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

Autor: Copeland I; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA., Wonkam-Tingang E; Childhood Complex Disease Genomics Section, National Human Genome Research Institute, NIH, Bethesda, USA., Gupta-Malhotra M; Department of Cardiology, Baylor College of Medicine, San Antonio, Texas, USA., Hashmi SS; Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas, USA., Han Y; Childhood Complex Disease Genomics Section, National Human Genome Research Institute, NIH, Bethesda, USA., Jajoo A; Childhood Complex Disease Genomics Section, National Human Genome Research Institute, NIH, Bethesda, USA., Hall NJ; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.; US Department of Agriculture Agricultural Research Service Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas, USA., Hernandez PP; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.; US Department of Agriculture Agricultural Research Service Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas, USA., Lie N; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.; Childhood Complex Disease Genomics Section, National Human Genome Research Institute, NIH, Bethesda, USA.; US Department of Agriculture Agricultural Research Service Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas, USA., Liu D; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA., Xu J; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA., Rosenfeld J; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.; Baylor Genetics, Houston, Texas, USA., Haldipur A; Childhood Complex Disease Genomics Section, National Human Genome Research Institute, NIH, Bethesda, USA., Desire Z; Childhood Complex Disease Genomics Section, National Human Genome Research Institute, NIH, Bethesda, USA., Coban-Akdemir ZH; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.; Human Genetics Center, The University of Texas Health Science Center at Houston, Houston, Texas, USA., Scott DA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.; Texas Children's Hospital, Houston, Texas, USA.; Department of Molecular Physiology and Biophysics., Li Q; Childhood Complex Disease Genomics Section, National Human Genome Research Institute, NIH, Bethesda, USA., Chao HT; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.; Division of Neurology and Developmental Neuroscience, Department of Pediatrics; and.; Department of Neuroscience, Baylor College of Medicine, Houston, Texas, USA.; Cain Pediatric Neurology Research Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital and Baylor College of Medicine, Houston, Texas, USA.; McNair Medical Institute, The Robert and Janice McNair Foundation, Houston, Texas, USA., Zaske AM; Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas, USA., Lupski JR; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.; Texas Children's Hospital, Houston, Texas, USA.; Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA., Milewicz DM; Department of Internal Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas, USA., Shete S; The University of Texas MD Anderson Cancer Center, Houston, Texas, USA., Posey JE; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.; McNair Medical Institute, The Robert and Janice McNair Foundation, Houston, Texas, USA., Hanchard NA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.; Childhood Complex Disease Genomics Section, National Human Genome Research Institute, NIH, Bethesda, USA.
Jazyk: angličtina
Zdroj: JCI insight [JCI Insight] 2024 May 08; Vol. 9 (9). Date of Electronic Publication: 2024 May 08.
DOI: 10.1172/jci.insight.172152
Abstrakt: 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.
Databáze: MEDLINE