Evidence map›Paper›PMID 40280028›Full record

ArticleEBioMedicine2025

Artificial intelligence-driven genotype-epigenotype-phenotype approaches to resolve challenges in syndrome diagnostics.

Christopher C Y Mak, Hannah Klinkhammer, Sanaa Choufani, Nikola Reko, Angela K Christman, Elise Pisan, Martin M C Chui, Mianne Lee, Fiona Leduc, Jennifer C Dempsey and 31 more

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Article in EBioMedicine, 2025. 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

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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.

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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

41 authors.

Christopher C Y MakDepartment of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong SAR, China.
Hannah KlinkhammerInstitute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany; Institute for Medical Biometry, Informatics and Epidemiology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany.
Sanaa ChoufaniGenetics and Genome Biology Program, Research Institute, The Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada.
Nikola RekoGenetics and Genome Biology Program, Research Institute, The Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada.
Angela K ChristmanDepartment of Pediatrics, University of Washington, Seattle, WA, 98195, USA.
Elise PisanLaboratory of Embryology and Genetics of Human Malformations, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Institut Imagine, Université Paris Cité, Paris, 75015, France.
Martin M C ChuiDepartment of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong SAR, China.
Mianne LeeDepartment of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong SAR, China.
Fiona LeducCHU Lille, Centre de Référence Anomalies du Développement et Syndromes Malformatifs, Lille, F-59000, France.
Jennifer C DempseyDepartment of Pediatrics, University of Washington, Seattle, WA, 98195, USA.
Pedro A Sanchez-LaraDepartment of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Pediatrics, Guerin Children's at Cedars Sinai Medical Center, Los Angeles, CA, USA.
Hannah M BombeiDivision of Medical Genetics and Genomics, Stead Family Department of Pediatrics, University of Iowa Hospitals, Iowa City, IA, USA.
John A BernatDivision of Medical Genetics and Genomics, Stead Family Department of Pediatrics, University of Iowa Hospitals, Iowa City, IA, USA.
Laurence FaivreCentre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHU TRANSLAD, Institut GIMI, Hôpital d'Enfants, CHU Dijon-Bourgogne, Dijon, France; Equipe GAD INSERM UMR1231, Université de Bourgogne Franche Comté, Dijon, France.
Frederic Tran Mau-ThemCentre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHU TRANSLAD, Institut GIMI, Hôpital d'Enfants, CHU Dijon-Bourgogne, Dijon, France; UF 6254 Innovation en diagnostic Génomique des Maladies Rares, Centre Hospitalier Universitaire de Dijon, Dijon, France.
Irene Valenzuela PalafollDepartment of Clinical and Molecular Genetics, University Hospital Vall d'Hebron and Medicine Genetics Group, Valle Hebron Research Institute, Barcelona, Spain.
Natalie CanhamLiverpool Centre for Genomic Medicine, Liverpool Women's Hospital, Crown Street, Liverpool, UK.
Ajoy SarkarDepartment of Clinical Genetics, Nottingham University Hospitals National Health Service Trust, Nottingham, NG5 1PB, UK.
Yuri A ZarateSection of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, AR, 72701, USA; Division of Genetics and Metabolism, University of Kentucky, Lexington, KY, USA.
Bert CallewaertCenter for Medical Genetics, Ghent University Hospital, Ghent, Belgium; Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.
Ewelina Bukowska-OlechDepartment of Laboratory Diagnostics, Poznan University of Medical Sciences, Poznan, Poland.
Aleksander JamsheerDepartment of Medical Genetics, Poznan University of Medical Sciences, Poznan, Poland; Diagnostyka GENESIS, Center for Medical Genetics in Poznan, Poland.
Andreas ZanklDepartment of Clinical Genetics, The Children's Hospital at Westmead, Sydney, Australia; Faculty of Medicine and Health, The University of Sydney, Sydney, Australia; Garvan Institute of Medical Research, Sydney, Australia.
Marjolaine WillemsUnité INSERM U 1051, Département de Génétique Médicale, CHRU de Montpellier, Montpellier, France.
Laura DuncanDepartment of Pediatrics at Vanderbilt University Medical Center, Nashville, TN, USA.
Bertrand IsidorService de Génétique Médicale and L'institut du Thorax, CHU Nantes, Nantes Université, CNRS, INSERM, Nantes, France.
Benjamin CogneMedical Genetics Service, Nantes University Hospital Center, Nantes, France.
Odile BouteCHU Lille, Centre de Référence Anomalies du Développement et Syndromes Malformatifs, Lille, F-59000, France.
Clémence VanlerbergheCHU Lille, Centre de Référence Anomalies du Développement et Syndromes Malformatifs, Lille, F-59000, France.
Alice GoldenbergNormandie Univ, UNIROUEN, Inserm U1245, CHU Rouen, Department of Genetics and Reference Center for Developmental Disorders, FHU G4 Génomique, Rouen, F-76000, France.
Elliot StolermanGreenwood Genetic Center, SC, USA.
Karen J LowCentre for Academic Child Health, Bristol Medical School, University of Bristol, UK; Department of Clinical Genetics, UHBW NHS Trust, Bristol, UK.
Vianney GilardDepartment of Pediatric Neurosurgery, Rouen University Hospital, Rouen, 76000, France.
Jeanne AmielLaboratory of Embryology and Genetics of Human Malformations, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Institut Imagine, Université Paris Cité, Paris, 75015, France.
Angela E LinMedical Genetics, Mass General for Children, Boston, MA, 02114, USA.
Christopher T GordonLaboratory of Embryology and Genetics of Human Malformations, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Institut Imagine, Université Paris Cité, Paris, 75015, France.
Dan DohertyDepartment of Pediatrics, University of Washington, Seattle, WA, 98195, USA.
Peter M KrawitzInstitute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany.
Rosanna WeksbergGenetics and Genome Biology Program, Research Institute, The Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada; Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, M5G 1X8, Canada. Electronic address: rweksb@sickkids.ca.
Tzung-Chien HsiehInstitute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany. Electronic address: thsieh@uni-bonn.de.
Brian H Y ChungDepartment of Paediatrics and Adolescent Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong SAR, China. Electronic address: bhychung@hku.hk.

