P16.09: Optimal genetic testing for failed cell‐free DNA result: a tricky task

Abstract

We report a 37-year old patient that requested cell-free DNA at 10 weeks due to her age. Cell-free DNA (Verify) was inconclusive and this was not due to low fetal fraction. A repeat test was also inconclusive. In fact, laboratory readings could not rule out the possibility of an abnormal chromosomal representation somewhere in the genome. A combined test was performed at 12 weeks and nuchal translucency, nasal bone, tricuspid valve flow, ductus venosus and fetal anatomy were normal as were PAAP-A and free-betahCG. Therefore the risk of trisomies was low and the patient decided against invasive testing. However, uterine artery mean PI was high and PLGF was low and the risks of PE and IUGR were increased. The patient was put on low-dose aspirin. Follow-up scans showed unremarkable fetal anatomy except for a small nasal bone. An amniocentesis was offered but declined. The fetus developed IUGR with abnormal uterine artery Doppler. There was growing suspicion of a placental confined mosaicism as the cause of both the inconclusive cell-free DNA result and the growth restriction. Umbilical artery Doppler was within the normal range until 35+4w when an increased PI was noted and the baby was delivered. The newborn weighted 1700g (<1st centile) with an 8/10 APGAR score presenting no obvious syndromic features. Karyotype in cord blood was normal (46, XX). However, 4 different sites of the placenta were also sent for karyotype and Trisomy 15 was found in three of these sites. In the remaining site there was a mosaic (47,XX,+15[4]/46,XX[16]). The newborn presented marked hypotonia and metilation studies revealed uniparental disomy in chromosome 15 (Prader Willi Syndrome), as a likely result of chromosomal rescue. This case illustrates that an SNP-based or mixed array capable of detecting uniparental disomy is required in addition to karyotype when deciding for prenatal invasive testing in failed cell free DNA results.