SPEN haploinsufficiency causes a neurodevelopmental disorder overlapping proximal 1p36 deletion syndrome with an episignature of X chromosomes in females

  • Am J Hum Genet. 2021 Mar 4;108(3):502-516. doi: 10.1016/j.ajhg.2021.01.015.
Francesca Clementina Radio  1 ,  Kaifang Pang  2 ,  Andrea Ciolfi  1 ,  Michael A Levy  3 ,  Andrés Hernández-García  4 ,  Lucia Pedace  5 ,  Francesca Pantaleoni  1 ,  Zhandong Liu  2 ,  Elke de Boer  6 ,  Adam Jackson  7 ,  Alessandro Bruselles  8 ,  Haley McConkey  3 ,  Emilia Stellacci  8 ,  Stefania Lo Cicero  8 ,  Marialetizia Motta  1 ,  Rosalba Carrozzo  1 ,  Maria Lisa Dentici  1 ,  Kirsty McWalter  9 ,  Megha Desai  9 ,  Kristin G Monaghan  9 ,  Aida Telegrafi  9 ,  Christophe Philippe  10 ,  Antonio Vitobello  10 ,  Margaret Au  11 ,  Katheryn Grand  11 ,  Pedro A Sanchez-Lara  11 ,  Joanne Baez  11 ,  Kristin Lindstrom  12 ,  Peggy Kulch  12 ,  Jessica Sebastian  13 ,  Suneeta Madan-Khetarpal  13 ,  Chelsea Roadhouse  14 ,  Jennifer J MacKenzie  14 ,  Berrin Monteleone  15 ,  Carol J Saunders  16 ,  July K Jean Cuevas  16 ,  Laura Cross  16 ,  Dihong Zhou  16 ,  Taila Hartley  17 ,  Sarah L Sawyer  17 ,  Fabíola Paoli Monteiro  18 ,  Tania Vertemati Secches  18 ,  Fernando Kok  18 ,  Laura E Schultz-Rogers  19 ,  Erica L Macke  19 ,  Eva Morava  20 ,  Eric W Klee  19 ,  Jennifer Kemppainen  19 ,  Maria Iascone  21 ,  Angelo Selicorni  22 ,  Romano Tenconi  23 ,  David J Amor  24 ,  Lynn Pais  25 ,  Lyndon Gallacher  24 ,  Peter D Turnpenny  26 ,  Karen Stals  26 ,  Sian Ellard  26 ,  Sara Cabet  27 ,  Gaetan Lesca  27 ,  Joset Pascal  28 ,  Katharina Steindl  28 ,  Sarit Ravid  29 ,  Karin Weiss  30 ,  Alison M R Castle  31 ,  Melissa T Carter  31 ,  Louisa Kalsner  32 ,  Bert B A de Vries  6 ,  Bregje W van Bon  33 ,  Marijke R Wevers  33 ,  Rolph Pfundt  33 ,  Alexander P A Stegmann  34 ,  Bronwyn Kerr  35 ,  Helen M Kingston  35 ,  Kate E Chandler  35 ,  Willow Sheehan  36 ,  Abdallah F Elias  36 ,  Deepali N Shinde  37 ,  Meghan C Towne  37 ,  Nathaniel H Robin  38 ,  Dana Goodloe  38 ,  Adeline Vanderver  39 ,  Omar Sherbini  38 ,  Krista Bluske  40 ,  R Tanner Hagelstrom  40 ,  Caterina Zanus  41 ,  Flavio Faletra  41 ,  Luciana Musante  41 ,  Evangeline C Kurtz-Nelson  42 ,  Rachel K Earl  42 ,  Britt-Marie Anderlid  43 ,  Gilles Morin  44 ,  Marjon van Slegtenhorst  45 ,  Karin E M Diderich  45 ,  Alice S Brooks  45 ,  Joost Gribnau  46 ,  Ruben G Boers  46 ,  Teresa Robert Finestra  46 ,  Lauren B Carter  47 ,  Anita Rauch  28 ,  Paolo Gasparini  48 ,  Kym M Boycott  17 ,  Tahsin Stefan Barakat  45 ,  John M Graham Jr  11 ,  Laurence Faivre  49 ,  Siddharth Banka  7 ,  Tianyun Wang  50 ,  Evan E Eichler  51 ,  Manuela Priolo  52 ,  Bruno Dallapiccola  1 ,  Lisenka E L M Vissers  6 ,  Bekim Sadikovic  3 ,  Daryl A Scott  53 ,  Jimmy Lloyd Holder Jr  2 ,  Marco Tartaglia  54
Affiliations
  • 1. Genetics and Rare Disease Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy.
