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Original research
O’Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum
  1. Clara Velmans1,
  2. Anne H O'Donnell-Luria2,3,
  3. Emanuela Argilli4,
  4. Frederic Tran Mau-them5,6,
  5. Antonio Vitobello5,6,
  6. Marcus CY Chan7,
  7. Jasmine Lee-Fong Fung7,
  8. Megan Rech8,
  9. Angela Abicht9,
  10. Marion Aubert Mucca10,
  11. Jason Carmichael11,
  12. Nicolas Chassaing10,
  13. Robin Clark12,
  14. Christine Coubes13,
  15. Anne-Sophie Denommé-Pichon5,6,
  16. John Karl de Dios14,
  17. Eleina England15,
  18. Benoit Funalot16,
  19. Marion Gerard17,
  20. Maries Joseph11,
  21. Colleen Kennedy11,
  22. Camille Kumps18,
  23. Marjolaine Willems19,
  24. Ingrid M B.H van de Laar20,
  25. Coranne Aarts-Tesselaar21,
  26. Marjon van Slegtenhorst20,
  27. Daphné Lehalle16,
  28. Kathleen Leppig22,
  29. Lennart Lessmeier1,
  30. Lynn S Pais3,
  31. Heather Paterson2,23,
  32. Subhadra Ramanathan12,
  33. Lance H Rodan23,24,
  34. Andrea Superti-Furga18,
  35. Brian H.Y. Chung7,
  36. Elliott Sherr4,
  37. Christian Netzer1,
  38. Christian P Schaaf8,25,26,
  39. Florian Erger1
  1. 1Institute of Human Genetics, University Hospital Cologne, Cologne, Nordrhein-Westfalen, Germany
  2. 2Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts, USA
  3. 3Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA
  4. 4Brain Development Research Program, Department of Neurology, University of California San Francisco Division of Hospital Medicine, San Francisco, California, USA
  5. 5UFR Des Sciences de Santé, INSERM UMR1231 GAD Génétique des Anomalies du Développement, FHU-TRANSLAD, Université de Bourgogne, Dijon, Bourgogne, France
  6. 6Unité Fonctionnelle d'Innovation diagnostique des maladies rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France
  7. 7Department of Paediatrics and Adolescent Medicine, University of Hong Kong, Hong Kong, Hong Kong
  8. 8Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
  9. 9Medical Genetics Center (MGZ), Munich, Germany
  10. 10Department of Medical Genetics, University Hospital Centre Toulouse, Toulouse, Midi-Pyrénées, France
  11. 11Department of Medical Genetics and Metabolism, Valley Children's Hospital, Madera, California, USA
  12. 12Pediatrics Specialty Clinics, Loma Linda University Medical Center, Loma Linda, California, USA
  13. 13Department of Medical Genetics, University Hospital Center Montpellier, Montpellier, Languedoc-Roussillon, France
  14. 14Department of Medical Genetics, Dayton Children's Hospital, Dayton, Ohio, USA
  15. 15Center for Mendelian Genomics and Medical and Population Genetics Program, Broad Institute, Cambridge, Massachusetts, USA
  16. 16Department of Clinical Genetics, Hopital Henri Mondor, Creteil, Île-de-France, France
  17. 17Service de Génétique, Centre Hospitalier Universitaire de Caen, Caen, Basse-Normandie, France
  18. 18Division of Genetic Medicine, Lausanne University Hospital, Lausanne, VD, Switzerland
  19. 19Medical Genetic Department for Rare Diseases and Personalized Medicine, Reference Center AD SOOR, AnDDI-RARE, Groupe DI, Inserm U1298, Montpellier University, Centre Hospitalier Universitaire de Montpellier, Montpellier, France
  20. 20Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
  21. 21Department of Pediatrics, Amphia Hospital, Breda, North Brabant, Netherlands
  22. 22Genetic Services, Kaiser Permanente Washington, Seattle, Washington, USA
  23. 23Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, USA
  24. 24Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA
  25. 25Institute of Human Genetics, Heidelberg University, Heidelberg, Baden-Württemberg, Germany
  26. 26Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, Texas, USA
  1. Correspondence to Dr Florian Erger, Institute of Human Genetics, University Hospital Cologne, 50931 Cologne, Nordrhein-Westfalen, Germany; florian.erger{at}uk-koeln.de

Abstract

Background O’Donnell-Luria-Rodan syndrome (ODLURO) is an autosomal-dominant neurodevelopmental disorder caused by pathogenic, mostly truncating variants in KMT2E. It was first described by O’Donnell-Luria et al in 2019 in a cohort of 38 patients. Clinical features encompass macrocephaly, mild intellectual disability (ID), autism spectrum disorder (ASD) susceptibility and seizure susceptibility.

Methods Affected individuals were ascertained at paediatric and genetic centres in various countries by diagnostic chromosome microarray or exome/genome sequencing. Patients were collected into a case cohort and were systematically phenotyped where possible.

Results We report 18 additional patients from 17 families with genetically confirmed ODLURO. We identified 15 different heterozygous likely pathogenic or pathogenic sequence variants (14 novel) and two partial microdeletions of KMT2E. We confirm and refine the phenotypic spectrum of the KMT2E-related neurodevelopmental disorder, especially concerning cognitive development, with rather mild ID and macrocephaly with subtle facial features in most patients. We observe a high prevalence of ASD in our cohort (41%), while seizures are present in only two patients. We extend the phenotypic spectrum by sleep disturbances.

Conclusion Our study, bringing the total of known patients with ODLURO to more than 60 within 2 years of the first publication, suggests an unexpectedly high relative frequency of this syndrome worldwide. It seems likely that ODLURO, although just recently described, is among the more common single-gene aetiologies of neurodevelopmental delay and ASD. We present the second systematic case series of patients with ODLURO, further refining the mutational and phenotypic spectrum of this not-so-rare syndrome.

  • human genetics
  • genetic counselling
  • genetics
  • behavioural
  • mutation

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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Footnotes

  • Presented at Excerpts from this study have been previously presented at the European Society of Human Genetics conference 2020.

  • Contributors CV: Data collection, data analysis, manuscript writing, manuscript editing. AHO-L/EA/FTM-T/AV/MCC/JL-FF/MR/AA/MAM/JC/NC/RC/CC/A-SD-P/JKdD/EE/BF/MG/MJ/CKe/CKu/MW/IMBHvdL/CA-T/MvS/DL/KL/LL/LSP/HP/SR/LHR/AS-F/BHYC/ES: Data collection, manuscript editing. CN/CPS: Study conception, data collection, manuscript writing, manuscript editing. FE: Study conception, data collection, data analysis, manuscript writing, manuscript editing. All authors have read and approved the final manuscript.

  • Funding AHO-L, EME and ES: Sequencing and analysis for some of the patients were provided by the Broad Institute of MIT and Harvard Centre for Mendelian Genomics (Broad CMG) and was funded by the National Human Genome Research Institute, the National Eye Institute, and the National Heart, Lung and Blood Institute grant UM1 HG008900 and in part by the National Human Genome Research Institute grant R01 HG009141. BHYC, MCYC, and JL-FF: Funding and support of the Society for the Relief of Disabled Children contributed to this project.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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