Exome sequencing implicates ancestry-related Mendelian variation at SYNE1 in childhood-onset essential hypertension.

TitleExome sequencing implicates ancestry-related Mendelian variation at SYNE1 in childhood-onset essential hypertension.
Publication TypeJournal Article
Year of Publication2024
AuthorsCopeland, I, Wonkam-Tingang, E, Gupta-Malhotra, M, S Hashmi, S, Han, Y, Jajoo, A, Hall, NJ, Hernández, PP, Lie, N, Liu, D, Xu, J, Rosenfeld, J, Haldipur, A, Desire, Z, Coban-Akdemir, ZH, Scott, DA, Li, Q, Chao, H-T, Zaske, AM, Lupski, JR, Milewicz, DM, Shete, S, Posey, JE, Hanchard, NA
JournalJCI Insight
Date Published2024 May 08
KeywordsAdolescent, Age of Onset, Child, Child, Preschool, Cytoskeletal Proteins, Essential Hypertension, Exome, Exome Sequencing, Female, Genetic Predisposition to Disease, Humans, Infant, Infant, Newborn, Male, Mutation, Missense, Nerve Tissue Proteins, Nuclear Proteins, Pedigree, rhoA GTP-Binding Protein, United States, Young Adult

Childhood-onset essential hypertension (COEH) is an uncommon form of hypertension that manifests in childhood or adolescence and, in the United States, disproportionately affects children of African ancestry. The etiology of COEH is unknown, but its childhood onset, low prevalence, high heritability, and skewed ancestral demography suggest the potential to identify rare genetic variation segregating in a Mendelian manner among affected individuals and thereby implicate genes important to disease pathogenesis. However, no COEH genes have been reported to date. Here, we identify recessive segregation of rare and putatively damaging missense variation in the spectrin domain of spectrin repeat containing nuclear envelope protein 1 (SYNE1), a cardiovascular candidate gene, in 3 of 16 families with early-onset COEH without an antecedent family history. By leveraging exome sequence data from an additional 48 COEH families, 1,700 in-house trios, and publicly available data sets, we demonstrate that compound heterozygous SYNE1 variation in these COEH individuals occurred more often than expected by chance and that this class of biallelic rare variation was significantly enriched among individuals of African genetic ancestry. Using in vitro shRNA knockdown of SYNE1, we show that reduced SYNE1 expression resulted in a substantial decrease in the elasticity of smooth muscle vascular cells that could be rescued by pharmacological inhibition of the downstream RhoA/Rho-associated protein kinase pathway. These results provide insights into the molecular genetics and underlying pathophysiology of COEH and suggest a role for precision therapeutics in the future.

Alternate JournalJCI Insight
PubMed ID38716726
PubMed Central IDPMC11141928
Grant ListUM1 HG006542 / HG / NHGRI NIH HHS / United States
K08 HG008986 / HG / NHGRI NIH HHS / United States
P30 CA125123 / CA / NCI NIH HHS / United States
T32 GM008307 / GM / NIGMS NIH HHS / United States
K23 HL089391 / HL / NHLBI NIH HHS / United States
P50 HD103555 / HD / NICHD NIH HHS / United States
U01 HG011758 / HG / NHGRI NIH HHS / United States

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