What question did this study set out to answer?

To explore the impact of rare coding variants on ischemic stroke risk and its subtypes in Saudi Arabia.

May 7, 2026BMC Neurology0 citationsOpen Access

Rare coding variation and stroke heterogeneity in Saudi Arabia: an exome‑wide association study across severity, etiology, vascular territory, and early‑onset disease

FAFahad AlkhamisKing Fahd Hospital of the University MAMajed M. AlabdaliKing Fahd Hospital of the University AAAbdullah S. AlamriKing Fahd Hospital of the University

Key Points

To explore the impact of rare coding variants on ischemic stroke risk and its subtypes in Saudi Arabia.
Analyzed whole-exome sequencing data from 514 stroke patients in a case-only study design.
Conducted gene-based rare variant burden analyses using SAIGE-GENE+ and SKAT-O tests.
Investigated variations across different phenotype contrasts including severity, age at onset, and etiology.
Identified significant candidate genes such as HSP90AB1, PRR23A, and LRRC42 associated with stroke severity.
Noted gene expression varied across brain and vascular tissues, indicating their potential role in stroke risk.
Functional annotations pointed to the intolerance of highlighted genes to loss-of-function variations.

Abstract

Ischemic stroke in Saudi Arabia arises in a highly consanguineous population with a distinctive genetic architecture, likely enriching rare coding variants that influence stroke risk. Yet the contribution of these variants to stroke susceptibility, age at onset, and subtype patterns in this setting remains incompletely defined. We analyzed whole-exome sequencing data from 514 stroke patients in a case only study design. Gene-based rare variant burden analyses was performed using SAIGE-GENE+ burden and SKAT-O tests across predefined phenotype contrasts within the cohort, stroke severity (modified Rankin Scale, mild 45 years; mid-life onset 45), etiological subtypes (TOAST classification), and vascular imaging patterns (intracranial vs. extracranial).Post-association functional annotations included GTEx expression, gnomAD constraint metrics, and draggability insights. Gene-level associations at a suggestive threshold (p < 0.005) identified several candidates including HSP90AB1, PRR23A, and LRRC42 (severity and age-at-onset); POGZ and SMIM34 (age-at-onset); and COL9A3, DCP1B, and ADGRV1 (imaging and etiology subtypes). The highlighted genes showed varying expression across brain and vascular tissues and intolerance to loss-of-function variation. Notably, HSP90AB1, a molecular chaperone highly expressed in the brain and vasculature, has small-molecule inhibitors, supporting its potential relevance to stroke biology. Our findings identify exploratory candidate gene-level signals across clinically defined ischemic stroke phenotypes based on case-only within-cohort comparisons, in underrepresented population. These results should be considered hypothesis-generating and require replication and functional validation before biological or clinical inferences can be made.

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