTN; 3) HTN despite on 3 > blood pressure-lowering medications: 4) clinical phenotypes associated with MGH. We sequenced 27 causative genes and validated them using sanger. The variant classification was assessed using current standard guidelines. We developed a long-range polymerase chain reaction to identify CYP11B1/CYP11B2 chimeric gene.
Four pathogenic or likely pathogenic (P/LP) variants in genes associated with catecholamine excess (RET) and sodium handling/hyperaldosteronism (WNK1, CY11B1) were identified in three patients (11%). One of these patients with a high aldosterone/renin ratio concomitantly harboured the CYP11B1/CYP11B2 hybrid gene, which causes familial hyperaldosteronism, type 1. The clinical phenotype did not differ significantly between patients with and without P/LP variants except that the former were more likely to have hyperkalemia. In five patients, we also identified rare allelic frequency (<0.01) variants in CLCN2, CYP21A2, CYP11B1, SCNN1A, SCNN1G genes (one per case) predicted to be deleterious but of unknown significance.
Our results broaden the genetic spectrum in patients with clinically suspected MGH in Singapore and highlight the potential benefit of targeted genetic screening, especially when presented with overlapping phenotypes.