  • 2. Division of Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
  • 3. Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON N6A5W9, Canada.
  • 4. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 5. Oncohaematology Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy.
  • 6. Department of Human Genetics, Radboudumc, 6525 GA Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, 6525 GA Nijmegen, the Netherlands.
  • 7. Division of Evolution & Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, M13 9 WL Manchester, UK; Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, M13 9WL Manchester, UK.
  • 8. Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy.
  • 9. GeneDx, Gaithersburg, MD 20877, USA.
  • 10. Inserm UMR 1231 GAD (Génétique des Anomalies du Développement), Université de Bourgogne, 21070 Dijon, France; UF Innovation en Diagnostic Génomique des Maladies Rares, CHU, Dijon Bourgogne, 21079 Dijon, France.
  • 11. Division of Medical Genetics, Department of Pediatrics, Cedars Sinai Medical Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90048, USA.
  • 12. Phoenix Children's Hospital, Phoenix, AZ 85016, USA.
  • 13. Division of Medical Genetics, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA.
  • 14. McMaster Children's Hospital, Hamilton, ON L8N 3Z5, Canada.
  • 15. Clinical genetics, NYU Langone Long Island School of Medicine, Mineola, NY 11501, USA.
  • 16. Center for Pediatric Genomic Medicine, Children's Mercy Hospital, Kansas City, MO 64108, USA.
  • 17. Children's Hospital of Eastern Ontario, Ottawa, ON K1H 8L1, Canada.
  • 18. Mendelics Genomic Analysis, Campo Belo - São Paulo 04013-000, Brazil.
  • 19. Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA.
  • 20. Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA; Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA.
  • 21. Ospedale Papa Giovanni XXIII, 24127 Bergamo, Italy.
  • 22. Azienda Socio Sanitaria Territoriale Lariana, 22100 Como, Italy.
  • 23. Dipartimento di Pediatria, Università di Padova, 35137 Padua, Italy.
  • 24. Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, VIC 3052, Australia.
  • 25. Medical and Populations Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 26. Royal Devon & Exeter NHS Foundation Trust, Exeter EX2 5DW, UK.
  • 27. Department of Genetics, Hospices Civils de Lyon, Groupement Hospitalier Est, Claude Bernard Lyon 1 University, 69002 Lyon, France.
  • 28. Institute of Medical Genetics, University of Zurich, 8952 Schlieren, Zurich, Switzerland.
  • 29. Pediatric Neurology Unit, Ruth Children's Hospital, Rambam Health Care Campus, Haifa 3109601, Israel.
  • 30. Genetics Institute, Rambam Health Care Campus, Rappaport Faculty of Medicine, Israel Institute of Technology, Haifa 3109601, Israel.
  • 31. Department of Genetics, CHEO, University of Ottawa, Ottawa, ON K1N 6N5, Canada.
  • 32. Connecticut Children's Medical Center, University of Connecticut School of Medicine, Farmington, CT 06032, USA.
  • 33. Department of Human Genetics, Radboudumc, 6525 GA Nijmegen, the Netherlands.
  • 34. Department of Human Genetics, Radboudumc, 6525 GA Nijmegen, the Netherlands; Department of Clinical Genetics, Maastricht University Medical Center+, 6229 HX Maastricht, the Netherlands.
  • 35. Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, M13 9WL Manchester, UK.
