Evidence map›Paper›PMID 39013459›Full record

ArticleAmerican journal of human genetics2024

Pathogenic variants in KMT2C result in a neurodevelopmental disorder distinct from Kleefstra and Kabuki syndromes.

Dmitrijs Rots, Sanaa Choufani, Victor Faundes, Alexander J M Dingemans, Shelagh Joss, Nicola Foulds, Elizabeth A Jones, Sarah Stewart, Pradeep Vasudevan, Tabib Dabir and 94 more

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Article in American journal of human genetics, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.

0numbers the graph read from it
0cells of the map it votes in
22citing 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

22 citing papers in PubMed.

  1. Article
  2. Article
  3. Article
  4. Review
  5. Article
  6. Article
  7. Article
  8. KMT2C and KMT2D amplify GRHL2-driven enhancer activation.bioRxiv : the preprint server for biology · 2026
    Article
  9. Article
  10. Review
  11. Review
  12. Biomolecules · 2025
    Article
  13. Review
  14. Article
  15. Article
  16. Article
  17. The Journal of international medical research · 2025
    Review
  18. Review
  19. Article
  20. 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

104 authors.

Dmitrijs RotsDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands; Genetics Laboratory, Children's Clinical University Hospital, Riga, Latvia.
Sanaa ChoufaniGenetics and Genome Biology Program, Research Institute, the Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
Victor FaundesLaboratorio de Genética y Enfermedades Metabólicas, Instituto de Nutrición y Tecnología de Los Alimentos (INTA), Universidad de Chile, Santiago, Chile; Manchester Centre for Genomic Medicine, Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Alexander J M DingemansDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
Shelagh JossWest of Scotland Centre for Genomic Medicine, Queen Elizabeth University Hospital, Glasgow, UK.
Nicola FouldsWessex Clinical Genetics Services, University Hospital Southampton NHS Foundation Trust, Southampton SO16 5YA, UK.
Elizabeth A JonesManchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK; Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Sarah StewartManchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK.
Pradeep VasudevanDepartment of Clinical Genetics, University Hospitals of Leicester, Leicester Royal Infirmary, Leicester LE1 7RH, UK.
Tabib DabirNorthern Ireland Regional Genetics Centre, Belfast City Hospital, Belfast, UK.
Soo-Mi ParkDepartment of Clinical Genetics, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
Rosalyn JewellYorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
Natasha BrownVictorian Clinical Genetics Service, Murdoch Children's Research Institute, Melbourne, VIC, Australia; Department of Paediatrics, Royal Children's Hospital, The University of Melbourne, Melbourne, VIC, Australia.
Lynn PaisCenter for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Sébastien JacquemontDepartment of Pediatrics, University of Montreal, Montreal, QC, Canada.
Khadijé JiziService de Génétique Médicale, CHU Ste-Justine, Montréal, QC, Canada.
Conny M A van Ravenswaaij-ArtsUniversity of Groningen, University Medical Centre Groningen, Department Genetics, Groningen, the Netherlands.
Hester Y KroesDivision Laboratories, Pharmacy and Biomedical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
Constance T R M StumpelDepartment of Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands; GROW-School for Oncology and Reproduction, Maastricht, the Netherlands.
Charlotte W OckeloenDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
Illja J DietsDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
Mathilde NizonService de Génétique Médicale, Centre Hospitalier Universitaire de Nantes, Nantes, France.
Marie VincentService de Génétique Médicale, Centre Hospitalier Universitaire de Nantes, Nantes, France.
Benjamin CognéService de Génétique Médicale, Centre Hospitalier Universitaire de Nantes, Nantes, France.
Thomas BesnardService de Génétique Médicale, Centre Hospitalier Universitaire de Nantes, Nantes, France.
Marios KambourisDivision of Genetics, Department of Pathology and Laboratory Medicine Department, Sidra Medicine, Doha, Qatar.
Emily AndersonLiverpool Centre for Genomic Medicine, Liverpool Women's NHS Foundation Trust, Liverpool, UK.
Elaine H ZackaiDivision of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Carey McDougallDivision of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Sarah DonoghueDivision of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Anne O'Donnell-LuriaCenter for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Zaheer ValivullahCenter for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Melanie O'LearyCenter for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA.
Siddharth SrivastavaDepartment of Neurology, Boston Children's Hospital, Boston, MA, USA.
Heather ByersDepartment of Pediatrics, Stanford University, Stanford, CA, USA.
Nancy LeslieDivision of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
