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

Area of Science:

• Genetics and Cardiovascular Disease
• Pediatric Hypertension Research

Background:

• Childhood-onset essential hypertension (COEH) disproportionately affects children of African ancestry in the U.S.
• The genetic basis of COEH remains largely unknown, despite evidence of heritability and skewed demographics.
• Previous studies have not identified specific genes responsible for COEH.

Purpose of the Study:

• To identify genetic variations associated with childhood-onset essential hypertension (COEH).
• To investigate the role of the SYNE1 gene in the pathogenesis of COEH.
• To explore the potential for precision therapeutics in treating COEH.

Main Methods:

• Exome sequencing was performed on 16 families with early-onset COEH and an additional 48 COEH families.
• Analysis included 1,700 in-house trios and public datasets to assess SYNE1 variation.
• In vitro studies utilized shRNA knockdown of SYNE1 in smooth muscle vascular cells to assess functional impact.

Main Results:

• Recessive, rare, and putatively damaging missense variations in the SYNE1 gene were identified in 3 of 16 COEH families.
• Compound heterozygous SYNE1 variations were significantly enriched in COEH individuals, especially those of African genetic ancestry.
• Reduced SYNE1 expression decreased vascular smooth muscle cell elasticity, which was reversible via RhoA/ROCK pathway inhibition.

Conclusions:

• Rare biallelic SYNE1 variations are implicated in the molecular genetics of childhood-onset essential hypertension (COEH).
• These findings reveal a novel pathophysiology involving SYNE1 and vascular smooth muscle cell elasticity.
• The study suggests a potential for targeted therapies for COEH based on SYNE1 genetic findings.