Birth of a child with trisomy 9 mosaicism syndrome associated with paternal isodisomy 9: case of a positive noninvasive prenatal test result unconfirmed by invasive prenatal diagnosis

Jingmei Ma, David S. Cram, Jianguang Zhang, Ling Shang, Huixia Yang, Hong Pan

Non-invasive prenatal testing (NIPT) is currently used as a frontline screening test to identify fetuses with common aneuploidies. Occasionally, incidental NIPT results are conveyed to the clinician suggestive of fetuses with rare chromosome disease syndromes. We describe a child with trisomy 9 (T9) mosaicism where the prenatal history reported a positive NIPT result for T9 that was unconfirmed by conventional prenatal diagnosis. NIPT was performed by low coverage whole genome plasma DNA sequencing. Karyotyping and fluorescent in situ hybridization (FISH) analysis with chromosome 9p-ter and 9q-ter probes was used to determine the somatic cell level of T9 mosaicism in the fetus and child. Quantitative fluorescent PCR (Q-PCR) of highly polymorphic short tandem repeat (STR) chromosome 9 markers was also performed to investigate the nature of the T9 mosaicism and the parental origin. A 22 month old girl presented with severe developmental delay, congenital cerebral dysplasia and congenital heart disease consistent with phenotypes associated with T9 mosaicism syndrome. Review of the prenatal testing history revealed a positive NIPT result for chromosome T9. However, follow up confirmatory karyotyping and FISH analysis of fetal cells returned a normal karyotype. Post-natal studies of somatic cell T9 mosaicism by FISH detected levels of approximately 20 % in blood and buccal cells. Q-PCR STR analysis of family DNA samples suggested that the T9 mosaicism originated by post-zygotic trisomic rescue of a paternal meiotic II chromosome 9 non-disjunction error resulting in the formation of two distinct somatic cell lines in the proband, one with paternal isodisomy 9 and one with T9. This study shows that NIPT may also be a useful screening technology to increase prenatal detection rates of rare fetal chromosome disease syndromes.