Evidence map›Paper›PMID 39333082›Full record

ArticleNature communications2024

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 and 17 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.

0numbers the graph read from it
0cells of the map it votes in
6citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

6 citing papers in PubMed.

  1. Review
  2. Multimodality Craniofacial Phenotyping of Congenital Facial Weakness Disorders.The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association · 2026
    Article
  3. Review
  4. Article
  5. Article
  6. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

27 authors.

Arthur S LeeDepartment of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA. arthur.lee@childrens.harvard.edu.ORCID 0000-0002-4513-4630
Lauren J AyersDepartment of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.ORCID 0000-0001-9236-7595
Michael KosickiEnvironmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
Wai-Man ChanDepartment of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.ORCID 0000-0002-2888-4739
Lydia N FozoDepartment of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.ORCID 0000-0003-2601-8287
Brandon M PrattDepartment of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
Thomas E CollinsDepartment of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
Boxun ZhaoManton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, USA.ORCID 0000-0003-2337-5756
Matthew F RoseDepartment of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
Alba Sanchis-JuanProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Jack M FuProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID 0000-0003-4152-5471
Isaac WongProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID 0000-0003-4877-5748
Xuefang ZhaoProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Alan P TenneyDepartment of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
Cassia LeeDepartment of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
Kristen M LaricchiaProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Brenda J BarryDepartment of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
Victoria R BradfordDepartment of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
Julie A JurgensDepartment of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
Eleina M EnglandProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Monkol LekProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID 0000-0003-1227-6293
Daniel G MacArthurProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Eunjung Alice LeeManton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, USA.
Michael E TalkowskiProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID 0000-0003-2889-0992
Harrison BrandProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Len A PennacchioEnvironmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.ORCID 0000-0002-8748-3732
Elizabeth C EngleDepartment of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA. elizabeth.engle@childrens.harvard.edu.ORCID 0000-0001-8194-7738

Funding

Generation of an In Vivo Human Genome Transcriptional Enhancer DatasetR01HG003988 · NHGRI · UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB · PI Len Alexander Pennacchio · 2006 to 2026
$24.1M
VASCULAR, PULMONARY AND RENAL INJURYT32HL007627 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI GIMBRONE, MICHAEL A, MITCHELL, RICHARD N · 1985 to 2019
$12.7M
TRAINING GRANT IN GENETICST32GM007748 · NIGMS · HARVARD UNIVERSITY (MEDICAL SCHOOL) · PI Anne O'Donnell-Luria, Louise Wilkins-Haug · 1985 to 2026
$12.0M
Genetic Analysis and Manipulation Core (GAEC)P50HD105351 · NICHD · BOSTON CHILDREN'S HOSPITAL · PI Hisashi Umemori · 2021 to 2026
$9.4M
Supplement request for Training GrantT32NS007473 · NINDS · CHILDREN'S HOSPITAL BOSTON · PI Elizabeth C. Engle, Thomas L. Schwarz · 1999 to 2026
$6.9M
Scalable tool and comprehensive maps to interpret structural variation across the neuropsychiatric spectrumR01MH115957 · NIMH · BROAD INSTITUTE, INC. · PI TALKOWSKI, MICHAEL E · 2019 to 2025
$5.4M
Mouse Neurodevelopmental Behavior CoreU54HD090255 · NICHD · BOSTON CHILDREN'S HOSPITAL · PI POMEROY, SCOTT LOREN · 2016 to 2020
$5.2M
Training Program in the Molecular Bases of Eye DiseasesT32EY007145 · NEI · SCHEPENS EYE RESEARCH INSTITUTE · PI Patricia Ann D'Amore, MEREDITH GREGORY-KSANDER · 1997 to 2026
$4.5M
Evaluating the Impact of Mutations in Distant-Acting Enhancers in Structural Birth DefectsR01HD114353 · NICHD · UNIVERSITY OF CALIF-LAWRENC BERKELEY LAB · PI Len Alexander Pennacchio, Axel Visel · 2023 to 2026
$3.3M
Dissecting ocular congenital cranial dysinnervation disorders through whole genome sequence analysisR01EY027421 · NEI · BOSTON CHILDREN'S HOSPITAL · PI ENGLE, ELIZABETH C. · 2017 to 2021
$3.1M
Mechanism for endogenous retroelements to mimic ancient exogenous identities in aging and diseased human tissueDP2AG072437 · NIA · BOSTON CHILDREN'S HOSPITAL · PI LEE, EUNJUNG ALICE · 2020 to 2020
$2.7M
Mapping Brainstem Motor Neuron Subtypes and Genetic Pathways Involved in their Differential Susceptibility to DiseaseK08NS099502 · NINDS · UNIVERSITY OF CALIFORNIA-IRVINE · PI ROSE, MATTHEW F · 2017 to 2021
$1.2M
Department of Energy DE-AC02-05CH11231NEI NIH HHS R01 EY027421NEI NIH HHS T32 EY007145NHGRI NIH HHS R01 HG003988NHLBI NIH HHS T32 HL007627NIA NIH HHS DP2 AG072437NICHD NIH HHS P50 HD105351NICHD NIH HHS R01 HD114353NICHD NIH HHS U54 HD090255NIGMS NIH HHS T32 GM007748NIMH NIH HHS R01 MH115957NINDS NIH HHS K08 NS099502NINDS NIH HHS T32 NS007473
6 · The paper itself

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.

Indexed as

Enhancer Elements, GeneticAnimalsChromatinEpigenomicsFemaleHumansMaleMiceMotor NeuronsPedigreeSingle-Cell AnalysisChromatin

Identifiers

PMID39333082
PMCPMC11436875

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.