Fetal sex discordance between noninvasive prenatal screening results and sonography: A single institution's experience and review of the literature

Abstract

Background With the increasing availability of noninvasive prenatal screening (NIPS) and high‐resolution ultrasound, more cases of sex discordance are being identified in routine clinical practice. This can be a source of much concern for families and clinicians. Knowledge about the limitations of NIPS and reasons for discordant results are critical for counseling parents. Aims Here, we present three cases from a single tertiary care referral center. We also review the literature to address potential limitations of NIPS in correctly identifying fetal sex chromosomes. Materials and Methods After Institutional Review Board approval, cases of discordant fetal sex were identified using ICD‐9 and ICD‐10 codes. In addition, departmental counseling database and cytogenetics laboratory logbooks were reviewed. Results In our first case, a 37‐year‐old G4 P2012 underwent NIPS at 11 weeks gestation and Monosomy X (associated with Turner syndrome) was identified. Morphological sonographic assessment at 20 weeks gestation was consistent with a female fetus following an amniocentesis at 16 weeks that revealed normal 46, XX karyotype. During the third trimester, the patient was diagnosed with Stage IV invasive ductal carcinoma of the breast. Postnatal follow‐up of the neonate was consistent with a phenotypic female. In the second case, a 22‐year‐old G2 P1001 obese female underwent NIPS at 14 weeks gestation and normal 46, XY karyotype was identified. Morphological sonographic assessment at 20 weeks was not consistent with a male fetus. The patient declined invasive testing. Postnatally, the karyotype was 46, XX and the neonate was phenotypically female. The reason for the discordant results was not identified. In the third case, a 25‐year‐old G1 P0 obese female underwent NIPS at 13 weeks gestation and normal 46, XY karyotype was identified. Morphological sonographic assessment at 20 weeks was indeterminate; however, follow‐up at 24 weeks was consistent with a female fetus. The patient declined invasive prenatal testing. Postnatally, the karyotype was 46, XX, and the neonate was phenotypically female with uterus present on ultrasound. The reason for the discordant results was not identified. Discussion Our cases demonstrate possible limitations of NIPS in correctly identifying sex chromosomes. Conclusions Providers and patients need to be aware of these limitations, and invasive diagnostic prenatal testing should be offered in cases of discordance between NIPS and sonographic sex assessment.

Limited ability of increased sequencing depth in detecting cases missed by noninvasive prenatal testing: a comparative analysis of 3 clinical cases

“…Another study 30 also reported 3 cases of sex inconsistency between NIPT and ultrasound results, and they suggested further examination and invasive prenatal diagnostic tests in cases with inconsistent results in sex assessment between NIPT and ultrasound. However, in China, sex is not allowed to be determined by NIPT, and therefore, it is impossible to obtain information about sex inconsistency between NIPT and ultrasound examination before birth.…”

Phenotype‐Genotype Discordance and a Case of a Disorder of Sexual Differentiation

“…After excluding the common explanations for discordance, invasive testing should be offered to confirm the genetic sex and evaluate for the presence of the SRY gene and pathogenic copy number variants on a microarray. A gene panel can look for common pathogenic mutations when a DSD is suspected [ 12 ].…”

Efficiency of Noninvasive Prenatal Testing for Sex Chromosome Aneuploidies

“…Yao et al [40] demonstrated for the first time that maternal genomic materials could affect NIPT accuracy. Afterward, many studies demonstrated that maternal factors could significantly affect the accuracy of NIPT for fetal SCAs [8, [16][17][18][19][20][21][22][23][24]41]. Wang et al [8] reported that maternal X chromosome aneuploidy and mosaicism were responsible for approximately 8.6% of discordant NIPT results for SCAs.…”

“…The positive predictive value (PPV) of SCAs screening was consistently lower in respect of autosomal trisomies. This could be related to confined placental mosaicism (CPM), abnormal maternal SCAs, including full maternal SCA, mosaic maternal SCA, and maternal copy number variants, as well as loss of an X chromosome from maternal cells as a natural part of aging [16][17][18][19][20][21][22]. Therefore, there is a lack of reliable data on SCA rates.…”