دورية أكاديمية
أعرض في EDS

Direct haplotype-resolved 5-base HiFi sequencing for genome-wide profiling of hypermethylation outliers in a rare disease cohort.

التفاصيل البيبلوغرافية
العنوان: Direct haplotype-resolved 5-base HiFi sequencing for genome-wide profiling of hypermethylation outliers in a rare disease cohort.
المؤلفون: Cheung WA; Department of Pediatrics, Genomic Medicine Center, Children's Mercy Kansas City, Kansas City, MO, USA., Johnson AF; Department of Pediatrics, Genomic Medicine Center, Children's Mercy Kansas City, Kansas City, MO, USA., Rowell WJ; Pacific Biosciences, Menlo Park, CA, USA., Farrow E; Department of Pediatrics, Genomic Medicine Center, Children's Mercy Kansas City, Kansas City, MO, USA.; Department of Pediatrics, School of Medicine, University of Missouri Kansas City, Kansas City, MO, USA., Hall R; Pacific Biosciences, Menlo Park, CA, USA., Cohen ASA; Department of Pediatrics, School of Medicine, University of Missouri Kansas City, Kansas City, MO, USA.; Department of Pathology and Laboratory Medicine, Children's Mercy Kansas City, Kansas City, MO, USA., Means JC; Department of Pediatrics, Genomic Medicine Center, Children's Mercy Kansas City, Kansas City, MO, USA., Zion TN; Department of Pediatrics, Genomic Medicine Center, Children's Mercy Kansas City, Kansas City, MO, USA., Portik DM; Pacific Biosciences, Menlo Park, CA, USA., Saunders CT; Pacific Biosciences, Menlo Park, CA, USA., Koseva B; Department of Pediatrics, Genomic Medicine Center, Children's Mercy Kansas City, Kansas City, MO, USA., Bi C; Department of Pediatrics, Genomic Medicine Center, Children's Mercy Kansas City, Kansas City, MO, USA., Truong TK; Center for Human Genetics and Genomics, Department of Pediatrics, Department of Neuroscience and Physiology, New York University Grossman School of Medicine, New York, NY, USA., Schwendinger-Schreck C; Department of Pediatrics, Genomic Medicine Center, Children's Mercy Kansas City, Kansas City, MO, USA., Yoo B; Department of Pediatrics, Genomic Medicine Center, Children's Mercy Kansas City, Kansas City, MO, USA., Johnston JJ; Department of Pediatrics, Genomic Medicine Center, Children's Mercy Kansas City, Kansas City, MO, USA., Gibson M; Department of Pediatrics, Genomic Medicine Center, Children's Mercy Kansas City, Kansas City, MO, USA., Evrony G; Center for Human Genetics and Genomics, Department of Pediatrics, Department of Neuroscience and Physiology, New York University Grossman School of Medicine, New York, NY, USA., Rizzo WB; Child Health Research Institute, Department of Pediatrics, Nebraska Medical Center, Omaha, NE, USA., Thiffault I; Department of Pediatrics, School of Medicine, University of Missouri Kansas City, Kansas City, MO, USA.; Department of Pathology and Laboratory Medicine, Children's Mercy Kansas City, Kansas City, MO, USA., Younger ST; Department of Pediatrics, Genomic Medicine Center, Children's Mercy Kansas City, Kansas City, MO, USA.; Department of Pediatrics, School of Medicine, University of Missouri Kansas City, Kansas City, MO, USA., Curran T; Children's Mercy Research Institute, Kansas City, MO, USA., Wenger AM; Pacific Biosciences, Menlo Park, CA, USA., Grundberg E; Department of Pediatrics, Genomic Medicine Center, Children's Mercy Kansas City, Kansas City, MO, USA. egrundberg@cmh.edu.; Department of Pediatrics, School of Medicine, University of Missouri Kansas City, Kansas City, MO, USA. egrundberg@cmh.edu., Pastinen T; Department of Pediatrics, Genomic Medicine Center, Children's Mercy Kansas City, Kansas City, MO, USA. tpastinen@cmh.edu.; Department of Pediatrics, School of Medicine, University of Missouri Kansas City, Kansas City, MO, USA. tpastinen@cmh.edu.
المصدر: Nature communications [Nat Commun] 2023 May 29; Vol. 14 (1), pp. 3090. Date of Electronic Publication: 2023 May 29.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [London] : Nature Pub. Group
مواضيع طبية MeSH: Rare Diseases*/genetics , DNA Methylation*/genetics, Humans ; Haplotypes ; Sequence Analysis, DNA ; Base Sequence ; High-Throughput Nucleotide Sequencing ; Nerve Tissue Proteins/genetics
مستخلص: Long-read HiFi genome sequencing allows for accurate detection and direct phasing of single nucleotide variants, indels, and structural variants. Recent algorithmic development enables simultaneous detection of CpG methylation for analysis of regulatory element activity directly in HiFi reads. We present a comprehensive haplotype resolved 5-base HiFi genome sequencing dataset from a rare disease cohort of 276 samples in 152 families to identify rare (~0.5%) hypermethylation events. We find that 80% of these events are allele-specific and predicted to cause loss of regulatory element activity. We demonstrate heritability of extreme hypermethylation including rare cis variants associated with short (~200 bp) and large hypermethylation events (>1 kb), respectively. We identify repeat expansions in proximal promoters predicting allelic gene silencing via hypermethylation and demonstrate allelic transcriptional events downstream. On average 30-40 rare hypermethylation tiles overlap rare disease genes per patient, providing indications for variation prioritization including a previously undiagnosed pathogenic allele in DIP2B causing global developmental delay. We propose that use of HiFi genome sequencing in unsolved rare disease cases will allow detection of unconventional diseases alleles due to loss of regulatory element activity.
(© 2023. The Author(s).)
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المشرفين على المادة: 0 (DIP2B protein, human)
0 (Nerve Tissue Proteins)
تواريخ الأحداث: Date Created: 20230529 Date Completed: 20230531 Latest Revision: 20230612
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC10226990
DOI: 10.1038/s41467-023-38782-1
PMID: 37248219
قاعدة البيانات: MEDLINE
الوصف
تدمد:2041-1723
DOI:10.1038/s41467-023-38782-1