Performance of the Illumina Infinium MethylationEPIC v.2 array with low DNA input from Swedish neonatal dry blood spots

The Swedish Phenylketonuria (PKU) screening biobank contains neonatal blood spots from over five million individuals born in Sweden since 1975, offering a unique research resource. While its value has been proven in several research areas, such as genetics, the feasibility of DNA methylation studies using archived dried blood spots remains uncertain. Here, we selected samples from seven random individuals born between 1985 and 2003 to evaluate the performance of the Illumina Infinium MethylationEPIC v2.0 array on DNA extracted from PKU blood spots. Despite DNA input quantities as low as 19.2 ng, probe call rates remained exceptionally high (mean 99.76% at p<0.01), with robust methylation site coverage across all samples. These findings challenge conventional assumptions about the DNA quantity and quality required for methylation arrays and demonstrate that decades-old neonatal blood spots can yield high-quality epigenetic data.