Case Report
Maternal Source of False-Positive Fetal Sex Chromosome Aneuploidy in Noninvasive Prenatal Testing Christopher J. McNamara, MD, Laura A. Limone, MS, CGC, Thomas Westover, MD, and Richard C. Miller, MD BACKGROUND: The intent of noninvasive prenatal testing is to screen for fetal aneuploidies. The assumption is that overrepresented and underrepresented chromosomes are of fetal origin. However, this is not always the case. CASES: We report three cases in which maternal sex chromosome aneuploidy (confirmed by karyotype), two cases of which were previously unknown, resulted in false-positive results. In each, results were positive for fetal aneuploidy, but neonatal karyotypes confirmed normal karyotype. CONCLUSION: Noninvasive prenatal testing assesses the proportion of chromosomes 21, 18, 13, and sex chromosomes in maternal circulation. Intrinsic to the analysis is that the underrepresentations and overrepresentations are of fetal origin. We present three cases in which this assumption is not valid. We suggest that maternal sex chromosome aneuploidy be considered when results suggest fetal sex chromosome aneuploidies. (Obstet Gynecol 2015;125:390–2) DOI: 10.1097/AOG.0000000000000547
From the Departments of Obstetrics and Gynecology, Saint Barnabas Medical Center, Livingston, Cooper University Hospital, Camden, and New Jersey Medical School, Rutgers University, Newark, and New Jersey Perinatal Associates, Livingston, New Jersey; and Saint George’s University School of Medicine, Grenada, West Indies. Presented as a poster at the 2014 American Congress of Obstetricians and Gynecologists Annual Clinical and Scientific Meeting, April 26–30, 2014, Chicago, Illinois. Corresponding author: Richard C. Miller, MD, Department of Obstetrics and Gynecology, Saint Barnabas Medical Center, 94 Old Short Hills Rd., Livingston, NJ 07052, (973) 322-5000; e-mail: [email protected]. Financial Disclosure Ms. Limone is a member of the speaker’s bureau for Sequenom Center for Molecular Medicine, the laboratory that performs MaterniT21 Plus. She receives an honorarium for lectures or discussions about MaterniT21 Plus and other tests offered by the laboratory. The other authors did not report any potential conflicts of interest. © 2015 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0029-7844/15
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Teaching Points 1. Maternal sex chromosome aneuploidy or sex chromosome aneuploidy mosaicism should be considered when noninvasive prenatal test results suggest fetal sex chromosome aneuploidy. 2. Maternal karyotype should be considered when there are maternal clinical factors suggestive of sex chromosome aneuploidy or prenatal diagnosis results fail to confirm a fetal sex chromosome aneuploidy.
N
oninvasive prenatal testing, using a maternal blood sample to analyze fetal and maternal cell-free DNA fragments in maternal plasma, is now widely available to screen for an increasing set of fetal aneuploidy diagnoses. Initially validated for detection of trisomies 21, 18, and 13, noninvasive prenatal testing is now able to detect sex chromosome aneuploidies and some select microdeletions. Although currently only recommended for high-risk pregnancies,1 there is a growing debate about whether noninvasive testing should be offered to low-risk patients as well.2 With increasing availability, it is important to understand the process of analysis and possible maternal causes of false-positive noninvasive prenatal testing results. The maternal serum sample contains cell-free DNA fragments from both maternal and fetal origin. Inherent to the analysis of maternal serum is the assumption that overrepresented and underrepresented chromosomes are of fetal origin. However, this is not always the case. We report three cases in which maternal sex chromosome aneuploidy caused falsepositive results from noninvasive prenatal testing. Three patients were assessed at two maternal– fetal medicine practices over 1 year. Testing is offered only to patients with four validated indications of high risk: advanced maternal age (35 or more years old at estimated date of delivery), fetal ultrasound abnormality suggestive of aneuploidy, personal or family history of chromosome abnormalities, or a positive serum screening test result. All noninvasive prenatal testing was conducted with massively parallel sequencing through the MaterniT21 PLUS test. Invasive prenatal testing is recommended for abnormal results. This noninvasive prenatal test analyzes the relative amount of cell-free chromosomal material
OBSTETRICS & GYNECOLOGY
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
for chromosomes 21, 18, and 13, and the presence of the Y chromosome from a maternal blood draw. Other chromosomal material, including fetal chromosomes 22 and 16, as well as sex chromosome (X and Y) representation, and select microdeletions are also evaluated, and reported as additional findings when an abnormality is detected. In the analysis, cell-free DNA fragments (of maternal and fetal origin) are sequenced, and then the quantity of fragments from each chromosome is assessed and compared with controls. The sequencing step does not differentiate which DNA fragments come from the mother and which from the fetus. Therefore, any overrepresented or underrepresented chromosomes, in relation to controls, are assumed to be of fetal origin. In a separate, parallel analysis, the fetal fraction of cell-free DNA fragments is determined using epigenetic markers. Samples whose fetal fraction is under 4% are not reported.3,4 All of our cases had a fetal fraction of at least 4%.
