ArticleAmerican journal of human genetics2022
An HNRNPK-specific DNA methylation signature makes sense of missense variants and expands the phenotypic spectrum of Au-Kline syndrome.
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Article in American journal of human genetics, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 26 papers.
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26 citing papers in PubMed, 34 citations in OpenAlex.
- Beyond in silico prediction: multi-omics to identify a pathogenic deep intronic HNRNPK variant in Au-Kline syndrome.Journal of human genetics · 2026Article
- hnRNPK condensates facilitate enhancer-promoter looping and RNA polymerase II recruitment.Nature genetics · 2026Article
- Heterogeneous nuclear ribonucleoprotein K in cancer biology and its therapeutic applications (Review).Molecular medicine reports · 2026Review
- Widespread hnRNP K Mislocalisation Suggests Differential Neuronal Vulnerability in the Neurodegenerative and Ageing Human Brain.Neuropathology and applied neurobiology · 2026Article
- A Phenotypic Paradigm for Cerebral Palsy Genetics.medRxiv : the preprint server for health sciences · 2026Article
- Case Report: A novelFrontiers in psychiatry · 2026Article
- Analysis Methods for Diagnosing Rare Neurodevelopmental Diseases with Episignatures: A Systematic Review of the Literature.Biomedicines · 2025Review
- DNA methylation data from Japanese patients with Rubinstein-Taybi syndrome.Human genome variation · 2025Article
- A Novel Intronic Variant in the KH3 Domain of HNRNPK Leads to a Mild Form of Au-Kline Syndrome.Clinical genetics · 2025Article
- The paradox of hnRNPK: both absence and excess impair skeletal muscle function in mice.Skeletal muscle · 2025Article
- Artificial intelligence-driven genotype-epigenotype-phenotype approaches to resolve challenges in syndrome diagnostics.EBioMedicine · 2025Article
- Recruitment of chromatin remodelers by XIST B-repeat region is variably dependent on HNRNPK.Human molecular genetics · 2025Article
- Validation of a hypomorphic variant in CDK13 as the cause of CHDFIDD with autosomal recessive inheritance through determination of an episignature.Clinical epigenetics · 2025Article
- Modeling craniofacial spliceosomopathies: a pathway toward deciphering disease mechanisms.Frontiers in cell and developmental biology · 2025Review
- Prenatal diagnosis of aFrontiers in genetics · 2025Article
- Clinical and molecular characteristics of Korean patients with Kabuki syndrome.Journal of human genetics · 2024Article
- Pathogenic variants in KMT2C result in a neurodevelopmental disorder distinct from Kleefstra and Kabuki syndromes.American journal of human genetics · 2024Article
- Deletion of heterogeneous nuclear ribonucleoprotein K in satellite cells leads to inhibited skeletal muscle regeneration in mice.Genes & diseases · 2024Article
- DNA methylation signatures for chromatinopathies: current challenges and future applications.Human genetics · 2024Article
- A new blood DNA methylation signature for Koolen-de Vries syndrome: Classification of missense KANSL1 variants and comparison to fibroblast cells.European journal of human genetics : EJHG · 2024Article
Corrections and comments
- Erratum issued
Authors and funding
62 authors at 20 institutions in 13 countries.
Sanaa ChoufaniGenetics and Genome Biology Program, Research Institute, the Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
Vanda McNivenDivision of Clinical and Metabolic Genetics, Department of Pediatrics, the Hospital for Sick Children, University of Toronto, Toronto, ON M5G 1X8, Canada; Fred A. Litwin Family Centre in Genetic Medicine, University Health Network and Mount Sinai Hospital, Toronto, ON M5T 3L9, Canada.
Cheryl CytrynbaumGenetics 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.
Maryam JangjooGenetics and Genome Biology Program, Research Institute, the Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
Margaret P AdamDivision of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98105, USA.
Hans T BjornssonMcKusick-Nathans Institute of Genetic Medicine, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland.
Jacqueline HarrisKennedy Krieger Institute, Baltimore, MD 21205, USA.
David A DymentChildren's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 5B2, Canada.
Gail E GrahamDivision of Genetics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
Marjan M NezaratiGenetics Program, North York General Hospital, Toronto, ON M2K 1E1, Canada.
Ritu B AulMackenzie Health, Richmond Hill, ON L4C 4Z3, Canada.
Claudia CastiglioniDepartmento de Neurologica Pediatrica, Clinica Las Condes, Santiago 7591046, Chile.
Jeroen BreckpotCenter for Human Genetics, University Hospitals Leuven, Leuven 3000, Belgium.
Koen DevriendtCenter for Human Genetics, University Hospitals Leuven, Leuven 3000, Belgium.
Helen StewartOxford Centre for Genomic Medicine, Nuffield Orthopaedic Centre, Oxford University Hospitals, NHS Foundation Trust, Headington, Oxford OX3 7HE, UK.
Benito Banos-PineroOxford Regional Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7LE, UK.
Sarju MehtaDepartment of Clinical Genetics, Addenbrookes Hospital, Cambridge CB2 0QQ, UK.
