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.
Defining homogeneous criteria for reporting variants prenatally is a significant challenge. In most countries, prenatal molecular diagnosis of a known mutation is acceptable only for variants classified as pathogenic/likely pathogenic according to American College of Medical Genetics guidelines.
Standardized guidelines about variants of unknown significance are not available, resulting in inhomogeneous conducts, even in the same country. American College of Medical Genetics suggests reporting variants of unknown significance in phenotype-fitting genes, especially for autosomal recessive conditions if a variant of unknown significance is found in ¿trans¿ with a pathogenic/likely pathogenic variant. However, the choice of reporting this kind of variant is currently ascribed to the single laboratory policy.
Inconclusive results could be also linked to a variant in a candidate gene (gene with limited evidence of disease association).
Our aim is to correlate initial indications to prenatal exome sequencing with the number and class of variants reported as potentially causative or as incidental/secondary findings. This will help in better defining both access criteria to prenatal exome sequencing and guidelines for variant reporting in such a delicate setting.