Detection of Maternal X Chromosome Abnormalities using Single Nucleotide Polymorphism-based Non-invasive Prenatal Testing

Abstract Background Maternal X chromosome abnormalities may cause discordant results between non-invasive prenatal screening tests and diagnostic evaluation of the fetus/newborn, leading to unnecessary invasive testing. Women with X chromosome abnormalities are at increased risk for reproductive, pregnancy or other health complications, which may be reduced or ameliorated by early diagnosis, monitoring and intervention. Objective To validate a single-nucleotide polymorphism-based non-invasive prenatal test to identify X chromosome abnormalities of maternal origin. Study Design All tests unable to evaluate fetal risk for aneuploidy due to uninformative algorithm results were eligible for inclusion. Two groups of cases were prospectively identified; Group A (n=106) where a maternal X chromosome abnormality was suspected and Group B (control group, n=107) where a fetal chromosome abnormality involving chromosome 13, 18, 21 or X was suspected, but did not meet criteria for reporting. Maternal DNA was isolated from the plasma-depleted cellular pellet and sent to a reference laboratory for blinded analysis using chromosomal microarray. A chromosome abnormality involving chromosomes 13, 18, 21 or X was reported by the reference laboratory if ≥5 Mb in size and present in ≥20% of the DNA. Results A maternal X chromosome abnormality was suspected in 1/1,305 tests (149/194,385; 0.08%). In Group A, a maternal X chromosome abnormality was confirmed in 100/106 cases (94.3% positive predictive value, one-sided 97.5% confidence interval 88.1–100.0%). Turner syndrome was the most commonly suspected maternal abnormality (58/106, 54.7%), with confirmation of mosaic or non-mosaic 45,X by microarray in 38/58 (65.5%) cases. Non-invasive prenatal screening tests suspected the presence of maternal 47,XXX with or without mosaicism in 40/106 (37.7%) cases, confirmed by microarray in 38/40 (95.0%). In Group B (n=107), no maternal microarray abnormalities were reported, providing a negative predictive value of 100% (one-sided 97.5% confidence interval: 96.6–100.0%). Conclusions When non-invasive prenatal testing suspected a maternal X chromosome abnormality, maternal microarray confirmed an X chromosome abnormality with 94.3% positive predictive value. Of the maternal X chromosome abnormalities detected by array, >50% were 45,X. When fetal chromosome abnormalities involving chromosomes 13, 18, 21 or X were suspected, no maternal chromosomes abnormalities were reported, yielding a negative predictive value of 100%. Women with maternal X abnormalities suspected with non-invasive prenatal testing may be at increased risk for reproductive and health complications; early evaluation and treatment may prevent long-term consequences or disability.