From the Human Genome Project to Pangenome and Multi-Omics: Rethinking Prenatal Genomic Diagnosis

Abstract Prenatal genomics has evolved rapidly in the decades following the Human Genome Project (HGP), moving from targeted aneuploidy screening toward genome-wide, noninvasive assessment using cell-free DNA (cfDNA). Yet, as these technologies have expanded, certain limitations have become more apparent rather than resolved. Much of current practice still relies on a linear reference genome that was not designed to reflect fetal–placental biology or population-level genomic diversity. In this systematic review, conducted in accordance with PRISMA 2020 principles, we examined how advances in reference genomics, emerging human pangenomes, and multi-omics approaches are reshaping prenatal diagnosis. Searches across major biomedical databases identified a heterogeneous body of literature spanning foundational cfDNA studies, clinical validation of noninvasive prenatal testing, genome-wide and monogenic applications, and early explorations of epigenomic and fragmentomic signals. Following structured screening and eligibility assessment, 44 studies were included. Across these studies, diagnostic performance has improved considerably, particularly for common chromosomal abnormalities. At the same time, challenges remain – often less technical than interpretive. Linear reference–based approaches show limited sensitivity to structural variation, ancestry-linked diversity, and placental mosaicism, all of which are highly relevant in prenatal contexts. Newer graph-based and multi-omics strategies offer a broader biological perspective, although most remain at an early stage of clinical translation. Overall, the field appears to be transitioning from data generation toward questions of interpretation, integration, and clinical responsibility. Rather than a completed foundation, the HGP may be better understood as a starting point – one that still requires adaptation to meet the complexities of contemporary prenatal medicine.