Enlarged NT (≥3.5 mm) in the first trimester – not all chromosome aberrations can be detected by NIPT

Abstract

BackgroundSince non-invasive prenatal testing (NIPT) in maternal blood became available, we evaluated which chromosome aberrations found in our cohort of fetuses with an enlarged NT in the first trimester of pregnancy (tested with SNP microarray) could be detected by NIPT as well.Method362 fetuses were referred for cytogenetic testing due to an enlarged NT (≥3.5 mm). Chromosome aberrations were investigated using QF-PCR, karyotyping and whole genome SNP array.ResultsAfter invasive testing a chromosomal abnormality was detected in 137/362 (38 %) fetuses. 100/362 (28 %) cases concerned trisomy 21, 18 or 13, 25/362 (7 %) an aneuploidy of sex chromosomes and 3/362 (0.8 %) triploidy. In 6/362 (1.6 %) a pathogenic structural unbalanced chromosome aberration was seen and in 3/362 (0.8 %) a susceptibility locus for neurodevelopmental disorders was found. We estimated that in 2–10 % of fetuses with enlarged NT a chromosome aberration would be missed by current NIPT approaches.ConclusionBased on our cohort of fetuses with enlarged NT we may conclude that NIPT, depending on the approach, will miss chromosome aberrations in a significant percentage of pregnancies. Moreover all abnormal NIPT results require confirmatory studies with invasive testing, which will delay definitive diagnosis in ca. 30 % of patients. These figures are important for pretest counseling enabling pregnant women to make informed choices on the prenatal test. Larger cohorts of fetuses with an enlarged NT should be investigated to assess the additional diagnostic value of high resolution array testing for this indication.

Nuchal translucency of 3.0‐3.4 mm an indication for NIPT or microarray? Cohort analysis and literature review

“…This justifies offering invasive testing followed by CMA, regardless of the local policy on reporting susceptibility CNVs. Our results confirmed the previously published data and showed that not all chromosome aberrations can be detected by offering NIPT to women with a high risk after CT 5,6,14,39,40 . It has been previously shown that CMA is the recommended method in these women if they want to be informed of as many chromosomal aberrations as possible 8,14,17 .…”

“…Nuchal translucency (NT) ≥3.5 mm (>p99) is a well‐recognized indication for invasive testing as it is a well‐studied ultrasound marker for common and uncommon aneuploidies as well as for a wide variety of genetic syndromes and structural anomalies 1‐6 . Although Kagan et al have previously shown that fetuses with NT of 95th centile ≥3.4 mm have a high risk for chromosomal aberrations (1:14), 7 only a few groups performed chromosomal microarray (CMA) analysis in fetuses with NT ≥3.0 mm 8‐11 .…”

Women's preference for non‐invasive prenatal DNA testing versus chromosomal microarray after screening for Down syndrome: a prospective study

“…The American College of Obstetricians and Gynecologists (ACOG) guideline recommended that CMA should be available to women undergoing invasive diagnostic testing for any indication, as approximately 1.7% of those with a normal ultrasound examination result and a normal karyotype had pathogenic or likely pathogenic copy number variants . Equally, not all chromosomal aberrations in fetuses with nuchal translucency (NT) of ≥3.5 mm are detectable by NIPT …”

“…17 Equally, not all chromosomal aberrations in fetuses with nuchal translucency (NT) of ≥3.5 mm are detectable by NIPT. 20,21 Previous studies indicated that Chinese women preferred detailed genetic results and would accept a procedure loss rate of up to 0.5%. 22,23 Whether women favour additional genetic information provided by CMA in preference to fetal safety provided by NIPT, once advised of the lower procedure loss rates, remains unknown.…”

DEGUM, ÖGUM, SGUM and FMF Germany Recommendations for the Implementation of First-Trimester Screening, Detailed Ultrasound, Cell-Free DNA Screening and Diagnostic Procedures

“…Particularly in the case of triploidy and unusual trisomies, the NT values are closer to the normal distribution while they are moderately elevated in unbalanced translocations [90]. In one study, the prevalence of submicroscopic chromosomal anomalies in the group of fetuses with a nuchal translucency ≥ 3.5 mm was not higher than in fetuses without anomalies detectable on ultrasound [91]. The prevalence of submicroscopic chromosomal structural anomalies that can only be detected via array-CGH (pathological CNVs) in populations with an abnormal NT is the subject of various studies using different NT cut-off values: Lund et al found pathological CNVs in 132 fetuses with NT values > 3.5 mm in 12.8 % of cases [92].…”