Exome Sequencing Implicates Ancestry-Related Mendelian Variation at SYNE1 in Childhood-Onset Essential Hypertension

Authors

Ian Copeland
Edmond Wonkam-Tingang
Monesha Gupta-Malhotra
S Shahrukh Hashmi
Yixing Han
Aarti Jajoo
Nancy J Hall
Paula P Hernandez
Natasha Lie
Dan Liu
Jun Xu
Jill Rosenfeld
Aparna Haldipur
Zelene Desire
Zeynep H Coban-Akdemir
Daryl A Scott
Qing Li
Hsiao-Tuan Chao
Ana M Zaske
James R Lupski
Dianna M Milewicz
Sanjay Shete
Jennifer E Posey
Neil A Hanchard

Publication Date

5-8-2024

Journal

JCI Insight

Abstract

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.

Keywords

Adolescent, Child, Female, Humans, Male, Age of Onset, Cytoskeletal Proteins, Essential Hypertension, Exome, Exome Sequencing, Genetic Predisposition to Disease, Mutation, Missense, Nerve Tissue Proteins, Nuclear Proteins, Pedigree, rhoA GTP-Binding Protein, United States, Infant, Newborn, Infant, Child, Preschool, Young Adult, Genetic variation, Hypertension, Population genetics

Comments

Supplementary Materials

PMID: 38716726