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

Arthur S. Lee (), Lauren J. Ayers, Michael Kosicki, Wai-Man Chan, Lydia N. Fozo, Brandon M. Pratt, Thomas E. Collins, Boxun Zhao, Matthew F. Rose, Alba Sanchis-Juan, Jack M. Fu, Isaac Wong, Xuefang Zhao, Alan P. Tenney, Cassia Lee, Kristen M. Laricchia, Brenda J. Barry, Victoria R. Bradford, Julie A. Jurgens, Eleina M. England, Monkol Lek, Daniel G. MacArthur, Eunjung Alice Lee, Michael E. Talkowski, Harrison Brand, Len A. Pennacchio and Elizabeth C. Engle ()
Additional contact information
Arthur S. Lee: Boston Children’s Hospital and Harvard Medical School
Lauren J. Ayers: Boston Children’s Hospital and Harvard Medical School
Michael Kosicki: Lawrence Berkeley National Laboratory
Wai-Man Chan: Boston Children’s Hospital and Harvard Medical School
Lydia N. Fozo: Boston Children’s Hospital and Harvard Medical School
Brandon M. Pratt: Boston Children’s Hospital and Harvard Medical School
Thomas E. Collins: Boston Children’s Hospital and Harvard Medical School
Boxun Zhao: Boston Children’s Hospital
Matthew F. Rose: Boston Children’s Hospital and Harvard Medical School
Alba Sanchis-Juan: Broad Institute of MIT and Harvard
Jack M. Fu: Broad Institute of MIT and Harvard
Isaac Wong: Broad Institute of MIT and Harvard
Xuefang Zhao: Broad Institute of MIT and Harvard
Alan P. Tenney: Boston Children’s Hospital and Harvard Medical School
Cassia Lee: Boston Children’s Hospital and Harvard Medical School
Kristen M. Laricchia: Broad Institute of MIT and Harvard
Brenda J. Barry: Boston Children’s Hospital and Harvard Medical School
Victoria R. Bradford: Boston Children’s Hospital and Harvard Medical School
Julie A. Jurgens: Boston Children’s Hospital and Harvard Medical School
Eleina M. England: Broad Institute of MIT and Harvard
Monkol Lek: Broad Institute of MIT and Harvard
Daniel G. MacArthur: Broad Institute of MIT and Harvard
Eunjung Alice Lee: Boston Children’s Hospital
Michael E. Talkowski: Broad Institute of MIT and Harvard
Harrison Brand: Broad Institute of MIT and Harvard
Len A. Pennacchio: Lawrence Berkeley National Laboratory
Elizabeth C. Engle: Boston Children’s Hospital and Harvard Medical School

Nature Communications, 2024, vol. 15, issue 1, 1-26

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52463-7

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