Genetic tests available in the prenatal setting have expanded rapidly with next generation sequencing, and fetal imaging can detect a breadth of many structural and functional abnormalities. To identify a fetal genetic disease, deep phenotyping is increasingly important to generate a differential diagnosis, choose the most appropriate genetic tests, and inform the results of those tests. The Human Phenotype Ontology (HPO) organizes and defines the features of human disease to support deep phenotyping, and ongoing efforts are being made to improve the scope of the HPO to comprehensively include fetal phenotypes. There are important limitations of fetal phenotyping to understand, including ongoing structural development and limited knowledge of how many genetic diseases present uniquely in utero. This article provides an overview of the use of HPO terms and artificial intelligence in the approach to fetal phenotyping and genetic testing.

Congenital myotonic dystrophy type 1 (DM1) is a rare congenital neuromuscular disorder associated with high morbidity and potential early mortality requiring lifelong symptomatic management. Prenatal presentations of DM1 have been associated with nonspecific ultrasound findings such as clubbed foot, polyhydramnios, ventriculomegaly, and decreased fetal movement, but many cases of DM1 have no ultrasound anomalies. We sought to compare the clinical course and prenatal imaging findings in two cases of DM1 using retrospective chart review. This report demonstrates potential expansion of the prenatal phenotype of DM1 including fetal SVT and frontal bossing. Both cases shared unique prenatal imaging features of lateral ventricle dilation involving the anterior bodies and frontal horns on fetal MRI. Because congenital DM1 is most often maternally inherited, attention to maternal symptoms, physical examination, and family history can be helpful in recognizing cases. Molecular diagnosis of DM1 requires specialized testing of the 3′ untranslated region of the DMPK gene, and DM1 will not be detected by current standard prenatal genetic testing with microarray, karyotype, or exome sequencing.

In utero fetal therapy offers the opportunity to prevent and treat diseases with a cellular or genetic basis. Components of successful fetal treatment include isolation of a replacement cell population, in utero stem cell transplantation, cell engraftment with fetal immune tolerance, and ongoing cell function. Fetal gene therapy with CRISPR-Cas9 represents an exciting potential therapy for genetic diseases not amenable to gene supplementation via adenoviral vector transduction. These fetal therapies have unique ethical and safety considerations. Clinical trials for in utero cell therapy are underway, as additional discoveries in stem cell biology and gene therapy move closer to clinical translation.

In utero interventions are transformative in addressing genetic and anatomic conditions during fetal development. Next generation sequencing enables early genetic testing, playing a pivotal role in prenatal decision‐making by supporting risk stratification, precise and timely diagnosis, which directly informs eligibility for fetal surgical and molecular therapies. Early diagnosis benefits both prenatal and postnatal care by guiding prenatal interventions, or selecting cases that might benefit from postnatal preparedness (when early postnatal treatment alters outcomes), and informing counseling (when it significantly influences pregnancy decision‐making) and reproductive planning. The integration of artificial intelligence into prenatal care holds the promise of end‐to‐end solutions that streamline diagnosis, counseling, and access to both standard and experimental in utero interventions. However, significant ethical and social challenges remain, including equity in access to testing and care, incidental findings, variants of uncertain significance, incomplete penetrance and uncertain phenotype prediction of rare variants and disorders. These complexities raise important questions about reproductive autonomy and justice and responsible use of emerging technologies. This review emphasizes the intimate interplay between early genetic testing and in utero interventions, while highlighting the need for equitable, precise, and community‐informed practices in prenatal genomic research and care.