Funding

Mechanisms of Brain Dysmorphology in MN1 C-Terminal Truncation Syndrome, a Novel Intellectual Developmental Disability Disorder P50HD103524 · NICHD · UNIVERSITY OF WASHINGTON · PI Sandra E Juul · 2020 to 2026
$9.9M
Intellectual and Developmental Disabilities Research CenterU54HD083091 · NICHD · UNIVERSITY OF WASHINGTON · PI GURALNICK, MICHAEL J · 2014 to 2019
$7.9M
NICHD NIH HHS P50 HD103524NICHD NIH HHS U54 HD083091
6 · The paper itself

Abstract

backgroundDecisions to split two or more phenotypic manifestations related to genetic variations within the same gene can be challenging, especially during the early stages of syndrome discovery. Genotype-based diagnostics with artificial intelligence (AI)-driven approaches using next-generation phenotyping (NGP) and DNA methylation (DNAm) can be utilized to expedite syndrome delineation within a single gene.

methodsWe utilized an expanded cohort of 56 patients (22 previously unpublished individuals) with truncating variants in the MN1 gene and attempted different methods to assess plausible strategies to objectively delineate phenotypic differences between the C-Terminal Truncation (CTT) and N-Terminal Truncation (NTT) groups. This involved transcriptomics analysis on available patient fibroblast samples and AI-assisted approaches, including a new statistical method of GestaltMatcher on facial photos and blood DNAm analysis using a support vector machine (SVM) model.

findingsRNA-seq analysis was unable to show a significant difference in transcript expression despite our previous hypothesis that NTT variants would induce nonsense mediated decay. DNAm analysis on nine blood DNA samples revealed an episignature for the CTT group. In parallel, the new statistical method of GestaltMatcher objectively distinguished the CTT and NTT groups with a low requirement for cohort number. Validation of this approach was performed on syndromes with known DNAm signatures of SRCAP, SMARCA2 and ADNP to demonstrate the effectiveness of this approach.

interpretationWe demonstrate the potential of using AI-based technologies to leverage genotype, phenotype and epigenetics data in facilitating splitting decisions in diagnosis of syndromes with minimal sample requirement.

fundingThe specific funding of this article is provided in the acknowledgements section.

Indexed as

Artificial IntelligenceEpigenesis, GeneticEpigenomicsGenetic Association StudiesGenotypeDNA MethylationFemaleGene Expression ProfilingHumansMalePhenotypeSyndromeTumor Suppressor ProteinsTumor Suppressor ProteinsGestaltMatcherMCTTMethylationMN1SplittingSupport vector machine

Identifiers

PMID40280028
PMCPMC12242594

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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.