Clinical Relevance Of Screening For Rare Autosomal Aneuploidies: A Case Of Maternal Uniparental Disomy

INTRODUCTION: Traditionally, fetal aneuploidy screening has focused on autosomal trisomies of chromosomes 21, 18, and 13. Subsequently, cell-free DNA (cfDNA) screening has expanded to include sex chromosome aneuploidies, select microdeletions, and recently genome-wide analysis. Though uncommon after the first trimester, aneuploidy of any autosome can occur in placental and fetal tissues. Some autosomal aneuploidies present at conception are rescued and restored to a euploid state. When this occurs with imprinted chromosomes, it can lead to a euploid fetus with a genetic syndrome due to uniparental disomy (UPD). METHODS: Maternal blood samples submitted to Sequenom® Laboratories for MaterniT® GENOME testing were subjected to DNA extraction, library preparation, and whole genome massively parallel sequencing. Data were analyzed using a novel algorithm to detect trisomies and other subchromosomal events. RESULTS: A 42 year old patient elected genome-wide cfDNA screening after genetic counseling. Screening was positive, indicating an increased representation of chromosome 15, consistent with mosaic trisomy 15. The patient elected amniocentesis which returned a normal fetal karyotype, 46,XX. Subsequent testing of amniocytes detected maternal UPD of chromosome 15. Maternal UPD15 is a cause of Prader-Willi syndrome. CONCLUSION: This case illustrates the clinical relevance of screening for esoteric trisomies with cfDNA. Though the fetus did not have trisomy 15, the cfDNA test detected a trisomy in the placenta, evidently rescued in fetal tissue, which led to maternal UPD of chromosome 15 and a fetal diagnosis of Prader-Willi syndrome. Diagnosing Prader-Willi syndrome prenatally allows patients to make reproductive decisions, including pregnancy termination, adoption, and preparing for a child with disabilities.