Richard SandfordDepartment of Clinical Genetics, Addenbrookes Hospital, Cambridge CB2 0QQ, UK.
Carolyn DunnDepartment of Clinical Genetics, Addenbrookes Hospital, Cambridge CB2 0QQ, UK.
Remi MathevetCentre de génétique humaine, CHU Besançon, Université de Bourgogne Franche-Comté, Besançon 25000, France.
Lionel van MaldergemCentre de génétique humaine, CHU Besançon, Université de Bourgogne Franche-Comté, Besançon 25000, France.
Juliette PiardCentre de génétique humaine, CHU Besançon, Université de Bourgogne Franche-Comté, Besançon 25000, France.
Elise Brischoux-BoucherCentre de génétique humaine, CHU Besançon, Université de Bourgogne Franche-Comté, Besançon 25000, France.
Antonio VitobelloInserm UMR1231 GAD, Génétique des Anomalies du Développement, Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement, CHU Dijon Bourgogne - Université de Bourgogne, Dijon 21079, France; UF diagnostic génomiques et maladies rares et FHU TRANSLAD, Centre Hospitalier Universitaire de Dijon-Bourgogne, Dijon 21079, France.
Laurence FaivreInserm UMR1231 GAD, Génétique des Anomalies du Développement, Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement, CHU Dijon Bourgogne - Université de Bourgogne, Dijon 21079, France; Centre de référence Anomalies du Développement et syndromes malformatifs et FHU TRANSLAD, Centre Hospitalier Universitaire de Dijon-Bourgogne, Dijon 21079, France.
Marie BournezInserm UMR1231 GAD, Génétique des Anomalies du Développement, Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement, CHU Dijon Bourgogne - Université de Bourgogne, Dijon 21079, France; Centre de référence Anomalies du Développement et syndromes malformatifs et FHU TRANSLAD, Centre Hospitalier Universitaire de Dijon-Bourgogne, Dijon 21079, France.
Frederic Tran-MauInserm UMR1231 GAD, Génétique des Anomalies du Développement, Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement, CHU Dijon Bourgogne - Université de Bourgogne, Dijon 21079, France; UF diagnostic génomiques et maladies rares et FHU TRANSLAD, Centre Hospitalier Universitaire de Dijon-Bourgogne, Dijon 21079, France.
Isabelle MaystadtDépartement de Génétique Clinique, Institut de Pathologie et de Génétique, Gosselies 6041, Belgium.
Alberto Fernández-JaénDepartment of. Pediatrics and Neurology, Hospital Universitario Quirónsalud, School of Medicine, Universidad Europea de Madrid, Madrid 28224, Spain.
Sara AlvarezGenonics and Medicine, NIMGenetics, Madrid 28108, Spain.
Irene Díez García-PrietoGenonics and Medicine, NIMGenetics, Madrid 28108, Spain.
Fowzan S AlkurayaDepartment of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
Hessa S AlsaifDepartment of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; Center of Excellence for Biomedicine, King Abdulaziz City for Science and Technology, Riyadh 12354, Saudi Arabia.
Zuhair RahbeeniDepartment of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
Karen El-AkouriDepartment of Adult and Pediatric Medical Genetics, Hamad Medical Corporation, Doha 3050, Qatar; Division of Genetic and Genomic Medicine, Sidra Medicine, Doha 26999, Qatar.
Mariam Al-MureikhiDepartment of Adult and Pediatric Medical Genetics, Hamad Medical Corporation, Doha 3050, Qatar; Division of Genetic and Genomic Medicine, Sidra Medicine, Doha 26999, Qatar.
Rebecca C SpillmannDepartment of Pediatrics-Medical Genetics, Duke University, Durham, NC 27710, USA.
Vandana ShashiDepartment of Pediatrics-Medical Genetics, Duke University, Durham, NC 27710, USA.
Pedro A Sanchez-LaraDepartment of Pediatrics, Medical Genetics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
John M GrahamDepartment of Pediatrics, Medical Genetics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Amy RobertsDepartment of Cardiology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Odelia ChorinCenter for Human Genetics & Genomics and, Department of Pediatrics, NYU Grossman School of Medicine, New York City, NY 10016, USA.
Gilad D EvronyCenter for Human Genetics & Genomics and, Department of Pediatrics, NYU Grossman School of Medicine, New York City, NY 10016, USA.
Minna Kraatari-TiriPEDEGO Research Unit, Medical Research Centre and Department of Clinical Genetics, University of Oulu and Oulu University Hospital, Oulu 90220, Finland.
Tracy Dudding-BythThe University of Newcastle, Newcastle 2308, Australia.
Anamaria RichardsonFaculty of Medicine, Department of Pediatrics, BC Children's Hospital and the University of British Columbia, Vancouver, BC V6H 3N1, Canada.
David HuntWessex Clinical Genetics Service, University Hospital Southampton NHS Foundation Trust, Southampton, UK; Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK.
Laura HamiltonWessex Clinical Genetics Service, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
Sarah DyackDivision of Medical Genetics, Department of Pediatrics, Dalhousie University, Halifax, NS B3K 6R8, Canada.
