Diagnostic cytogenetic testing following positive noninvasive prenatal screening results of sex chromosome abnormalities: Report of five cases and systematic review of evidence

Abstract

BackgroundFollow‐up cytogenetic analysis has been recommended for cases with positive noninvasive prenatal screening (NIPS) results. This study of five cases with numerical and structural sex chromosomal abnormalities (SCA) and a review of large case series of NIPS provided guidance to improve prenatal diagnosis for SCA.MethodsFollowing positive NIPS results for SCA, karyotype analysis, chromosomal microarray analysis (CMA), fluorescence in situ hybridization (FISH), and locus‐specific quantitative PCR were performed on cultured amniocytes, chorionic villi cells, and stimulated lymphocytes. Review of large case series was performed to evaluate the NIPS positive rate, follow‐up rate of cytogenetic analysis, positive predictive value (PPV) for major types of SCA, and relative frequencies of subtypes of major SCA.ResultsOf the five cases with positive NIPS for SCA, case 1 showed a mosaic pattern of monosomy X and isodicentric Y; case 2 showed a mosaic pattern of monosomy X confined to the placenta; cases 3 and 4 had an isochromosome of Xq, and case 5 showed a derivative chromosome 14 from a Yq/14p translocation of maternal origin. Review of literature showed that mean positive rate of NIPS for SCA was 0.61%, follow‐up rate of cytogenetics analysis was 76%, and mean PPV for SCA was 48%. Mosaic patterns and structural rearrangements involving sex chromosomes were estimated in 3%–20% and 3% of SCA cases, respectively.ConclusionThese five cases further demonstrated the necessity to pursue follow‐up cytogenetic analysis to characterize mosaic patterns and structural abnormalities involving sex chromosomes and their value for prenatal genetic counseling. A workflow showing the performance of current NIPS and cytogenetic analysis for SCA was summarized. These results could facilitate an evidence‐based approach to guide prenatal diagnosis of SCA.

Current controversies in prenatal diagnosis: Expanded NIPT that includes conditions other than trisomies 13, 18, and 21 should be offered

“…Using data from the TRIDENT2 trial, in an average population, screening will potentially benefit 0.4% of screened women and is associated with very low false positive rate and no incidental findings given the analysis is limited to just 3 chromosomes. 22 In comparison, for the sex chromosomal abnormalities, based on positive rate, uptake of diagnostic testing and PPV, 58 screening might benefit 0.2% of the population screened but 0.5% of women will have uninterpretable results leading to increased anxiety and unnecessary procedures, and women with true positive results will experience the stress and dilemma of what to do given the milder and variable phenotype of sex chromosomal abnormalities. Furthermore, in an average population without ultrasound anomalies, screening for the microdeletions syndromes will benefit 0.05% of the population but 3.7% of the screened population will have a risk unchanged for microdeletion 22q11.2 and 20% a risk unchanged for one of the other microdeletion syndromes tested.…”

Efficiency of Noninvasive Prenatal Testing for Sex Chromosome Aneuploidies

“…To date, NIPT has also been utilized to screen sex chromosome aneuploidy (SCA)-45,X, 47,XXX, 47,XXY, and 47,XYY that cannot be identified by conventional screening tests [7,[11][12][13][14][15][16]. Prior to NIPT application, most of SCAs are identified accidentally when prenatal diagnosis is performed for any indication.…”

“…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.…”

“…To our best knowledge, few studies have been published on the NIPT for screening of SCAs, and the accuracy varies among different studies [16,18,19,[22][23][24]. In this study, we aimed to investigate the screening efficiency of cfDNA for SCAs.…”

A ritka kromoszóma-rendellenességek és a fetoplacentaris mozaikosság jelentősége a praenatalis diagnosztikában a nem invazív szűrővizsgálatok tükrében

“…A praenatalis vizsgálatok során a lepényi eredetű trophoblast-és mesenchymalis sejtekben, illetve a magzatvízben található amniocytákban az egyes sejtvonalak menynyisége és eloszlása határozza meg a mozaikosság típusát. Az adott sejtben vagy szövetben igazolt kromoszómaeloszlás alapján lepényre korlátozódó mozaikosságot (CPM) vagy valódi magzati mozaikosságot (TFM) különböztetünk meg [12,13], melyek gyakorisága jelentősen eltérhet egymástól az egyes kromoszóma-rendellenességekben [14][15][16]. A fetoplacentaris mozaikosság ráadásul a szűrőtesztek diszkordáns eredményeiért is jelentős mértékben felelős lehet [17].…”