Evidence map›Paper›PMID 41407309›Full record

ArticleMolecular genetics & genomic medicine2025

Phenotypic Variability and Paternal Inheritance of a CHD8 Variant Causing Intellectual Developmental Disorder With Autism and Macrocephaly Confirmed by Epigenetic and Structural Analyses.

Yutaka Furuta, Kimberly M Ezell, Rizwan Hamid, Joy D Cogan, Thomas A Cassini, Lynette Rives, Ashley McMinn, Shailee Shah, Amanda C Peltier, Stephen Layfield and 18 more

Abstract readCase Reports
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular genetics & genomic medicine, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing 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

1 citing paper in PubMed.

  1. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

28 authors.

Yutaka FurutaDivision of Medical Genetics and Genomic Medicine, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.ORCID https://orcid.org/0009-0001-7278-8242
Kimberly M EzellDivision of Medical Genetics and Genomic Medicine, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Rizwan HamidDivision of Medical Genetics and Genomic Medicine, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Joy D CoganDivision of Medical Genetics and Genomic Medicine, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Thomas A CassiniDivision of Medical Genetics and Genomic Medicine, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Lynette RivesDivision of Medical Genetics and Genomic Medicine, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Ashley McMinnDivision of Medical Genetics and Genomic Medicine, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Shailee ShahDepartment of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Amanda C PeltierDepartment of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Stephen LayfieldDepartment of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Robin S FletcherGreenwood Genetic Center, Greenwood, South Carolina, USA.
Matthew L TedderGreenwood Genetic Center, Greenwood, South Carolina, USA.
Raymond J LouieGreenwood Genetic Center, Greenwood, South Carolina, USA.ORCID https://orcid.org/0000-0002-6788-1151
Jennifer A LeeGreenwood Genetic Center, Greenwood, South Carolina, USA.ORCID https://orcid.org/0000-0003-2890-7483
Jennifer KerkhofMolecular Genetics Laboratory, Division of Molecular Diagnostics, London Health Sciences, London, Canada.
Jessica RzasaMolecular Genetics Laboratory, Division of Molecular Diagnostics, London Health Sciences, London, Canada.
Bekim SadikovicMolecular Genetics Laboratory, Division of Molecular Diagnostics, London Health Sciences, London, Canada.
Abdullah Al MamunDepartment of Biomedical Data Science, Meharry School of Applied Computational Sciences, Nashville, Tennessee, USA.
Jonathan H SheehanDivision of Infectious Diseases, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
Christopher W MothDepartment of Chemistry, Pharmacology, and Biomedical Informatics, Center for Structural Biology and Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee, USA.
Jens MeilerDepartment of Chemistry, Pharmacology, and Biomedical Informatics, Center for Structural Biology and Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee, USA.
Marissa Vawter-LeeDepartment of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
Paola Maria Mendoza-SengcoDepartment of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
Jennifer B HolzenTennessee Pediatrics, Hendersonville, Tennessee, USA.
Sumit PruthiDepartment of Radiology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
John A PhillipsDivision of Medical Genetics and Genomic Medicine, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Rory J TinkerDepartment of Medical Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, New York, USA.ORCID https://orcid.org/0000-0001-7093-8844
Undiagnosed Diseases Network

Funding

Overall: Eunice Kennedy Shriver Intellectual and Developmental Disabilities Research Center at VanderbiltP50HD103537 · NICHD · VANDERBILT UNIVERSITY MEDICAL CENTER · PI Jeffrey L Neul · 2020 to 2026
$10.3M
National Human Genome Research Institute (NHGRI) 15-HG-0130NICHD NIH HHS P50 HD103537
6 · The paper itself

Abstract

backgroundIntellectual developmental disorder with autism and macrocephaly (IDDAM, OMIM #615032) is an autosomal dominant neurodevelopmental disorder characterized primarily by intellectual disability, autism spectrum disorder, macrocephaly, tall stature, gastrointestinal symptoms, and variable neurological manifestations. Most cases result from de novo pathogenic variants in CHD8.

methodsWe conducted genome sequencing through the Undiagnosed Diseases Network (UDN) in a female proband harboring a CHD8 variant of uncertain significance (VUS), whose clinical presentation was consistent with IDDAM but included atypical features such as ptosis and hearing loss. Variant pathogenicity was further evaluated using EpiSign DNA methylation analysis and structural biology modeling.

resultsGenome sequencing confirmed the CHD8 variant inherited from her father, who exhibited a subtle feature, including traits consistent with attention-deficit/hyperactivity disorder. Pathogenicity was confirmed through epigenetic signature testing (EpiSign), demonstrating characteristic methylation patterns and structural biology analysis, predicting significant protein destabilization.

conclusionWe describe the case of IDDAM caused by a paternally inherited CHD8 variant. Our findings highlight the importance of considering parental inheritance in IDDAM diagnoses and suggest epigenetic and structural biology analyses as valuable tools for reclassifying VUS when variant pathogenicity remains uncertain.

Indexed as

Autistic DisorderDNA-Binding ProteinsIntellectual DisabilityMegalencephalyPaternal InheritanceTranscription FactorsDNA MethylationEpigenesis, GeneticFemaleHumansMalePedigreePhenotypeCHD8 protein, humanDNA-Binding ProteinsTranscription FactorsCHD8epigeneticsintellectual developmental disorder with autism and macrocephaly (IDDAM)phenotypic variability

Identifiers

PMID41407309
PMCPMC12711360

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

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.