Inherited variants in autosomal dominant disease genes are a significant cause of fetal structural anomalies

Monogenic disorders are a major cause of fetal structural anomalies. Most genetic diagnoses involve de novo, biallelic or X linked variants; however, inherited variants in autosomal dominant disease genes have been detected across multiple studies. The overall contribution of such variants to fetal structural anomalies is unclear and variant filtering strategies may exclude them. In this study, we aimed to characterise the inherited variants in autosomal dominant disease genes detected by prenatal exome sequencing in a large, well-phenotyped cohort.

The outcomes of prenatal exome sequencing for fetuses with structural anomalies referred to our laboratory from April 2019 to February 2025 were reviewed.

Prenatal exome sequencing was carried out in 1185 fetuses, resulting in a diagnosis in 30.0% of cases. Autosomal dominant disorders accounted for 59.9% of diagnoses and a risk of recurrence was identified for 19.2% of these. Autosomal dominant conditions with an increased risk for recurrence were therefore identified in 3.5% of fetuses referred for sequencing, and accounted for 11.5% of prenatal exome sequencing diagnoses. Recurrent diagnoses involving inherited variants included rasopathies and type I/II collagen disorders.

Inherited variants in autosomal dominant disease genes are a significant contributor to fetal structural anomalies and may have implications for parents' own health as well as management of the current pregnancy and reproductive options. The requirements for genomic counselling, clinical assessment and genetic testing of parents and family members following an inherited finding must be taken into account when planning delivery of a prenatal sequencing service.