Abstract Body: Childhood-onset essential hypertension (COEH) is an uncommon form of hypertension in which children under the age of 18 have sustained blood pressures greater or equal to the 95th percentile for their age, sex, and height. Childhood blood pressure is known to be a predictor of future blood pressure status; thus, children with COEH are at risk for developing hypertension-related complications as adults, including heart attack, stroke, and renal disease. The heritability of COEH is quoted as between 70-80%, however, the genes and genetic models underlying COEH susceptibility remain unknown and understudied. The relative rarity, high heritability, low correlation with environmental factors, and overrepresentation in African ancestries of COEH suggest a role for rare genetic variation in its pathogenesis. Using genome sequencing, we identified rare and putatively damaging variants in HCMN1—an essential component of the extracellular matrix architecture in vascular smooth muscle—segregating in an autosomal recessive manner in two families with COEH. To evaluate its functional context, we developed a mouse model of HMCN1, in which we measured the blood pressure of juvenile Hmcn1^-/-, Hmcn1^+/-, and wild-type mice (4-8 weeks) via non-invasive tail cuffs daily for two weeks, and subsequently measured the same mice as adults via telemetry hourly for two weeks (N=6 per sex, 2 per genotype). Tail cuff data revealed female Hmcn1^-/- mice to have lower blood pressures than female wild-type mice on average (Systolic 126±14 vs. 113±18 mmHg, p>0.05), while male Hmcn1^-/- mice had significantly higher blood pressures than male wild-type mice (Systolic 120±13 vs. 131±12 mmHg, p<0.05). Telemetry data revealed an interactive effect between activity level and genotype on blood pressure—as activity level increased, female Hmcn1^-/- mice had significantly lower blood pressures than wild-type, whereas male Hmcn1^-/- mice had significantly higher blood pressures than wild-type (p<0.01). Post-mortem histology of a female Hmcn1^-/- mouse revealed degeneration and a focal dissecting aneurysm in the aorta. There are currently no published data on the functional impact of HCMN1 on blood pressure or heart function, making our study the first of its kind. Additional studies, specifically those investigating age-related effects on blood pressure in our mouse model, to confirm our findings and understand the pathophysiological effects of HCMN1 loss-of-function on blood pressure are underway.