A cell type-aware framework for nominating non-coding variants in Mendelian regulatory disorders

Unsolved Mendelian cases often lack obvious pathogenic coding variants, suggesting potential non-coding etiologies. Here, we present a single cell multi-omic framework integrating embryonic mouse chromatin accessibility, histone modification, and gene expression assays to discover cranial motor neuron (cMN) cis-regulatory elements and subsequently nominate candidate non-coding variants in the congenital cranial dysinnervation disorders (CCDDs), a set of Mendelian disorders altering cMN development. We generate single cell epigenomic profiles for ~86,000 cMNs and related cell types, identifying ~250,000 accessible regulatory elements with cognate gene predictions for ~145,000 putative enhancers. We evaluate enhancer activity for 59 elements using an in vivo transgenic assay and validate 44 (75%), demonstrating that single cell accessibility can be a strong predictor of enhancer activity. Applying our cMN atlas to 899 whole genome sequences from 270 genetically unsolved CCDD pedigrees, we achieve significant reduction in our variant search space and nominate candidate variants predicted to regulate known CCDD disease genes MAFB, PHOX2A, CHN1, and EBF3 - as well as candidates in recurrently mutated enhancers through peak- and gene-centric allelic aggregation. This work delivers non-coding variant discoveries of relevance to CCDDs and a generalizable framework for nominating non-coding variants of potentially high functional impact in other Mendelian disorders.

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Publication Details

Journal
Nature Communications
Published
2024-09-27
DOI
https://doi.org/10.1038/s41467-024-52463-7
Citations
8
Primary Topic
Genomics and Chromatin Dynamics
Type
article
Field-Weighted Citation Impact
1.87

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article

A cell type-aware framework for nominating non-coding variants in Mendelian regulatory disorders

Wai‐Man Chan, Harrison Brand, Daniel G. MacArthur, Kristen M. Laricchia et al.
8 citations
Nature Communications
Genomics and Chromatin Dynamics
1.87
article

A cell type-aware framework for nominating non-coding variants in Mendelian regulatory disorders

Wai‐Man Chan, Harrison Brand, Daniel G. MacArthur, Kristen M. Laricchia, Jack Fu, Monkol Lek, Alan P. Tenney, L Pennacchio, Eleina England, Eunjung Alice Lee, Brandon M. Pratt, Michael Kosicki, Michael E. Talkowski, Elizabeth C. Engle, Julie A. Jurgens, Thomas E. Collins, Brenda J. Barry, Arthur S. Lee, Alba Sanchis‐Juan, Xuefang Zhao, Isaac Wong, Boxun Zhao, Victoria R. Bradford, Matthew F. Rose, Lydia Fozo, Lauren J. Ayers, Cassia Lee
article en
8 citations

Abstract

Unsolved Mendelian cases often lack obvious pathogenic coding variants, suggesting potential non-coding etiologies. Here, we present a single cell multi-omic framework integrating embryonic mouse chromatin accessibility, histone modification, and gene expression assays to discover cranial motor neuron (cMN) cis-regulatory elements and subsequently nominate candidate non-coding variants in the congenital cranial dysinnervation disorders (CCDDs), a set of Mendelian disorders altering cMN development. We generate single cell epigenomic profiles for ~86,000 cMNs and related cell types, identifying ~250,000 accessible regulatory elements with cognate gene predictions for ~145,000 putative enhancers. We evaluate enhancer activity for 59 elements using an in vivo transgenic assay and validate 44 (75%), demonstrating that single cell accessibility can be a strong predictor of enhancer activity. Applying our cMN atlas to 899 whole genome sequences from 270 genetically unsolved CCDD pedigrees, we achieve significant reduction in our variant search space and nominate candidate variants predicted to regulate known CCDD disease genes MAFB, PHOX2A, CHN1, and EBF3 - as well as candidates in recurrently mutated enhancers through peak- and gene-centric allelic aggregation. This work delivers non-coding variant discoveries of relevance to CCDDs and a generalizable framework for nominating non-coding variants of potentially high functional impact in other Mendelian disorders.

Nature CommunicationsVol. 15(1)
Broad Institute (US), Brigham and Women's Hospital (US), Boston Children's Hospital (US), Howard Hughes Medical Institute (US), Harvard University (US), Garvan Institute of Medical Research (AU), Lawrence Berkeley National Laboratory (US), St. Elizabeth's Medical Center (US), UNSW Sydney (AU), Massachusetts General Hospital (US), Harvard College Observatory (US), Murdoch Children's Research Institute (AU), Boston Children's Museum (US), Dana-Farber/Boston Children's Cancer and Blood Disorders Center (US)
U.S. Department of Energy, Broad Institute, National Institutes of Health, Intellectual and Developmental Disabilities Research Center, Harvard Stem Cell Institute, Manton Center for Orphan Disease Research, Boston Children's Hospital, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Human Genome Research Institute, National Eye Institute, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke, Lawrence Berkeley National Laboratory
Openalex Percentile: Top 14%
Genomics and Chromatin Dynamics
1.87
DOIOpen Access PDFOpenAlex
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