CASES All three patients had sex chromosome aneuploidies. One was previously known, and the other two were detected after the noninvasive prenatal test results were received. The patient in Case 1 was a 27-year-old woman, gravida 4 para 0, who presented for evaluation and whose maternal karyotype was known before pregnancy to be 47, XXX. Noninvasive prenatal testing showed an increased representation of chromosome X, suggesting a fetal karyotype of 47, XXX. Invasive prenatal testing was declined, and the neonatal blood karyotype was found by extended cell count to be 46, XX. The patient in Case 2 was a 37-year-old woman, gravida 4 para 2, who underwent noninvasive prenatal testing for advanced maternal age. Noninvasive prenatal testing showed an underrepresentation of the X chromosome, suggesting the fetus had a 45, X karyotype. Amniocyte karyotype showed 46, XX (35 of 35 cells) in multiple cultures. Owing to maternal short stature (she was 152.4 cm [5 foot, 0 inches], 17.78 cm [7 inches] shorter than her familial average), maternal blood karyotype was obtained, showing 10% Turner syndrome mosaicism (5 of 50 cells) in two cultures. She had no other overt physical findings corresponding to Turner syndrome phenotype. Neonatal blood karyotype revealed 46, XX karyotype by extended cell count. The patient in Case 3 was a 36-year-old woman, gravida 3 para 1, who underwent noninvasive prenatal testing for advanced maternal age. Noninvasive prenatal testing suggested 45, X. Because of the previous case, maternal karyotype was obtained, even though she displayed no overt phenotypic characteristics of Turner syndrome. Maternal karyotype showed 13% Turner syndrome
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mosaicism (7 of 52 cells) in two cultures. Invasive prenatal testing was declined. Neonatal blood karyotype results were 46, XX (50 of 50 cells) by extended cell count.
DISCUSSION Noninvasive prenatal testing assesses the proportion of chromosomes 21, 18, 13, and sex chromosomes in maternal circulation. Although the fetal portion of cell-free DNA fragments from maternal serum is determined using epigenetic markers, the sequencing step itself does not distinguish between fragments of maternal and fetal origin. Intrinsic to the analysis is that the underrepresentation or overrepresentations of chromosomal fragments, compared with controls, are assumed to be of fetal origin. We present three cases in which this assumption is not valid, causing false-positive results for fetal sex chromosome aneuploidies. In actuality, the test was detecting a maternal sex chromosome aneuploidy. Because more than 90–95% of cell-free DNA in maternal blood is maternal in origin and generally less than 10% is fetal in origin, low levels of undetected maternal chromosomal mosaicism may have a meaningful effect on noninvasive prenatal testing results. In our case of maternal XXX karyotype, the patient’s karyotype was known before pregnancy. XXX is the most common female chromosomal abnormality, occurring in 1 in 1,000 female births. Because of the variable phenotype from asymptomatic to severe manifestations, it is estimated that only 10% of individuals with trisomy X are diagnosed.5 You et al reports a previously undiagnosed maternal trisomy X that resulted in a false-positive fetal noninvasive prenatal test result with a confirmed normal fetal karyotype.6 Wang et al performed maternal karyotypes on 187 consecutive abnormal noninvasive prenatal tests for sex chromosome aneuploidies, including 63 with positive noninvasive prenatal test results for trisomy X. Of these, six had positive maternal karyotype for trisomy X mosaicism (9.5%). In this series, data on fetal outcomes/karyotypes were not collected.7 The two cases of maternal Turner syndrome mosaicism in this report were not detected before pregnancy. Turner syndrome occurs in 1 in 2,500 to 1 in 3,000 liveborn girls. Among diagnosed cases of Turner syndrome, about 13% are mosaic for 45, X and 46, XX, but these patients usually are diagnosed owing to phenotypic features.8 According to the American College of Medical Genetics guidelines, the reporting of monosomy X mosaicism is generally considered at 10% or more 45, X cells among all measured. They also suggest that, with lower
