Multigene panel analysis of connective tissue and vascular genes in patients with a bleeding disorder of unknown cause or a cerebrovascular event.

BACKGROUND

Bleeding disorder of unknown cause (BDUC) refers to patients with a significant bleeding phenotype despite normal hemostatic evaluation. Cerebrovascular events (CVEs) are neurologic deficits from intracerebral hemorrhages to hemorrhagic or ischemic strokes. A multigene panel for inherited connective tissue and vascular disorders (BLEED_panel) may improve diagnostic assessment.

OBJECTIVES

This study aimed to evaluate the diagnostic yield and clinical value of the BLEED_panel in patients with BDUC or CVE and to characterize their bleeding manifestations.

METHODS

In this retrospective single-center study, all patients tested with the BLEED_panel between January 2019 and August 2025 were included. Demographics, bleeding phenotype, family history, and genetic results were extracted. Variants were classified using American College of Medical Genetics and Genomics criteria. Descriptive statistics assessed the diagnostic yield and genotype-phenotype correlations.

RESULTS

In the BDUC cohort (n = 69), 61% were children (median age, 13 years) and 61% were female; 75% had a positive International Society on Thrombosis and Hemostasis Bleeding Assessment Tool score, and 54% had a positive family history. Mucocutaneous bleeding was most common, and 36% had surgery-related bleeding. Diagnostic yield, including variants of uncertain significance, was 15%, with (likely) pathogenic variants in ENG and COL5A1; no significant genotype-phenotype associations were found. In the CVE cohort (n = 38), 89% were children (median age, 0 years) and 47% were female; 74% had a positive International Society on Thrombosis and Hemostasis Bleeding Assessment Tool score, and 16% had a positive family history. Most presented with central nervous system hemorrhage (79%). Diagnostic yield, including variants of uncertain significance, was 29%, with (likely) pathogenic variants in COL4A1, COL4A2, and ENG.

CONCLUSION

The BLEED_panel adds no diagnostic value in patients with BDUC. It may be useful in selected CVE cases, particularly for COL4A1 and COL4A2.