Genetics of childhood-onset hypertension

National Human Genome Research Institute

Investigators

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Abstract

Our previous studies focused on coding-region (exome) sequencing of 16 probands with early onset COEH without a family history, representing a high likelihood of finding a genetic cause for CEOH. From this initial sequence we identified 4 probands from 3 families with rare, predicted protein-damaging, biallelic variation in trans in SYNE1. We showed that this proportion is significantly more than expected by chance, and that the frequency of rare variants in SYNE1 is highest among individuals with African ancestries. siRNA knockdown (KD) of SNYE1 transcripts in vascular smooth muscle cells reduced cellular stiffness and resulted in abnormal actin filament contraction, both consistent with the pathophysiology of COEH, and was rescued through administration of a downstream pharmacological agent. In the current reporting period, we identified similar rare, predicted protein-damaging, biallelic variation in trans in two other genes from two more of the original 16 high-yield families. We validated these variants using orthogonal methods. Both genes have ancillary evidence for their involvement in vascular hypertension from model organism and human studies. We also submitted the remaining 56 probands and their family members (a total of 183 samples) for whole-genome sequencing through the NHGRI intramural sequencing core (NISC). We have engaged with local and extramural collaborators to develop a protocol for sequencing samples from an international cohort of hypertensive children and to refine a clinical protocol for prospective and retrospective recruitment of COEH families for clinical, molecular, and laboratory phenotyping.