McNamara et al
False Noninvasive Prenatal Test Result
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
391
values, age should be taken into account9 because X chromosome loss with aging has been described.10 Turner syndrome mosaic patients can have a variable phenotype from normal to full phenotypic expression of Turner syndrome. Therefore, the true prevalence of asymptomatic 45, X and 46, XX mosaicism is difficult to ascertain. Of Wang’s 187 consecutive abnormal noninvasive prenatal testing sex chromosome aneuploidies, 124 were positive for Turner syndrome. On maternal karyotyping, 10 (8.06%) were positive for maternal Turner syndrome mosaicism, but, again, no data on fetal or neonatal karyotype were determined.7 There is one reported case of a falsepositive noninvasive prenatal test result for Turner syndrome with maternal mosiacism of 11% shown on maternal karyotype and confirmed normal fetal karyotype. Maternal phenotype was significant only for history of three spontaneous abortions.11 In our two cases, one was of short stature and the other had no obvious phenotypic characteristics. Given the phenotypic variability and prevalence of undiagnosed maternal sex chromosome aneuploidy in women who have a positive noninvasive prenatal test result for fetal sex chromosome aneuploidy, our three confirmed cases of false-positive noninvasive prenatal test results due to maternal sex chromosome aneuploidy, and the two cases found in the literature, we suggest that maternal sex chromosome aneuploidy be considered when noninvasive prenatal test results suggest fetal sex chromosome aneuploidies. More specifically, maternal karyotype should be considered on a case-by-case basis. It should be based, at least in part, on maternal features, clinical history, gestational age, prenatal diagnosis results (if applicable), and statistical data from the laboratory, because some
392
McNamara et al
laboratories have gained enough experience to estimate whether the results represent maternal mosaicism or fetal karyotype. REFERENCES 1. Noninvasive prenatal testing for fetal aneuploidy. Committee Opinion No. 545. American College of Obstetricians and Gynecologists. Obstet Gynecol 2012;120:1532–4. 2. Bianchi DW, Parker RL, Wentworth J, Madankumar R, Saffer C, Das AF, et al. DNA sequencing versus standard prenatal aneuploidy screening. N Engl J Med 2014;370: 799–808. 3. Palomaki GE, Kloza EM, Lambert-Messerlian GM, Haddow JE, Neveux LM, Ehrich M, et al. DNA sequencing of maternal plasma to detect Down syndrome: an international clinical validation study. Genet Med 2011;13:913–20. Oeth P, Wang H, Jensen T, Tynan J, 4. Mazloom AR, Dzakula Z, et al. Noninvasive prenatal detection of sex chromosomal aneuploidies by sequencing circulating cell-free DNA from maternal plasma. Prenat Diagn 2013;33:591–7. 5. Tartaglia NR, Howell S, Sutherland A, Wilson R, Wilson L. A review of trisomy X (47,XXX). Orphanet J Rare Dis 2010;5:8. 6. Yao H, Zhang L, Zhang H, Jiang F, Hu H, Chen F, et al. Noninvasive prenatal genetic testing for fetal aneuploidy detects maternal trisomy X. Prenat Diagn 2012;32:1114–6. 7. Wang Y, Chen Y, Tian F, Zhang J, Song Z, Wu Y, et al. Maternal mosaicism is a significant contributor to discordant sex chromosomal aneuploidies associated with noninvasive prenatal testing. Clin Chem 2014;60:251–9. 8. Sybert VP, McCauley E. Turner’s syndrome. N Engl J Med 2004;351:1227–38. 9. Wolff DJ, Van Dyke DL, Powell CM. Laboratory guideline for Turner syndrome. Genet Med 2010;12:52–5. 10. Russell LM, Strike P, Browne CE, Jacobs PA. X chromosome loss and ageing. Cytogenet Genome Res 2007;116:181–5. 11. Lau TK, Jiang FM, Stevenson RJ, Lo TK, Chan MK, Lo PS, et al. Secondary findings from non-invasive prenatal testing for common fetal aneuploidies by whole genome sequencing as a clinical service. Prenat Diagn 2013;33:602–8.
