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

Creator(s)

Warren A. Cheung, Children's Mercy HospitalFollow
Adam F. Johnson, Children's Mercy Kansas CityFollow
William J. Rowell
Emily G. Farrow, Children's Mercy HospitalFollow
Richard Hall
Ana S A Cohen, Children's Mercy HospitalFollow
John C. Means, Children's Mercy HospitalFollow
Tricia N. Zion, Children's Mercy Kansas CityFollow
Daniel M. Portik
Christopher T. Saunders
Boryana Koseva, Children's Mercy HospitalFollow
Chengpeng Bi, Children's Mercy HospitalsFollow
Tina K. Truong
Carl F. Schreck, Children's Mercy Kansas CityFollow
Byunggil Yoo, Children's Mercy HospitalFollow
Jeffrey J. Johnston, Children's Mercy HospitalFollow
Margaret Gibson, Children's Mercy HospitalFollow
Gilad Evrony
William B. Rizzo
Isabelle Thiffault, Children's Mercy HospitalFollow
Scott T. Younger, Children's Mercy HospitalFollow
Tom Curran, Children's Mercy HospitalFollow
Aaron M. Wenger
Elin Grundberg, Children's Mercy HospitalFollow
T Pastinen, Children's Mercy HospitalFollow

Document Type

Article

Publication Date

5-29-2023

Identifier

DOI: 10.1038/s41467-023-38782-1; PMCID: PMC10226990

Abstract

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.

Journal Title

Nat Commun

Volume

14

Issue

1

First Page

3090

Last Page

3090

MeSH Keywords

Humans; Haplotypes; Rare Diseases; DNA Methylation; Sequence Analysis, DNA; Base Sequence; High-Throughput Nucleotide Sequencing; Nerve Tissue Proteins

Keywords

Haplotypes; Rare Diseases; DNA Methylation; DNA Sequence Analysis; Base Sequence; High-Throughput Nucleotide Sequencing; Nerve Tissue Proteins

Comments

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Publisher's Link: https://www.nature.com/articles/s41467-023-38782-1

Recommended Citation

Cheung WA, Johnson AF, Rowell WJ, et al. Direct haplotype-resolved 5-base HiFi sequencing for genome-wide profiling of hypermethylation outliers in a rare disease cohort. Nat Commun. 2023;14(1):3090. Published 2023 May 29. doi:10.1038/s41467-023-38782-1