Sarah MazzolaCenter for Personalized Genetic Healthcare, Cleveland Clinic, Cleveland, OH, USA.
George E TillerDepartment of Genetics, Kaiser Permanente, Los Angeles, CA, USA.
Moin VeraDepartment of Genetics, Kaiser Permanente, Los Angeles, CA, USA.
Joseph J ShenDivision of Genetics, Department of Pediatrics, UCSF Fresno, Fresno, CA, USA; Division of Genomic Medicine, Department of Pediatrics, University of California Davis, Sacramento, CA, USA.
Richard BolesNeuraBilities Healthcare, Philadelphia, PA, USA.
Vani JainAll Wales Medical Genomics Service, Wales Genomic Health Centre, Cardiff Edge Business Park, Longwood Drive, Whitchurch, Cardiff CF14 7YU, UK.
Elise Brischoux-BoucherCentre de Génétique Humaine, CHU de Besançon, Université de Franche-Comté, Besançon, France.
Esther KinningClinical Genetics, Birmingham Women's and Children's, Birmingham, UK.
Brittany N SimpsonDivision of Human Genetics, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, OH, USA.
Jacques C GiltayDivision Laboratories, Pharmacy and Biomedical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
Jacqueline HarrisKennedy Krieger Institute, Baltimore, MD, USA; Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Boris KerenDepartment of Genetics, APHP Sorbonne University, Paris, France.
Anne GuimierService de Médecine Genomique des Maladies Rares, CRMR Anomalies Du Développement, Hôpital Necker-Enfants Malades, Assistance Publique des Hôpitaux de Paris, Paris, France.
Pierre MarijonLaboratoire de Biologie Médicale Multisites Seqoia FMG2025, 75014 Paris, France.
Bert B A de VriesDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
Constance S MotterGenetic Center, Akron Children's Hospital, Akron, OH, USA.
Bryce A MendelsohnDepartment of Medical Genetics, Kaiser Permanente, Oakland, CA, USA.
Samantha CoffinoDepartment of Pediatric Neurology, Kaiser Permanente, Oakland, CA, USA.
Erica H GerkesDepartment of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Alexandra AfenjarAPHP Sorbonne Université, Centre de Référence Malformations et Maladies Congénitales Du Cervelet et Déficiences Intellectuelles de Causes Rares, Département de Génétique et Embryologie Médicale, Hôpital Trousseau, Paris, France.
Paola ViscontiIRCCS Istituto Delle Scienze Neurologiche di Bologna, UOSI Disturbi Dello Spettro Autistico, Bologna, Italy.
Elena BacchelliPharmacy and Biotechnology Department, University of Bologna, Bologna, Italy.
Elena MaestriniPharmacy and Biotechnology Department, University of Bologna, Bologna, Italy.
Andree Delahaye-DuriezMedical Genomics and Clinical Genetics Unit, AP-HP, Hôpital Jean Verdier, Bondy, France.
Catherine GoochDivision of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St Louis, MO, USA.
Yvonne HendriksDepartment of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands.
Hieab AdamsDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands.
Christel Thauvin-RobinetUnité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, Dijon, France; Inserm, UMR1231, Equipe GAD, Bâtiment B3, Université de Bourgogne Franche Comté, Dijon Cedex, France; Centre de Référence Déficiences Intellectuelles de Causes Rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France.
Sarah Josephi-TaylorDepartment of Clinical Genetics, The Children's Hospital at Westmead, Sydney, NSW, Australia; Discipline of Genomic Medicine, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia.
Marta BertoliNorthern Genetics Service, Newcastle Upon Tyne NHS Foundation Trust, Newcastle Upon Tyne, UK.
Michael J ParkerDepartment of Clinical Genetics, Sheffield Children's Hospital, Sheffield, UK.
Julie W RuttenDepartment of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands.
Oana CaluseriuDepartment of Medical Genetics, University of Alberta, Edmonton, Canada.
Hilary J VernonJohns Hopkins University School of Medicine, Baltimore, MD, USA.
Jonah KaziyevDivision of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Jia ZhuDivision of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Jessica KremenDivision of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Zoe FrazierRosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Hailey OsikaRosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
David BreaultDivision of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Sreelata NairDepartment of Fetal Medicine, Lifeline Super Specialty Hospital, Kerala, India.
Suzanne M E LewisDepartment of Medical Genetics, BC Children's Hospital Research Institute, The University of British Columbia, Vancouver, BC, Canada.
Fabiola CeroniPharmacy and Biotechnology Department, University of Bologna, Bologna, Italy; Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, UK.
Marta ViggianoPharmacy and Biotechnology Department, University of Bologna, Bologna, Italy.
Annio PosarIRCCS Istituto Delle Scienze Neurologiche di Bologna, UOSI Disturbi Dello Spettro Autistico, Bologna, Italy; Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