False Noninvasive Prenatal Test Result
OBSTETRICS & GYNECOLOGY
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Maternal Source of False-Positive Fetal Sex Chromosome Aneuploidy in Noninvasive Prenatal Testing Christopher J. McNamara, MD, Laura A. Limone, MS, CGC, Thomas Westover, MD, and Richard C. Miller, MD BACKGROUND: The intent of noninvasive prenatal testing is to screen for fetal aneuploidies. The assumption is that overrepresented and underrepresented chromosomes are of fetal origin. However, this is not always the case. CASES: We report three cases in which maternal sex chromosome aneuploidy (confirmed by karyotype), two cases of which were previously unknown, resulted in false-positive results. In each, results were positive for fetal aneuploidy, but neonatal karyotypes confirmed normal karyotype. CONCLUSION: Noninvasive prenatal testing assesses the proportion of chromosomes 21, 18, 13, and sex chromosomes in maternal circulation. Intrinsic to the analysis is that the underrepresentations and overrepresentations are of fetal origin. We present three cases in which this assumption is not valid. We suggest that maternal sex chromosome aneuploidy be considered when results suggest fetal sex chromosome aneuploidies. (Obstet Gynecol 2015;125:390–2) DOI: 10.1097/AOG.0000000000000547
From the Departments of Obstetrics and Gynecology, Saint Barnabas Medical Center, Livingston, Cooper University Hospital, Camden, and New Jersey Medical School, Rutgers University, Newark, and New Jersey Perinatal Associates, Livingston, New Jersey; and Saint George’s University School of Medicine, Grenada, West Indies. Presented as a poster at the 2014 American Congress of Obstetricians and Gynecologists Annual Clinical and Scientific Meeting, April 26–30, 2014, Chicago, Illinois. Corresponding author: Richard C. Miller, MD, Department of Obstetrics and Gynecology, Saint Barnabas Medical Center, 94 Old Short Hills Rd., Livingston, NJ 07052, (973) 322-5000; e-mail: [email protected]. Financial Disclosure Ms. Limone is a member of the speaker’s bureau for Sequenom Center for Molecular Medicine, the laboratory that performs MaterniT21 Plus. She receives an honorarium for lectures or discussions about MaterniT21 Plus and other tests offered by the laboratory. The other authors did not report any potential conflicts of interest. © 2015 by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0029-7844/15
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VOL. 125, NO. 2, FEBRUARY 2015
Teaching Points 1. Maternal sex chromosome aneuploidy or sex chromosome aneuploidy mosaicism should be considered when noninvasive prenatal test results suggest fetal sex chromosome aneuploidy. 2. Maternal karyotype should be considered when there are maternal clinical factors suggestive of sex chromosome aneuploidy or prenatal diagnosis results fail to confirm a fetal sex chromosome aneuploidy.
N
oninvasive prenatal testing, using a maternal blood sample to analyze fetal and maternal cell-free DNA fragments in maternal plasma, is now widely available to screen for an increasing set of fetal aneuploidy diagnoses. Initially validated for detection of trisomies 21, 18, and 13, noninvasive prenatal testing is now able to detect sex chromosome aneuploidies and some select microdeletions. Although currently only recommended for high-risk pregnancies,1 there is a growing debate about whether noninvasive testing should be offered to low-risk patients as well.2 With increasing availability, it is important to understand the process of analysis and possible maternal causes of false-positive noninvasive prenatal testing results. The maternal serum sample contains cell-free DNA fragments from both maternal and fetal origin. Inherent to the analysis of maternal serum is the assumption that overrepresented and underrepresented chromosomes are of fetal origin. However, this is not always the case. We report three cases in which maternal sex chromosome aneuploidy caused falsepositive results from noninvasive prenatal testing. Three patients were assessed at two maternal– fetal medicine practices over 1 year. Testing is offered only to patients with four validated indications of high risk: advanced maternal age (35 or more years old at estimated date of delivery), fetal ultrasound abnormality suggestive of aneuploidy, personal or family history of chromosome abnormalities, or a positive serum screening test result. All noninvasive prenatal testing was conducted with massively parallel sequencing through the MaterniT21 PLUS test. Invasive prenatal testing is recommended for abnormal results. This noninvasive prenatal test analyzes the relative amount of cell-free chromosomal material
OBSTETRICS & GYNECOLOGY
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
for chromosomes 21, 18, and 13, and the presence of the Y chromosome from a maternal blood draw. Other chromosomal material, including fetal chromosomes 22 and 16, as well as sex chromosome (X and Y) representation, and select microdeletions are also evaluated, and reported as additional findings when an abnormality is detected. In the analysis, cell-free DNA fragments (of maternal and fetal origin) are sequenced, and then the quantity of fragments from each chromosome is assessed and compared with controls. The sequencing step does not differentiate which DNA fragments come from the mother and which from the fetus. Therefore, any overrepresented or underrepresented chromosomes, in relation to controls, are assumed to be of fetal origin. In a separate, parallel analysis, the fetal fraction of cell-free DNA fragments is determined using epigenetic markers. Samples whose fetal fraction is under 4% are not reported.3,4 All of our cases had a fetal fraction of at least 4%.
