Maternal Y chromosome derived copy number variant causes false positive klinefelter syndrome (XXY) sex chromosome results during noninvasive prenatal testing

Absera Tsegay1, Nicola Flowers1, Olivia Giouzeppos1, Grace Shi1, Damien Bruno1, Mark Pertile1,2 

1Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, Melbourne, Australia.
2Department of Paediatrics, University of Melbourne, Parkville, Australia.

Noninvasive prenatal testing (NIPT) uses massive parallel sequencing to test cell free DNA (cfDNA) isolated from maternal plasma. The major component of the cfDNA is maternally derived, while the fetal component is derived from the placental trophoblast. The specificity of NIPT for sex chromosome aneuploidies (SCA) is reduced in comparison to trisomy 21, which results in an increased frequency of false positive findings. In particular, maternal 45,X mosaicism and 47,XXX complements have been implicated in false positive NIPT SCA results.


Here we present three cases of XXY results reported as high risk by NIPT but which were false positive findings. Diagnostic prenatal testing returned normal results in two cases, while a third case was associated with female genitalia on second trimester ultrasound scan after the patient declined prenatal diagnosis. In all three cases, chromosomal microarray (CMA) performed on maternal blood indicated the presence of a 1.5 Mb Y chromosome derived copy number variant (CNV).


These cases demonstrate a maternal biological cause for each false positive XXY NIPT result. In our patient cohort, 10/13 (77%) high risk XXY results have been confirmed in the fetus, while 3/13 (23%) were false positive results caused by a maternal Y chromosome derived CNV. Where an XXY NIPT result is not confirmed after diagnostic testing, maternal CMA testing should be considered.



My name is Absera Tsegay most people know me as Sera. I am a Medical Scientist at Victorian Clinical Genetics Services for about a year and and 6 months now and i work as part of the Noninvasive prenatal testing (NIPT) team.

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