Language

English

Publication Date

10-24-2025

Journal

Genome Medicine

DOI

10.1186/s13073-025-01563-0

PMID

41137173

PMCID

PMC12551315

PubMedCentral® Posted Date

10-24-2025

PubMedCentral® Full Text Version

Post-print

Abstract

Background: Previous genomic efforts on chromosome 9p deletion and duplication syndromes have utilized low-resolution strategies (i.e., karyotypes, chromosome microarrays). These studies have provided important initial insights into these syndromes. This current study is the first large-scale whole-genome sequencing (WGS) study of 100 individuals from families with chromosome 9p syndromes.

Methods: Through the newly formed 9P-ARCH (Advanced Research in Chromosomal Health: Genomic, Phenotypic, and Functional Aspects of 9p-Related syndromes) research network, we assembled a cohort of individuals from families with chromosome 9p syndromes. WGS was applied to 100 individuals, and other genomic technologies were applied to a subset of individuals. To prioritize genes on 9p, we utilized two independent approaches: statistical analyses of genomic data and spatial transcriptomic profiling of embryonic mouse tissue. To assess the enrichment of DNVs within genomic regions, we developed a computational tool, DiamondsDenovo ( https://github.com/TNTurnerLab/DiamondsDenovo ).

Results: Unlike previous low-resolution studies, we analyzed the genomic architecture of chromosome 9p syndromes, highlighting fundamental features and their commonalities and differences across individuals. A machine-learning model was developed to predict 9p deletion syndrome based on gene copy number estimates using WGS data. We identified two late-replicating regions containing most structural variant breakpoints in 9p deletion syndrome, pointing to replication-based issues as a potential cause of structural variant formation in most individuals and structural rearrangements in some individuals. Genes on 9p were prioritized based on statistical assessment of human genomic variation and through spatial transcriptomics, with 24 genes (AK3, BRD10, CD274, CDC37L1, DMRT1, DMRT2, DMRT3, DOCK8, GLIS3, JAK2, KANK1, KDM4C, PLPP6, PTPRD, PUM3, RANBP6, RCL1, RFX3, RIC1, SLC1A1, SMARCA2, UHRF2, VLDLR, and ZNG1A) identified as important for the majority (83%) of individuals with 9p deletion syndrome. Testing of the mitochondrial genome revealed excess copy number in individuals with 9p deletion syndrome.

Conclusions: This study introduces the 9P-ARCH research network that is actively pursuing genomic, phenotypic, and functional aspects of 9p-related syndromes. We advanced the study of 9p-related syndromes both at the individual level and across the cohort through the largest, most comprehensive genomic analysis of 9p-related syndromes to date.

Keywords

Humans, Chromosomes, Human, Pair 9, Whole Genome Sequencing, Female, Male, Chromosome Disorders, Animals, Mice, DNA Copy Number Variations, Cohort Studies, Syndrome, Chromosome Deletion, Deletion, Duplication, 9p, Chromosome, Syndrome

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