CASES All three patients had sex chromosome aneuploidies. One was previously known, and the other two were detected after the noninvasive prenatal test results were received. The patient in Case 1 was a 27-year-old woman, gravida 4 para 0, who presented for evaluation and whose maternal karyotype was known before pregnancy to be 47, XXX. Noninvasive prenatal testing showed an increased representation of chromosome X, suggesting a fetal karyotype of 47, XXX. Invasive prenatal testing was declined, and the neonatal blood karyotype was found by extended cell count to be 46, XX. The patient in Case 2 was a 37-year-old woman, gravida 4 para 2, who underwent noninvasive prenatal testing for advanced maternal age. Noninvasive prenatal testing showed an underrepresentation of the X chromosome, suggesting the fetus had a 45, X karyotype. Amniocyte karyotype showed 46, XX (35 of 35 cells) in multiple cultures. Owing to maternal short stature (she was 152.4 cm [5 foot, 0 inches], 17.78 cm [7 inches] shorter than her familial average), maternal blood karyotype was obtained, showing 10% Turner syndrome mosaicism (5 of 50 cells) in two cultures. She had no other overt physical findings corresponding to Turner syndrome phenotype. Neonatal blood karyotype revealed 46, XX karyotype by extended cell count. The patient in Case 3 was a 36-year-old woman, gravida 3 para 1, who underwent noninvasive prenatal testing for advanced maternal age. Noninvasive prenatal testing suggested 45, X. Because of the previous case, maternal karyotype was obtained, even though she displayed no overt phenotypic characteristics of Turner syndrome. Maternal karyotype showed 13% Turner syndrome
VOL. 125, NO. 2, FEBRUARY 2015
mosaicism (7 of 52 cells) in two cultures. Invasive prenatal testing was declined. Neonatal blood karyotype results were 46, XX (50 of 50 cells) by extended cell count.
DISCUSSION Noninvasive prenatal testing assesses the proportion of chromosomes 21, 18, 13, and sex chromosomes in maternal circulation. Although the fetal portion of cell-free DNA fragments from maternal serum is determined using epigenetic markers, the sequencing step itself does not distinguish between fragments of maternal and fetal origin. Intrinsic to the analysis is that the underrepresentation or overrepresentations of chromosomal fragments, compared with controls, are assumed to be of fetal origin. We present three cases in which this assumption is not valid, causing false-positive results for fetal sex chromosome aneuploidies. In actuality, the test was detecting a maternal sex chromosome aneuploidy. Because more than 90–95% of cell-free DNA in maternal blood is maternal in origin and generally less than 10% is fetal in origin, low levels of undetected maternal chromosomal mosaicism may have a meaningful effect on noninvasive prenatal testing results. In our case of maternal XXX karyotype, the patient’s karyotype was known before pregnancy. XXX is the most common female chromosomal abnormality, occurring in 1 in 1,000 female births. Because of the variable phenotype from asymptomatic to severe manifestations, it is estimated that only 10% of individuals with trisomy X are diagnosed.5 You et al reports a previously undiagnosed maternal trisomy X that resulted in a false-positive fetal noninvasive prenatal test result with a confirmed normal fetal karyotype.6 Wang et al performed maternal karyotypes on 187 consecutive abnormal noninvasive prenatal tests for sex chromosome aneuploidies, including 63 with positive noninvasive prenatal test results for trisomy X. Of these, six had positive maternal karyotype for trisomy X mosaicism (9.5%). In this series, data on fetal outcomes/karyotypes were not collected.7 The two cases of maternal Turner syndrome mosaicism in this report were not detected before pregnancy. Turner syndrome occurs in 1 in 2,500 to 1 in 3,000 liveborn girls. Among diagnosed cases of Turner syndrome, about 13% are mosaic for 45, X and 46, XX, but these patients usually are diagnosed owing to phenotypic features.8 According to the American College of Medical Genetics guidelines, the reporting of monosomy X mosaicism is generally considered at 10% or more 45, X cells among all measured. They also suggest that, with lower
