A Case Report of a Feto-Placental Mosaicism Involving a Segmental Aneuploidy: A Challenge for Genome Wide Screening by Non-Invasive Prenatal Testing of Cell-Free DNA in Maternal Plasma.

Non-invasive prenatal testing (NIPT) using cell-free DNA can detect fetal chromosomal anomalies with high clinical sensitivity and specificity. In approximately 0.1% of clinical cases, the NIPT result and a subsequent diagnostic karyotype are discordant. Here we report a case of a 32-year-old pregnant patient with a 44.1 Mb duplication on the short arm of chromosome 4 detected by NIPT at 12 weeks' gestation. Amniocentesis was carried out at 18 weeks' gestation, followed by conventional and molecular cytogenetic analysis on cells from the amniotic fluid. SNP array analysis found a de novo deletion of 1.2 Mb at chromosome 4, and this deletion was found to be near the critical region of the Wolf-Hirschhorn syndrome. A normal 46,XY karyotype was identified by G-banding analysis. The patient underwent an elective termination and molecular investigations on tissues from the fetus, and the placenta confirmed the presence of type VI true fetal mosaicism. It is important that a patient receives counselling following a high-risk call on NIPT, with appropriate diagnostic analysis advised before any decisions regarding the pregnancy are taken. This case highlights the importance of genetic counselling following a high-risk call on NIPT, especially in light of the increasing capabilities of NIPT detection of sub-chromosomal deletions and duplications.

Different Mechanisms Cause Hypomethylation of Both H19 and KCNQ1OT1 Imprinted Differentially Methylated Regions in Two Cases of Silver-Russell Syndrome Spectrum.

Silver-Russell syndrome is an imprinting disorder characterised by pre- and post-natal growth retardation and several heterogeneous molecular defects affecting different human genomic loci. In the majority of cases, the molecular defect is the loss of methylation (LOM) of the H19/IGF2 differentially methylated region (DMR, also known as IC1) at the telomeric domain of the 11p15.5 imprinted genes cluster, which causes the altered expression of the growth controlling genes, IGF2 and H19. Very rarely, the LOM also affects the KCNQ1OT1 DMR (also known as IC2) at the centromeric domain, resulting in an SRS phenotype by an unknown mechanism. In this study, we report on two cases with SRS features and a LOM of either IC1 and IC2. In one case, this rare and complex epimutation was secondary to a de novo mosaic in cis maternal duplication, involving the entire telomeric 11p15.5 domain and part of the centromeric domain but lacking CDKN1C. In the second case, neither the no 11p15.5 copy number variant nor the maternal-effect subcortical maternal complex (SCMC) variant were found to be associated with the epimutation, suggesting that it arose as a primary event. Our findings further add to the complexity of the molecular genetics of SRS and indicate how the LOM in both 11p15.5 DMRs may result from different molecular mechanisms.