Follow-Up Studies of cf-DNA Testing from 101 Consecutive Fetuses and Related Ultrasound Findings

Abstract

Purpose To determine the true- and false-positive rates of cf-DNA testing in a cohort of patients from tertiary care centers and assess the impact of ultrasound examinations in pregnancy management.

Materials and Methods Clinical, cytogenetic and ultrasound data of 101 consecutive fetuses were collected retrospectively. Cases were classified into five groups according to the ultrasound findings. Karyotyping, interphase FISH and microarray techniques were used for follow-up studies.

Results The overall false-positive rate was low for trisomy 21 (T21, 8.2 %), but significantly higher for trisomy 18 (T18, 40 %), monosomy X (MX, 50 %), X/Y trisomies (57.1 %), trisomy 13 (T13, 71.4 %). While single cases of trisomy 16, trisomy 22 and 8q duplication positive in cf-DNA were confirmed, 3 microdeletions (1p36 and two 22q11.2) were not. About 75 % of confirmed T21’s and all confirmed T18 and T13 had major markers and/or malformations. While false-negative cases (two T21, one T18 and one T13) were identified due to abnormal ultrasound findings, all false-positive cases were normal sonographically. Ultrasound findings of confirmed trisomy 16, 22, dup8q, monosomy X and other X/Y aneuploidies were unspecific. Term placenta studies were helpful to assess the role of confined mosaicism in unconfirmed cf-DNA test results. A vanishing twin has been observed as the likely cause of one false-positive T18.

Conclusion Our study contributes clinical data on discrepant cf-DNA testing results, corroborates the need for confirmational invasive testing and underscores the benefit of expert ultrasound in the prevention of fatal diagnostic errors.

Zusammenfassung

Zweck Ermittlung der Korrekt- und Falsch-Positiv-Rate von NIPT bei Patienten eines Zentrums der Tertiärversorgung sowie des Nutzens von Ultraschalluntersuchungen im Schwangerschaftsmanagement.

Material und Methoden Klinische, zytogenetische und Ultraschalldaten von 101 konsekutiven Schwangerschaften wurden retrospektiv ausgewertet. Abhängig vom Ultraschallbefund wurden diese in fünf Gruppen unterteilt. Für Nachfolgestudien wurden Karyotypisierung, Interphasen-FISH und Microarray-Techniken verwendet.

Ergebnisse Die Falsch-Positiv-Rate für Trisomie 21 war niedrig (T21, 8,2 %), jedoch deutlich höher für Trisomie 18 (T18, 40 %), Monosomie X (MX, 50 %), XXY, XXX, XYY (57,1 %) und Trisomie 13 (T13, 71,4 %). Während Einzelfälle für Trisomie 16, Trisomie 22 und 8q Duplikation bestätigt werden konnten, war dies für 3 Mikrodeletionen (1p36 und zwei 22q11.2) nicht der Fall. Etwa 75 % der bestätigten T21 und alle bestätigten T18 und T13 hatte auffällige Ultraschallbefunde. Alle falsch-negativen Fälle (zwei T21, ein T18 und ein T13) wurden aufgrund von auffälligen Ultraschallbefunden identifiziert, dagegen waren alle falsch-positiven Fälle sonografisch unauffällig. Die Ultraschallbefunde bei bestätigter Trisomie 16, Trisomie 22, Dup8q, Monosomie X und andere X/Y-Aneuploidien waren unspezifisch. Nachfolgende Plazentauntersuchungen waren hilfreich, um die Rolle von plazentalen Mosaiken in den Fällen mit falsch-positiver Testung zu beurteilen. Ein vanished twin war die wahrscheinliche Ursache eines falsch-positiven Trisomie18-Befundes im NIPT.

Schlussfolgerung Unsere Studie liefert weitere klinische Daten zu nicht bestätigten cf-DNA-Testergebnissen, bekräftigt die Notwendigkeit eines invasiven Tests zur Bestätigung und unterstreicht die Bedeutung von spezialisierten Ultraschalluntersuchungen zur Vermeidung von fatalen diagnostischen Fehlern.

Key words

cf-DNA - false positive - false negative - ultrasound - follow-up

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