Spotlight on… genomics

Genomics has shifted from a research tool to an integral part of obstetric and gynaecological care. The wider '-omics' family—genomics (DNA sequence and variation), transcriptomics (RNA expression), proteomics (protein expression) and metabolomics (metabolic profiles)—all contribute, but genomics currently has the greatest clinical relevance. Over a decade ago, Horgan and Kenny (TOG 2011;13:189-95)1 predicted that '-omics' would unlock biomarkers, sharpen diagnostics and deliver personalised care. Today, that vision is taking shape: genomics is driving precision medicine, replacing one-size-fits-all models with targeted strategies that improve outcomes for women and their families. The history of Down syndrome testing shows the leap from demographic risk to precision screening. Maternal age-based models detected only ~30% of cases. By the 2000s, combining first-trimester biochemistry with ultrasound markers achieved >85% detection with ~5% false positives (Al Mahri and Nicolaides, TOG 2019:21;51-7).2 Non-invasive prenatal testing (NIPT) using cell-free fetal DNA now delivers >99% sensitivity and specificity for trisomy 21 while sharply reducing invasive procedures. Iceland's experience, with near-universal uptake and almost all diagnosed cases ending in termination, illustrates both clinical effectiveness and the profound ethical dimensions—around reproductive choice, disability and societal values (Levy et al., 2024).3 Challenges remain. Confined placental mosaicism can complicate results, with amniocentesis often more reliable than chorionic villus sampling (Reilly et al., TOG 2023;25:28-37).4 Sensitive counselling is essential, helping parents interpret results and navigate difficult decisions (Mackie et al., TOG 2017;19:211-8).5 Large-scale sequencing has transformed the diagnosis of unexplained fetal anomalies. In non-immune hydrops fetalis, a tiered approach—standard tests followed by exome sequencing—identifies a cause in up to 90% of cases (Khairudin et al., TOG 2023;25:110-20).6 For ultrasound-detected anomalies, a stepwise workflow (QF PCR/karyotype → microarray → trio exome sequencing) yields up to 80% diagnoses in selected cases (Reilly et al., TOG 2023;25:121-30).7 These results guide prognosis, recurrence risk and pregnancy management. Prenatal medicine has therefore shifted from population-based risk to personalised genomic care—improving outcomes for mother and baby. The reach of genomics in pregnancy now extends beyond aneuploidy. NIPD can detect single-gene disorders such as cystic fibrosis, achondroplasia and FGFR3-related skeletal dysplasias using cell-free fetal DNA in maternal plasma (Chitty & Lo, 2015).8 By identifying paternal or de novo variants without invasive sampling, NIPD combines safety with accuracy. Clinical value is clear in conditions where fetal sexing directs care—such as haemophilia or congenital adrenal hyperplasia—and in targeting anti-D prophylaxis through fetal RHD genotyping (Clausen et al., 2014).9 As sequencing becomes more powerful and affordable, NIPD's scope will expand further, offering parents earlier reassurance and informed choices. Genomics is also transforming fertility care. For couples with chromosomal translocations, PGT for structural rearrangements (PGT-SR) enables selection of embryos with balanced karyotypes, reducing miscarriage risk and improving live birth outcomes (Scriven, Handyside & Ogilvie, 2013).10 Similarly, PGT for monogenic disease (PGT-M) prevents transmission of conditions such as thalassaemia, sickle cell disease and BRCA-associated cancer predisposition (Harper et al., 2018).11 These advances move genomic medicine 'upstream', embedding precision into conception itself. Yet PGT also raises ethical and equity questions—around access, embryo selection and the responsibilities of clinicians in guiding reproductive decisions. Molecular testing of germline and somatic BRCA1/2 and homologous recombination deficiency (HRD) panels now guides targeted maintenance therapy. PARP inhibitors exploit DNA repair weakness in BRCA-deficient tumours, improving progression-free survival. Combination strategies, such as PARP inhibitors with bevacizumab in HRD-positive patients, highlight how DNA repair and tumour biology insights are reshaping ovarian cancer care (Darwish et al., TOG 2023;25:220-8).12 Around 2%–7% of adenocarcinomas are HPV-independent, defined by mutations in TP53, PTEN, KRAS, CTNNB1 and ARID1A/B with absent p16 expression (Aggarwal et al., TOG 2023;25:47-58).13 Typically diagnosed later in older women, these tumours have worse outcomes. Current treatment mirrors HPV-driven disease, but biomarker-guided therapies may soon provide targeted options. Minimally invasive molecular sampling (cervical brushings, vaginal swabs, urine) can detect tumour mutations, methylated DNA or proteomic markers. When combined with imaging and patient risk factors (BMI, Lynch syndrome), these tools could deliver smarter triage—accelerating diagnosis for high-risk women and sparing low-risk patients invasive procedures (Jones et al., TOG 2021;23:103-12).14 Lynch syndrome, caused by mutations in mismatch repair genes, increases lifetime risk of colorectal, endometrial and ovarian cancers. Universal molecular screening of endometrial tumours (IHC, MSI or sequencing with MLH1 methylation) identifies patients for germline testing and cascade screening (Ryan et al., TOG 2021;23:9-20).15 For women with pathogenic variants, preventative surgery is sometimes indicated. BRCA1/2 carriers may consider prophylactic bilateral salpingo-oophorectomy after childbearing (NICE, 2024).16 Women with Lynch syndrome mutations may benefit from hysterectomy and, in some cases, daily aspirin (Burn et al., 2011).17 For women at average risk, the decision is more complex. Elective oophorectomy before 50 can increase cardiovascular, bone and cognitive risks without overall survival benefit (Asfour et al., TOG 2022;24:131-6).18 These findings emphasise counselling around ovarian conservation. In high-risk women, prophylactic surgery usually outweighs long-term health costs, with hormone replacement therapy mitigating many adverse effects. Risk-stratified planning, shared decision-making and emerging options such as salpingectomy with delayed oophorectomy help balance cancer prevention with quality of life. Genomics is paving the way for new approaches in reproductive health. Integrating genetic, environmental and functional data promises more accurate diagnoses and targeted treatments beyond standard assisted reproduction (Karavolos et al., TOG 2020;22:267-74).19 A UCSF–Stanford study (Wang et al., 2024)20 showed that pregnant individuals with a high burden of mutations in uterine muscle-related genes respond poorly to synthetic progesterone. This suggests that pharmacogenomics could tailor therapies for preterm birth prevention—though not yet part of routine care. Genomics is beginning to reshape obstetric and gynaecological care, from cell-free DNA screening in pregnancy to molecular profiling in cancer. These advances are important steps toward safer, more personalised medicine. Yet the impact on routine practice remains modest. For clinicians, a balanced view is essential: recognising progress while preparing for genomics' growing role in diagnosis, counselling, equitable access and patient outcomes. I wish to acknowledge colleagues in the Clinical Genetics Department, Birmingham Women's and Children's NHS Foundation Trust, and especially Professor Eamonn Maher and Dr James Castleman, for their valuable input on this work.