Ricerc@Sapienza

Birth defects affect 3-4% of the population, representing a significant public health concern. Prenatal detection of malformations is improving and fetal genetic testing provides valuable information in parental decision, prenatal care and neonatal management. It can be crucial to proper genetic counseling, and necessary to propose future reproductive options.
Microarray analysis increases the diagnostic ability above standard karyotype, but 80% of tested fetuses remain without diagnosis. Next Generation Sequencing has revolutionized clinical practice in Medical Genetics, becoming a staple of prenatal diagnosis. Exome sequencing can be proposed when other tests fail in determining the diagnosis in fetuses with structural anomalies, and familial history or prenatal presentation suggesting monogenic disorders.
Despite the growing availability and application of this technique, there are no homogeneous access criteria, and a consensus on clinical management is lacking. The actual diagnostic value varies extensively, and the role of incidental/secondary or inconclusive findings and negative results has not been fully ascertained, and can hamper genetic counseling, especially in prenatal diagnosis.
Incidental and secondary findings are genetic variants unrelated to the primary indication. Incidental findings are nonactionable, whereas secondary findings are medically actionable variants from a specific gene list from the American College of Medical Genetics and Genomics.
In order to improve the interpretation of inconclusive findings, a postnatal clinical reassessment of fetal cases will be performed. As numerous fetuses with structural anomalies are brought to our attention, we will perform a metanalysis comparing our retrospectively collected clinical and molecular results to the cohorts reported in literature. Our goal is to propose appropriate diagnostic approaches and access criteria for prenatal exome sequencing.