Diagnostic inversion in prenatal genomics: counselling, governance and the expanded role of clinical genetics

Graham et al make an important contribution by demonstrating that inherited variants in autosomal dominant (AD) disease genes account for a substantial and likely under-recognised proportion of prenatal exome sequencing (pES) diagnoses in fetuses with structural anomalies.1 Their findings, however, illuminate a broader shift in genomic medicine that extends beyond variant filtering strategies or parental phenotyping alone. Increasingly, pES is functioning not solely as a fetal diagnostic test but as a pathway for unanticipated parental and familial diagnosis.

Classical clinical genetics traditionally proceeds from an affected individual to targeted family investigation and cascade testing. Graham et al describe a systematic reversal of this model. In many families, the fetus became the index case for a previously unrecognised parental disorder, including Noonan syndrome, osteogenesis imperfecta and PLAG1-related SilverRussell syndrome.1 This ‘diagnostic inversion’ is not merely an incidental consequence of trio sequencing; it represents a structural transformation in how…