prader-Willi (pWS) and Angelman (AS) syndromes are two clinically distinct imprinted disorders characterized by genetic abnormalities at 15q11-q13. Early diagnosis of both syndromes provides improved treatment and accurate genetic counseling. Whole blood (WB) is the most common DNA source of many methodologies to detect PWS and AS, however, the need of WB makes a massive screening difficult in newborns due to economic and technical limitations. The aim of this study was to adapt a Methylation-sensitive High-Resolution Melting (MS-HRM) approach from dried blood spot (DBS) samples, assessing the different DNA isolation techniques and diagnostic performance. Over a 1-year period, we collected 125 DBS cards, of which 45 had already been diagnosed by MS-HRM (20 PWS, 1 AS, and 24 healthy individuals). We tested three different DBS-DNA extraction techniques assessing the DNA concentration and quality, followed by MS-HRM and statistical comparison. Each DBS-DNA extraction method was capable of accuracy in detecting all PWS and AS individuals. However, the efficiency to detect healthy individuals varied according to methodology. In our experience, DNA extracted from DBS analyzed by the MS-HRM methodology provides an accurate approach for genetic screening of imprinting related disorders in newborns, offering several benefits compared to traditional whole blood methods. Prader-Willi (PWS) and Angelman (AS) syndromes are complex disorders arising from genetic abnormalities in chromosome 15. Both syndromes are considered rare due to the estimated prevalence of 1 in 10,000-30,000 individuals 1,2. While they occur in the same genomic region, multiple genetic alterations and very distinct clinical characteristics are present. The main features associated with PWS are severe neonatal hypotonia, short stature, small hands and feet, dysmorphic face, early onset of hyperphagia, development of morbid obesity, hypogonadism, and cognitive impairment 3. Congenital hypotonia represents a diagnostic challenge, especially in newborns, because it is present in several disorders, as metabolic diseases, acute or chronic illness, genetic syndromes, endocrinopathies, myopathies, and central or peripheral nervous system abnormalities 4. AS patients present delayed psychomotor development, severe mental retardation, absence of speech, seizures, motor oddities, and epilepsy 5 .