Abstract Background Partial trisomy 21 is a rare chromosomal aberration that can provide unique insights into genotype-phenotype correlations in Down syndrome (DS). While non-invasive prenatal testing (NIPT) has become a widely used screening tool for common aneuploidies, its sensitivity is limited in cases of low-level mosaicism or partial duplications. We report a de novo partial trisomy 21 encompassing the entire Down syndrome critical region (DSCR) that escaped NIPT. Case presentation A 38-year-old first gravida underwent NIPT for evaluation of fetal trisomies 13, 18 or 21 as well as monosomy X, which showed normal results. Ultrasound at 19 + 5 weeks of gestation revealed polyhydramnios and a left-sided fetal hydrothorax, prompting amniocentesis. By karyotyping, a derivative chromosome 21 carrying additional material on the p-arm was identified. PCR-based microsatellite analysis, FISH and array-based studies on amniotic cells characterized the attached material as a de novo terminal duplication of 11.8 Mb of chromosome 21q22.12q22.3, fully encompassing the DSCR and without evidence of mosaicism. Comprehensive genetic counselling was provided, and the pregnancy was electively terminated at 24 weeks of gestation. Postmortem examination of the fetus revealed phenotypic features consistent with Down syndrome. In contrast to the non-mosaic duplication observed in amniotic fluid cells, post-termination tissue analysis demonstrated placental mosaicism, comprising predominantly a normal male cell line and a chromosomal aberrant male cell line with partial duplication of 21q22.12q22.3 in 28% of interphase nuclei in short-term cultured chorionic villi. This constellation likely explains the normal NIPT result. Conclusion This case illustrates the limitations of NIPT in detecting partial trisomies and low-grade placental mosaicism. It emphasizes the importance of further invasive prenatal investigations when results of ultrasound and NIPT are discrepant and it contributes to the understanding of genotype-phenotype correlations in partial trisomy 21. Clinicians should be aware that partial duplications of 21q22 can produce a full DS phenotype despite unremarkable NIPT results. This case highlights the challenges of technical choices in prenatal diagnostics and emphasizes the need for careful interpretation of screening tests and targeted counselling.
Dittrich et al. (Sat,) studied this question.