Expanded map of genomic imprinting reveals insight into human disease

作者：Craig Smail, Warren Cheung, Boryana Koseva, Adam F. Johnson, Chengpeng Bi, Carl F. Schreck, Michael Lydic, Kristin Holoch, Elena Repnikova, John Herriges, Courtney Marsh, Isabelle Thiffault, Tomi Pastinen, Elin Grundberg · 发表于：medRxiv · 年份：2025 · DOI：10.1101/2025.09.15.25335770 · 被引用次数：1 · 研究领域：Genetic Syndromes and Imprinting

Summary Genomic imprinting involves parent-of-origin effect (POE) of regulatory element activity, often measured through methylation of CpG (5-mC) dinucleotides. While a dozen clinical syndromes are linked to defective imprinting, the extent this epigenetic phenomenon is linked to phenotypic variation and disease susceptibility remains undetermined. We show long-read HiFi genome sequencing for single-molecular profiling of 5-mC, together with pedigree-based phasing in early developmental tissue, provides critical insight into previously uncharted loci in the human genome. Using this approach in 75 samples from 25 trios, we develop a 10-fold enhanced map of human imprinting during development. The majority of POE was maternal (90%) with germ cell hypermethylation was confirmed at most loci (72%) showing signature of paternal imprinting. Integrating summary statistics from population GWAS finds enrichment of common (birthweight) and rare (congenital anomalies) disease loci in newly identified imprinting regions. Accessing pedigree-based rare disease cohorts, we show preponderance of paternal inheritance of pathogenic variants mapping to autosomal dominant OMIM genes with a maternal POE-bin identifying two genes ( BNC2 , DNMT1 ) as novel candidate imprinting disorder loci. Our enhanced human map of POE of 5-mC significantly extends the current “imprintome” and uncovers previously underappreciated genes and variants that appear crucial for human development and disease.