  • 36. Department of Medical Genetics, Shodair Children's Hospital, Helena, MT 59601, USA.
  • 37. Ambry Genetics, Aliso Viejo, CA 92656, USA.
  • 38. Department of Genetics, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
  • 39. Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 40. Illumina Clinical Services Laboratory, San Diego, CA 92122, USA.
  • 41. Institute for Maternal and Child Health, IRCCS "Burlo Garofolo," 34137 Trieste, Italy.
  • 42. Department of Psychiatry & Behavioral Sciences, University of Washington, Seattle, WA 98195, USA.
  • 43. Department of Molecular Medicine and Surgery, Karolinska Institutet and Department of Clinical Genetics, Karolinska University Hospital, 17176 Stockholm, Sweden.
  • 44. CA de Génétique Clinique & Oncogénétique, CHU Amiens-Picardie, 80054 Amiens, France.
  • 45. Department of Clinical Genetics, Erasmus MC University Medical Center, 3015 GD Rotterdam, the Netherlands.
  • 46. Department of Developmental Biology, Oncode Institute, Erasmus MC, University Medical Center, 3015 GD Rotterdam, the Netherlands.
  • 47. Department of Pediatrics, Division of Medical Genetics, Levine Children's Hospital Atrium Health, Charlotte, NC 28203, USA.
  • 48. Institute for Maternal and Child Health, IRCCS "Burlo Garofolo," 34137 Trieste, Italy; Department of Medicine, Surgery & Health Science, University of Trieste, 34143 Trieste, Italy.
  • 49. Centre de Référence Maladies Rares « Anomalies du Développement et Syndromes Malformatifs », Centre de Génétique, FHU-TRANSLAD et Institut GIMI, 77908 Dijon, France; UMR 1231 GAD, Inserm - Université Bourgogne-Franche Comté, 77908 Dijon, France.
  • 50. Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
  • 51. Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA.
  • 52. UOSD Genetica Medica del Grande Ospedale Metropolitano "Bianchi Melacrino Morelli" di Reggio Calabria, 89124 Reggio Calabria, Italy.
  • 53. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 54. Genetics and Rare Disease Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy. Electronic address: [email protected].
PMID: 33596411 DOI: 10.1016/j.ajhg.2021.01.015
Abstract

Deletion 1p36 (del1p36) syndrome is the most common human disorder resulting from a terminal autosomal deletion. This condition is molecularly and clinically heterogeneous. Deletions involving two non-overlapping regions, known as the distal (telomeric) and proximal (centromeric) critical regions, are sufficient to cause the majority of the recurrent clinical features, although with different facial features and dysmorphisms. SPEN encodes a transcriptional repressor commonly deleted in proximal del1p36 syndrome and is located centromeric to the proximal 1p36 critical region. Here, we used clinical data from 34 individuals with truncating variants in SPEN to define a neurodevelopmental disorder presenting with features that overlap considerably with those of proximal del1p36 syndrome. The clinical profile of this disease includes developmental delay/intellectual disability, autism spectrum disorder, anxiety, aggressive behavior, attention deficit disorder, hypotonia, brain and spine anomalies, congenital heart defects, high/narrow palate, facial dysmorphisms, and Obesity/increased BMI, especially in females. SPEN also emerges as a relevant gene for del1p36 syndrome by co-expression analyses. Finally, we show that haploinsufficiency of SPEN is associated with a distinctive DNA methylation episignature of the X chromosome in affected females, providing further evidence of a specific contribution of the protein to the epigenetic control of this chromosome, and a paradigm of an X chromosome-specific episignature that classifies syndromic traits. We conclude that SPEN is required for multiple developmental processes and SPEN haploinsufficiency is a major contributor to a disorder associated with deletions centromeric to the previously established 1p36 critical regions.

Keywords
1p36; DNA methylome analysis; SPEN; X chromosome; distal 1p36 deletion syndrome; episignature; genotype-phenotype correlations; neurodevelopmental disorder; obesity; proximal 1p36 deletion syndrome.