Desafios do diagnóstico molecular da síndrome de Silver-Russell

Abstract

Because of imprinting, an epigenetic phenomenon, a few dozen human genes have differential expression, being active only in one of the parental alleles. The activity of these genes is controlled based on the methylation of Imprinting Control Regions (ICs). Abnormalities in the imprinting pattern can result in diseases and syndromes. An example of an imprinting disorder is Silver-Russell syndrome (SRS), which has as its main causes loss of methylation in IC1 (locus 11p15.5) and maternal uniparental disomy on chromosome 7, but mutations in different chromosomes can also be the etiology of the syndrome. The clinical manifestation of SRS varies between patients, and the lack of a pathognomonic feature makes clinical diagnosis challenging, which is given based on clinical scoring systems, such as the Netchine-Harbinson, which identifies the presence of a set of signs. Due to the etiological heterogeneity, the diagnostic difficulty is not limited to the clinics, it also extends to the molecular area. There are many tools available for the genetic and epigenetic analysis of the syndrome, however, the most used is the MS-MLPA, despite its limitations. Aiming to improve the molecular investigation of SRS, we used public methylomas to search for possibly more significant targets in detecting hypomethylation in 11p15.5. In this way, we found and validated dozens of cytosines with differential methylation, so that they can be included in molecular tests in order to leverage the current diagnostic performance.