A French Approach to Test Fetuses with Ultrasound Abnormalities Using a Customized Microarray as First-Tier Genetic Test

Abstract

Cytogenetic microarray analysis is now the first-tier genetic test used in a postnatal clinical setting to explore genomic imbalances in individuals with developmental disability and/or birth defects. However, in a prenatal setting, this technique is not widely implemented, largely because the clinical impact of some copy number variants (CNVs) remains difficult to assess. This limitation is especially true in France where termination of pregnancy for medical reasons may be performed at any stage of gestation. During a period of 15 months, we investigated 382 fetuses presenting with ultrasound anomalies, using a customized microarray designed to avoid the detection of CNVs raising challenges for genetic counseling. After excluding common aneuploidies, 20/374 (5.3%) fetuses had a pathogenic CNV, among which 12/374 (3.2%) could have been detected by karyotyping, whereas 8/374 (2.1%) were cryptic. Within these 374 cases, 300 were ongoing pregnancies at the time of array comparative genomic hybridization (aCGH) testing. For these pregnancies, we detected 18/300 (6%) pathogenic CNVs, among which 6/300 (2%) were cryptic. Using this approach, only 2/300 (0.6%) of the detected CNVs raised difficulties for genetic counseling. This study confirms the added value of this strategy in a prenatal clinical setting to minimize ethical issues for genetic counseling while enhancing the detection of genomic imbalances.

Diagnostic yield of chromosomal microarray analysis in fetuses with isolated increased nuchal translucency: a French multicenter study

“…One of three different types of microarray was used by each center: Agilent 60 K, Agilent 180 K or Agilent PreCytoNEM® (Agilent Technologies, Santa Clara, CA, USA). The PreCytoNEM, a customized oligonucleotide microarray, was used by three centers to limit the identification of variants of uncertain significance (VOUS) and CNVs predisposing to neurodevelopmental disorders, as described previously.…”

Experience of chromosomal microarray applied in prenatal and postnatal settings in Hong Kong

“…Recent studies (Chung et al, n.d.; Humphrey, Griffin, Shaffer, & Caughey, ) showed that CMA is a cost‐effective diagnostic test in pregnancies with fetal ultrasound anomalies. Most countries and major societies already endorsed the use of CMA in place of karyotyping for prenatal diagnosis (Armour et al, ; Committee on Genetics & the Society for Maternal‐Fetal Medicine, ; Malan et al, ; RANZCOG, ; Vanakker et al, ). CMA has been commonly accepted as part of prenatal diagnosis in the last several years in Hong Kong not only to improve the prenatal care (Cheng, Kan, Hui, Lee, & Tang, ; Kan & Chan, ), but also to understand the underlying causes of the fetal abnormalities (Au et al, ; Cheung et al, ; Hui et al, ; Lau et al, ; Leung et al, ; Luk et al, ).…”

Large Duplications Can Be Benign Copy Number Variants: A Case of a 3.6-Mb Xq21.33 Duplication

“…Molecular Cytogenetics aCGH analysis was performed on uncultured amniocytes and peripheral blood samples from the parents and grandparents using a 60k array (CGH Microarray platform, Agilent Technologies, Santa Clara, CA, USA) as described previously [Malan et al, 2015;Leroy et al, 2016]. Male or female genomic DNA (Promega TM ) was used as a reference in sex-match hybridizations.…”