Helen BrittainDepartment of Clinical Genetics, Birmingham Women's & Children's NHS Trust, Birmingham, UK.
Traficante GiovannaMedical Genetics Unit, Meyer Children's Hospital IRCCS Florence, Florence, Italy.
Gori GiuliaMedical Genetics Unit,Meyer Children's Hospital IRCCS, Florence, Italy.
Lina QuteinehDivision of Genetic Medicine, Geneva University Hospitals, 1205 Geneva, Switzerland.
Russia Ha-Vinh LeuchterDivision of Development and Growth, Department of Pediatrics, University of Geneva, Geneva, Switzerland.
Evelien Zonneveld-HuijssoonDepartment of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
Cecilia MelladoSección de Genética y Errores Congénitos Del Metabolismo, División de Pediatría, Pontificia Universidad Católica de Chile, Santiago, Chile.
Isabelle MareyCHU Grenoble Alpes, Grenoble, France.
Alicia CoudertCHU Grenoble Alpes, Grenoble, France.
Mariana Inés Aracena AlvarezUnit of Genetics and Metabolic Diseases, Division of Pediatrics, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
Milou G P KennisDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
Arianne BoumanDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
Maian RoifmanThe Prenatal Diagnosis and Medical Genetics Program, Division of Maternal Fetal Medicine, Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Canada.
María Inmaculada Amorós RodríguezDeparment of Pediatrics, Hospital Punta Europa Algeciras, Cadiz, Spain.
Juan Dario Ortigoza-EscobarMovement Disorders Unit, Institut de Recerca Sant Joan de Déu, CIBERER-ISCIII and European Reference Network for Rare Neurological Diseases (ERN-RND), Barcelona, Spain.
Vivian VernimmenDepartment of Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands; GROW-School for Oncology and Reproduction, Maastricht, the Netherlands.
Margje SinnemaDepartment of Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands.
Rolph PfundtDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
Han G BrunnerDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, the Netherlands.
Lisenka E L M VissersDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands; Research Institute for Medical Innovation, Radboud University Medical Center, Nijmegen, the Netherlands.
Tjitske KleefstraDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands; Center of Excellence for Neuropsychiatry, Vincent van Gogh Institute for Psychiatry, Venray, the Netherlands. Electronic address: t.kleefstra@erasmusmc.nl.
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.
Siddharth BankaManchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK; Manchester Centre for Genomic Medicine, Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Trithorax-related H3K4 methyltransferases, KMT2C and KMT2D, are critical epigenetic modifiers. Haploinsufficiency of KMT2C was only recently recognized as a cause of neurodevelopmental disorder (NDD), so the clinical and molecular spectrums of the KMT2C-related NDD (now designated as Kleefstra syndrome 2) are largely unknown. We ascertained 98 individuals with rare KMT2C variants, including 75 with protein-truncating variants (PTVs). Notably, ∼15% of KMT2C PTVs were inherited. Although the most highly expressed KMT2C transcript consists of only the last four exons, pathogenic PTVs were found in almost all the exons of this large gene. KMT2C variant interpretation can be challenging due to segmental duplications and clonal hematopoesis-induced artifacts. Using samples from 27 affected individuals, divided into discovery and validation cohorts, we generated a moderate strength disorder-specific KMT2C DNA methylation (DNAm) signature and demonstrate its utility in classifying non-truncating variants. Based on 81 individuals with pathogenic/likely pathogenic variants, we demonstrate that the KMT2C-related NDD is characterized by developmental delay, intellectual disability, behavioral and psychiatric problems, hypotonia, seizures, short stature, and other comorbidities. The facial module of PhenoScore, applied to photographs of 34 affected individuals, reveals that the KMT2C-related facial gestalt is significantly different from the general NDD population. Finally, using PhenoScore and DNAm signatures, we demonstrate that the KMT2C-related NDD is clinically and epigenetically distinct from Kleefstra and Kabuki syndromes. Overall, we define the clinical features, molecular spectrum, and DNAm signature of the KMT2C-related NDD and demonstrate they are distinct from Kleefstra and Kabuki syndromes highlighting the need to rename this condition.

Indexed as

Abnormalities, MultipleChromosome DeletionChromosomes, Human, Pair 9Craniofacial AbnormalitiesDNA-Binding ProteinsDNA MethylationFaceHematologic DiseasesIntellectual DisabilityNeurodevelopmental DisordersVestibular DiseasesAdolescentChildChild, PreschoolFailure to ThriveFemaleDNA-Binding ProteinsHistone-Lysine N-MethyltransferaseKMT2C protein, humanNeoplasm ProteinsDNA methylationEHMT1Kabuki syndromeKleefstra syndromeKMT2CKMT2Dneurodevelopmental disorder

Identifiers

PMID39013459
PMCPMC11339626

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