Prenatal genomic testing for ultrasound-detected fetal structural anomalies

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

Prenatal Genomic Testing for Ultrasound-Detected Fetal Structural Anomalies Reilly K et al. Prenatal genomic testing for ultrasound-detected fetal structural anomalies. TOG 2023;25:121–130. doi:10.1111/tog.12870

3–5% 0.5% ≤80% PREGNANCIES AFFECTED BY FSA MISCARRIAGE RISK, INVASIVE TESTING MAX DIAGNOSTIC YIELD, EXOME SEQUENCING

DO N' T-M IS S FA C TS

1. FSAs affect 3–5% of pregnancies; ~50% have a genetic/chromosomal cause

2. Testing order: QF-PCR (48h) → karyotype (~10d, gold standard for mosaicism/rearrangements) or CMA (10–14d, +3.5– 6% yield) → trio exome sequencing (10–14d)

3. CMA offered with normal QF-PCR plus NT ≥3.5 mm (CRL 45–84 mm), ≥1 FSA, or unexplained sex chromosome aneuploidy; commonest CNV = 22q11.2 deletion

4. PAGE study (n=610): diagnostic ES yield 8.5%, VUS 3.9%; key genes KMT2D, CHD7, PTPN11

5. R21 rapid exome requires normal QF-PCR + CMA first; not used if TOP decided or fetal demise imminent

6. Only class IV/V variants reported as diagnostic (Sanger-validated); VUS not reported but may be reclassified

7. Invasive testing miscarriage risk 0.5%; maternal cell contamination 1–2%

8. Recurrence: autosomal recessive 1/4, autosomal dominant 1/2, gonadal mosaicism up to 4% even if "de novo"

TESTING TIERS AT A GLANCE

QF-PCR 48h → ~25% yield CMA 10–14d → +3.5–6% yield Exome sequencing 10–14d → up to 80% (selected)

ABBREVIATION KEY

FSA — fetal structural anomaly FISH — fluorescence in situ hybridization

QF-PCR — quantitative fluorescence-polymerase chain reaction CVS — chorionic villus sampling

CMA — chromosome microarray TAT — turnaround time

CGH — comparative genomic hybridisation NT — nuchal translucency

SNP — single nucleotide polymorphism MDT — multidisciplinary team

CNV — copy number variant NIPD — non-invasive prenatal diagnosis

NGS — next generation sequencing PGD — preimplantation genetic diagnosis

ES — exome sequencing RCOG — Royal College of Obstetricians and Gynaecologists

WGS — whole genome sequencing PAGE — Prenatal Assessment of Genomes and Exomes study

VUS — variant of uncertain significance R21 — NHS England rapid prenatal exome test code

Source: The Obstetrician & Gynaecologist (TOG), RCOG journal — doi:10.1111/tog.12870

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