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Researchers validated a DNA methylation signature (episignature) that can identify VACTERL association, a constellation of birth defects, with 85.7% sensitivity in an independent cohort of 38 participants. The episignature also detected some related conditions like oculoauriculofrontonasal dysplasia and rhomboencephalosynapsis, but showed variable results across other recurrent embryonic malformation conditions. These findings suggest that while some malformation conditions share common epigenetic patterns, others have distinct molecular origins.
Why it matters
This validated episignature could serve as the first molecular biomarker for VACTERL association, which currently lacks definitive diagnostic tests and remains a clinical diagnosis of exclusion. The test could improve diagnostic accuracy, enable earlier identification of affected individuals, and help distinguish between related but etiologically distinct congenital malformation conditions.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Background: Recurrent constellations of embryonic malformations (RCEMs) comprise multiple malformation conditions with largely unexplained etiologies and no established molecular biomarkers. A shared DNA methylation episignature was recently identified in VACTERL association and oculoauriculovertebral spectrum (OAVS). We sought to validate this episignature in an independent, deeply phenotyped cohort and evaluate its detection across related RCEMs. Methods: Genome-wide DNA methylation profiling was performed on peripheral blood from 38 participants with clinically diagnosed RCEMs, including VACTERL (n=21), partial VACTERL (n=3), OAVS (n=3), and other RCEM-related conditions (n=11). Results: The Episign V5 RCEM episignature demonstrated robust sensitivity for VACTERL (18/21, 85.7% positive), while the remaining three participants showed intermediate positivity. Of three participants with partial VACTERL, one with tracheoesophageal fistula demonstrated intermediate positivity, whereas the other two were negative. Episignature positivity was also identified in oculoauriculofrontonasal dysplasia (1/1, robust) and rhomboencephalosynapsis (1/2, robust) but was limited in OAVS (1/3, intermediate) and absent in frontonasal dysplasia (0/4). Conclusions: Independent validation establishes the Episign V5 RCEM episignature as a reproducible molecular biomarker for VACTERL, a condition that remains a diagnosis of exclusion. Variable detection across related malformation conditions suggests etiologic heterogeneity, whereas overlap among selected phenotypes supports epigenomic convergence across the RCEM spectrum.