Study: New DNA-reading technology holds promise for rare disease research

(Press-News.org) Cutting-edge DNA mapping technology identified new genetic information that can help researchers decipher more genetic diseases, a new study found. The research will be presented at the Pediatric Academic Societies (PAS) 2025 Meeting, held April 24-28 in Honolulu. 

The technology identified more genomic imprinting in DNA—10 times as much—than previously published data. Genomic imprinting occurs when only one parent’s gene is expressed in a child’s genetic makeup, which contributes to rare pediatric diseases, according to researchers. 

Study authors said the technology, known as HiFi long-read sequencing, helps identify patterns in DNA that could show which parent is linked to genomic imprinting. 

“Genomic research is uniquely powerful and new technologies continue to enhance understanding of rare diseases,” said Elin Grundberg, PhD, Genomic Medicine Center, Children’s Mercy Kansas City and presenting author. “The novel HiFi long-read sequencing technology helps researchers uncover insights into human development and potentially identify diseases that have eluded science.” 

Researchers applied the technology to more than 200 genetic samples from cells of nearly 70 six-to-eight-week-old placentas at Children’s Mercy Kansas City. 

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EDITOR:
Dr. Elin Grundberg will present “Mapping Parent of Origin Methylation by Long-Read Sequencing Reveals Novel Imprinting and Insight into Pediatric Disease” on Sat., April 26 from 7:30-7:45 PM ET. 
Reporters interested in an interview with Dr. Grundberg should contact Amber Fraley at amber.fraley@pasmeeting.org.
The PAS Meeting connects thousands of pediatricians and other health care providers worldwide. For more information about the PAS Meeting, please visit www.pas-meeting.org.

About the Pediatric Academic Societies Meeting
Pediatric Academic Societies (PAS) Meeting connects thousands of leading pediatric researchers, clinicians, and medical educators worldwide united by a common mission: Connecting the global academic pediatric community to advance scientific discovery and promote innovation in child and adolescent health. The PAS Meeting is produced through the partnership of four leading pediatric associations; the American Academy of Pediatrics (AAP), the Academic Pediatric Association (APA), the American Pediatric Society (APS), and the Society for Pediatric Research (SPR). For more information, please visit www.pas-meeting.org. Follow us on X @PASMeeting and like us on Facebook PASMeeting. 

Abstract: Mapping Parent of Origin Methylation by Long-Read Sequencing Reveals Novel Imprinting and Insight into Pediatric Disease

Presenting Author: Elin Grundberg, PhD

Organization 
Children's Mercy Hospitals and Clinics

Topic 
Genomics/Epigenomics

Background
Human genomic imprinting involves parent-of-origin effect (POE) of regulatory element activity often measured through methylation of CpG (mCG) dinucleotides. Current estimates of the number of human imprinted genes vary widely but those that have been robustly validated remain fewer than 100. Imprinted genes play a key role in the regulation of fetal growth and placental function and a dozen rare pediatric diseases are known to arise from defects in genomic imprinting including Angelman and Prader-Willi Syndrome, respectively.

Objective
We hypothesize that wide spectrum of genomic imprinting is only partially accessed to date due to technological challenges in analyzing parental haplotypes and lack of large sized non-blood-based trio cohorts. To this end, we aimed to leverage the long-read sequencing platform implemented in our Genomic Answers for Kids program using parental and placental biospecimens to provide novel insight into genomic imprinting.

Design/Methods
We applied 5-base long-read HiFi genome sequencing (5mC-HiFi-GS) for single-molecular profiling of mCG together with pedigree-based phasing from long contiguous reads in over 200 samples from almost 70 trios including early developmental (~6-8 weeks gestation) chorionic villi as well as on paternal germ cells and proband/parental peripheral blood tissue.

Results
Using genome-wide haplotype-resolved differential mCG testing, we identified widespread POE of mCG in chorionic villi (95% maternal) at thousands of novel loci. Paternal POE was rare but integrating of 5-base HiFi-GS from germ cells revealed sperm hypermethylation at 98% of identified loci showing signature of paternal imprinting. We further showed that less than 30% of loci maintain POE across cell types and developmental stages restricting genomic imprinting mostly to the placenta. Single-nuclei multiome profiling of chorionic villi revealed 2-fold enrichment of allele-specific expression of genes mapping to our identified loci in fetal vs. maternal cells. Finally, we investigated disease relevance using over 10,000 pediatric rare disease cases by restricting to POE loci mapping near genes highly intolerant to loss-of-function (LOF) (pLI = 1) identifying four candidates as novel imprinting disorder.

Conclusion(s)
Our enhanced map of genomic imprinting in human tissues significantly extends the current "imprintome" and uncovers previously under-appreciated genes and variants likely crucial for human development and pediatric disease.

END