Episignature-based modelled first-tier diagnostic approach in the Dutch Caribbean: advancing equal care through...

Access to advanced genetic testing in the Dutch Caribbean is limited due to financial and logistical constraints. As a result, many patients with rare disorders remain undiagnosed or receive uncertain results, leading to unequal genetic care. DNA methylation profiles, or episignatures, provide sensitive and specific biomarkers. The clinically validated EpiSign™ assay offers a cost-effective and rapid diagnostic approach.

In this study, we evaluated EpiSign™ as a modelled first-tier screening approach within a proposed diagnostic workflow in a resource-limited setting and assessed its diagnostic yield and clinical utility in 19 patients from the Dutch Caribbean. Peripheral blood DNA was analyzed using the EPIC array, and methylation profiles were classified via a support vector machine algorithm against the EpiSign™ Knowledge Database. All patients underwent ID-WES and/or CGH-array analysis as part of the diagnostic workup. Positive EpiSign™ findings were subsequently confirmed by these molecular analyses.

EpiSign™ helped provide a clinical diagnosis for six cases, including Fragile X syndrome, Intellectual Developmental Disorder X-linked 93 (MRX93), ReNU syndrome, and Kleefstra syndrome 1, all confirmed by subsequent analyses. Several patients harbored variants of uncertain significance in genes not yet associated with known episignatures.

These results demonstrate that EpiSign™ provides actionable diagnostic insights as a first-tier diagnostic tool, particularly when combined with genomic analyses in the absence of parental samples. Its dynamic database allows reanalysis as new episignatures are identified, increasing its potential clinical utility in resource-limited settings.