Clinical interpretation of cell-based non-invasive prenatal testing for monogenic disorders including repeat expansion disorders: potentials and pitfalls

Line Dahl Jeppesen^1,2, Lotte Hatt¹, Ripudaman Singh¹,  Palle Schelde¹, Katarina Ravn¹, Christian Liebst Frisk Toft^3,4, Maria Bach Laursen¹, Jakob Hedegaard¹, Inga Baasch Christensen¹, Bolette Hestbek Nicolaisen¹, Lotte Andreasen⁵, Lars Henning Pedersen^6,7,8, Ida Vogel^2,6 and Dorte Launholt Lildballe^2,9

Frontiers in Genetics, 2023

¹ARCEDI, Vejle, Denmark

²Center for Fetal Diagnostics, Aarhus University, Aarhus, Denmark

³Department of Molecular Diagnostics, Aalborg University Hospital, Aalborg, Denmark

⁴Center for Preimplantation Genetic Testing, Aalborg University Hospital, Aalborg, Denmark

⁵Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark

⁶Department of Gynecology and Obstetrics, Aarhus University Hospital, Aarhus, Denmark

⁷Department of Clinical Medicine, Aarhus University, Aarhus, Denmark

⁸Department of Biomedicine, Aarhus University, Aarhus, Denmark

⁹Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark

DOI: 10.3389/fgene.2023.1188472

PMID: 16648021

Abstract:

Introduction:

Circulating fetal cells isolated from maternal blood can be used for prenatal testing, representing a safe alternative to invasive testing. The present study investigated the potential of cell-based noninvasive prenatal testing (NIPT) for diagnosing monogenic disorders dependent on the mode of inheritance.

Methods:

Maternal blood samples were collected from women opting for prenatal diagnostics for specific monogenic disorders (N = 7). Fetal trophoblasts were enriched and stained using magnetic activated cell sorting and isolated by fluorescens activated single-cell sorting. Individual cells were subject to whole genome amplification, and cells of fetal origin were identified by DNA-profiling using short tandem repeat markers. The amplified fetal DNA was input for genetic testing for autosomal dominant-, autosomal recessive-, X-linked and repeat expansion disorders by direct variant analysis and haplotyping. The cell-based NIPT results were compared with those of invasive testing. 

Results:

In two cases at risk of skeletal dysplasia, caused by variants in the FGFR3 gene (autosomal dominant disorders), cell-based NIPT correctly stated an affected fetus, but allelic dropout of the normal alleles were observed in both cases. Cell-based NIPT gave an accurate result in two cases at risk of autosomal recessive disorders, where the parents carried either different diastrophic dysplasia causing variants in the SLC26A2 gene or the same cystic fibrosis disease-causing variant in the CFTR gene. Cell-based NIPT accurately identified an affected male fetus in a pregnancy at risk of Duchenne muscular dystrophy (DMD gene, X-linked recessive disorders). In two cases at risk of the myotonic dystrophy type 1 (DMPK gene, repeat expansion disorder), cell-based NIPT correctly detected an affected and an unaffected fetus, respectively.

Discussion:

Circulating fetal cells can be used to detect both maternally- and paternally inherited monogenic disorders irrespective of the type of variant, however, the risk of allelic dropout must be considered. We conclude that the clinical interpretation of the cell-based NIPT result thus varies depending on the disorders’ mode of inheritance.

Keywords:

noninvasive prenatal testing, fetal cells, extravillous trophoblasts, monogenic disorders, repeat expansion disorders, clinical interpretation

Hent en PDF-version af artiklen her (Open Access)