Applications for cell-free fetal DNA testing beyond common aneuploidy

M R C O G PA R T 2 · S O S P O C K E T C A R D · K N O W L E D G E A R E A 5 – A N T E N ATA L C A R E

Applications for Cell-Free Fetal DNA Testing Beyond Common Aneuploidy Ferguson G, Kilby MD, Mone F. Applications for cell-free fetal DNA testing beyond common aneuploidy. TOG 2025;27:197–206. doi:10.1111/tog.12988

90% / 10% ~50% 9% MATERNAL / FETAL-PLACENTAL CFDNA COLLECTIVE PPV, ANY SCA POOLED PPV, RARE AUTOSOMAL TRISOMY

DO N' T-M IS S FA C TS

  1. Confirm every high-chance expanded cffDNA result with amniocentesis (not CVS) — overcomes confined placental mosaicism

  2. Any SCA: collective PPV ~50%; monosomy X lowest (29.5–32%); FPR up to 90% in low-risk cohorts — consider undiagnosed maternal SCA

  3. RAT pooled PPV 9%; >97% are CPM; commonest is trisomy 7; no international body recommends RAT screening

  4. CNV platforms resolve only >7 Mb; sensitivity 14–20% for CNVs <5 Mb. No UK body endorses CNV screening; ACMG offers 22q11.2 to all

  5. Maternal carriage of a CNV is a contraindication to cffDNA screening for that CNV

  6. Trisomy 6, 7, 11, 14, 15 or 20 confirmed on invasive testing → methylation studies for UPD + clinical genetics referral

  7. Multiple aneuploidies on NIPT → think maternal malignancy (70% confirmed in Dutch series, mostly lymphoma); MDT pathway, IDENTIFY study ongoing

  8. UK Ground E TOP after 24 weeks is hard to justify for SCA given the wide phenotypic spectrum; beware indirect sex selection

PPV AT A GLANCE

22q11.2 (SMART): 52.6% Any SCA: ~50% Segmental CNV: 37.5–44.1% RAT: 9%

ABBREVIATION KEY

cfDNA — cell-free DNA UPD — uniparental disomy

cffDNA — cell-free fetal DNA PPV — positive predictive value

NIPT — non-invasive prenatal screening/testing FPR — false positive rate

NIPD — non-invasive prenatal diagnosis POC — products of conception

SCA — sex chromosome aneuploidy SNP — single nucleotide polymorphism

CNV — copy number variant ACMG — American College of Medical Genetics and Genomics

RAT — rare autosomal trisomy TOP — termination of pregnancy

CPM — confined placental mosaicism Mb — megabase

Source: The Obstetrician & Gynaecologist (TOG), RCOG journal — 206. doi:10.1111/tog.12988

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