McNamara et al
False Noninvasive Prenatal Test Result
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
391
values, age should be taken into account9 because X chromosome loss with aging has been described.10 Turner syndrome mosaic patients can have a variable phenotype from normal to full phenotypic expression of Turner syndrome. Therefore, the true prevalence of asymptomatic 45, X and 46, XX mosaicism is difficult to ascertain. Of Wang’s 187 consecutive abnormal noninvasive prenatal testing sex chromosome aneuploidies, 124 were positive for Turner syndrome. On maternal karyotyping, 10 (8.06%) were positive for maternal Turner syndrome mosaicism, but, again, no data on fetal or neonatal karyotype were determined.7 There is one reported case of a falsepositive noninvasive prenatal test result for Turner syndrome with maternal mosiacism of 11% shown on maternal karyotype and confirmed normal fetal karyotype. Maternal phenotype was significant only for history of three spontaneous abortions.11 In our two cases, one was of short stature and the other had no obvious phenotypic characteristics. Given the phenotypic variability and prevalence of undiagnosed maternal sex chromosome aneuploidy in women who have a positive noninvasive prenatal test result for fetal sex chromosome aneuploidy, our three confirmed cases of false-positive noninvasive prenatal test results due to maternal sex chromosome aneuploidy, and the two cases found in the literature, we suggest that maternal sex chromosome aneuploidy be considered when noninvasive prenatal test results suggest fetal sex chromosome aneuploidies. More specifically, maternal karyotype should be considered on a case-by-case basis. It should be based, at least in part, on maternal features, clinical history, gestational age, prenatal diagnosis results (if applicable), and statistical data from the laboratory, because some
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McNamara et al
laboratories have gained enough experience to estimate whether the results represent maternal mosaicism or fetal karyotype. REFERENCES 1. Noninvasive prenatal testing for fetal aneuploidy. Committee Opinion No. 545. American College of Obstetricians and Gynecologists. Obstet Gynecol 2012;120:1532–4. 2. Bianchi DW, Parker RL, Wentworth J, Madankumar R, Saffer C, Das AF, et al. DNA sequencing versus standard prenatal aneuploidy screening. N Engl J Med 2014;370: 799–808. 3. Palomaki GE, Kloza EM, Lambert-Messerlian GM, Haddow JE, Neveux LM, Ehrich M, et al. DNA sequencing of maternal plasma to detect Down syndrome: an international clinical validation study. Genet Med 2011;13:913–20. Oeth P, Wang H, Jensen T, Tynan J, 4. Mazloom AR, Dzakula Z, et al. Noninvasive prenatal detection of sex chromosomal aneuploidies by sequencing circulating cell-free DNA from maternal plasma. Prenat Diagn 2013;33:591–7. 5. Tartaglia NR, Howell S, Sutherland A, Wilson R, Wilson L. A review of trisomy X (47,XXX). Orphanet J Rare Dis 2010;5:8. 6. Yao H, Zhang L, Zhang H, Jiang F, Hu H, Chen F, et al. Noninvasive prenatal genetic testing for fetal aneuploidy detects maternal trisomy X. Prenat Diagn 2012;32:1114–6. 7. Wang Y, Chen Y, Tian F, Zhang J, Song Z, Wu Y, et al. Maternal mosaicism is a significant contributor to discordant sex chromosomal aneuploidies associated with noninvasive prenatal testing. Clin Chem 2014;60:251–9. 8. Sybert VP, McCauley E. Turner’s syndrome. N Engl J Med 2004;351:1227–38. 9. Wolff DJ, Van Dyke DL, Powell CM. Laboratory guideline for Turner syndrome. Genet Med 2010;12:52–5. 10. Russell LM, Strike P, Browne CE, Jacobs PA. X chromosome loss and ageing. Cytogenet Genome Res 2007;116:181–5. 11. Lau TK, Jiang FM, Stevenson RJ, Lo TK, Chan MK, Lo PS, et al. Secondary findings from non-invasive prenatal testing for common fetal aneuploidies by whole genome sequencing as a clinical service. Prenat Diagn 2013;33:602–8.
False Noninvasive Prenatal Test Result
OBSTETRICS & GYNECOLOGY
Copyright ª by The American College of Obstetricians and Gynecologists. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
