Genetics of childhood-onset hypertension

National Human Genome Research Institute

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Abstract

Our previous report identified probands and families with CEOH segregating rare, predicted protein-damaging, biallelic variation in trans in a strong COEH candidate gene. We showed that siRNA knockdown (KD) of the gene transcripts in vascular smooth muscle cells, reduced cellular stiffness and resulted in abnormal actin filament contraction, both consistent with the underlying pathophysiology of COEH, and was rescued through administration of a downstream pharmacological agent. This information has been incorporated into a manuscript that is presently under review. In the current reporting period, we completed analyses of genome sequence data from 77 families. We identified five additional candidate genes with strong suspicion of involvement in COEH, alongside another 14 candidate genes with moderate evidence of a relationship to COEH. Clinically, the probands of these families (n=24) were generally young, without cardiovascular disease comorbidities such as obesity or diabetes. The five top candidates have high expression in blood vessels and a low tolerance for homozygous loss-of-function. In silico protein-protein interactions reveal close relationships between these genes and a collectively high expression in vascular and other hypertension-related genes. We are presenting functionally validating these findings in cellular and organismal models. We have also entered a formal collaboration with the Hypertension in African Children project based out of South Africa and completed genome-sequencing of the first set of samples from this cohort. We have also developed a clinical natural history protocol to identify and recruit individuals from the community with CEOH in order to assess their molecular and clinical phenotypes.