Bryce A MendelsohnDepartment of Medical Genetics, Kaiser Permanente Oakland, 3505 Broadway, Oakland, CA 94611, USA.
Nicolás RodríguezPediatrician Department, Hospital General Universitario de Alicante Dr. Balmis, Pintor Baeza, 11, 03010 Alicante, Spain.
Rosario Sánchez-MartínezInternal Medicine Department, Hospital General Universitario de Alicante Dr. Balmis, Institute for Health and Biomedical Research of Alicante, Pintor Baeza, 11, 03010 Alicante, Spain.
Jair Tenorio-CastañoCIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid 28042, Spain; INGEMM-Idipaz, Institute of Medical and Molecular Genetics, University Hospital La Paz, Madrid 28046 Spain; ITHACA, European Reference Network, Brussels 1000, Belgium.
Julián NevadoCIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid 28042, Spain; INGEMM-Idipaz, Institute of Medical and Molecular Genetics, University Hospital La Paz, Madrid 28046 Spain; ITHACA, European Reference Network, Brussels 1000, Belgium.
Pablo LapunzinaCIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid 28042, Spain; INGEMM-Idipaz, Institute of Medical and Molecular Genetics, University Hospital La Paz, Madrid 28046 Spain; ITHACA, European Reference Network, Brussels 1000, Belgium.
Pilar TiradoNeuropediatrics Service, La Paz University Hospital, Madrid 28046, Spain.
Maria-Teresa Carminho Amaro RodriguesDepartment of Genetic Medicine, University Hospitals of Geneva, 1205 Geneva, Switzerland.
Lina QuteinehDepartment of Genetic Medicine, University Hospitals of Geneva, 1205 Geneva, Switzerland.
A Micheil InnesAlberta Children's Hospital Research Institute for Child and Maternal Health, Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
Antonie D KlineHarvey Institute for Human Genetics, Greater Baltimore Medical Center, Baltimore, MD 21204, USA.
P Y Billie AuAlberta Children's Hospital Research Institute for Child and Maternal Health, Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada. Electronic address: billie.au@albertahealthservices.ca.
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.
Inserm · FRUniversité de Bourgogne · FRAddenbrooke's Hospital · GBCentre for Biomedical Network Research on Rare Diseases · ESCedars-Sinai Medical Center · USCenter for Human Genetics · USDuke University · USHamad Medical Corporation · QAHospital for Sick Children · CAHospital General Universitario de Alicante Doctor Balmis · ESKing Faisal Specialist Hospital & Research Centre · SAUniversity Hospital of Geneva · CHUniversity Hospital Southampton NHS Foundation Trust · GBUniversity of Calgary · CAUniversity of Ottawa · CAUniversity of Toronto · CABoston Children's Hospital · USClínica Las Condes · CLDalhousie University · CAGreater Baltimore Medical Center · US
Funding
No grant is acknowledged in the PubMed record.
Abstract
Au-Kline syndrome (AKS) is a neurodevelopmental disorder associated with multiple malformations and a characteristic facial gestalt. The first individuals ascertained carried de novo loss-of-function (LoF) variants in HNRNPK. Here, we report 32 individuals with AKS (26 previously unpublished), including 13 with de novo missense variants. We propose new clinical diagnostic criteria for AKS that differentiate it from the clinically overlapping Kabuki syndrome and describe a significant phenotypic expansion to include individuals with missense variants who present with subtle facial features and few or no malformations. Many gene-specific DNA methylation (DNAm) signatures have been identified for neurodevelopmental syndromes. Because HNRNPK has roles in chromatin and epigenetic regulation, we hypothesized that pathogenic variants in HNRNPK may be associated with a specific DNAm signature. Here, we report a unique DNAm signature for AKS due to LoF HNRNPK variants, distinct from controls and Kabuki syndrome. This DNAm signature is also identified in some individuals with de novo HNRNPK missense variants, confirming their pathogenicity and the phenotypic expansion of AKS to include more subtle phenotypes. Furthermore, we report that some individuals with missense variants have an "intermediate" DNAm signature that parallels their milder clinical presentation, suggesting the presence of an epi-genotype phenotype correlation. In summary, the AKS DNAm signature may help elucidate the underlying pathophysiology of AKS. This DNAm signature also effectively supported clinical syndrome delineation and is a valuable aid for variant interpretation in individuals where a clinical diagnosis of AKS is unclear, particularly for mild presentations.
Indexed as
DNA MethylationIntellectual DisabilityAbnormalities, MultipleChromatinEpigenesis, GeneticFaceHematologic DiseasesHeterogeneous-Nuclear Ribonucleoprotein KHumansPhenotypeVestibular DiseasesChromatinHeterogeneous-Nuclear Ribonucleoprotein KHNRNPK protein, humanAu-Kline syndromeDNA methylation signatureepigeneticsepisignatureHNRNPKKabuki syndromeneurodevelopmental disorderOkamoto syndromeRNA processing gene
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