De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome PMID: 27545680

ADC Targets in Oncology

2026-04-10

De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome

Am J Hum Genet. 2016 Sep 1;99(3):711-719. doi: 10.1016/j.ajhg.2016.06.029.

Jung-Hyun Kim ¹ , Deepali N Shinde ² , Margot R F Reijnders ³ , Natalie S Hauser ⁴ , Rebecca L Belmonte ⁵ , Gregory R Wilson ⁵ , Daniëlle G M Bosch ³ , Paula A Bubulya ⁶ , Vandana Shashi ⁷ , Slavé Petrovski ⁸ , Joshua K Stone ¹ , Eun Young Park ¹ , Joris A Veltman ⁹ , Margje Sinnema ¹⁰ , Connie T R M Stumpel ¹⁰ , Jos M Draaisma ¹¹ , Joost Nicolai ¹² , University of Washington Center for Mendelian Genomics , Helger G Yntema ³ , Kristin Lindstrom ¹³ , Bert B A de Vries ³ , Tamison Jewett ¹⁴ , Stephanie L Santoro ¹⁵ , Julie Vogt ¹⁶ , Deciphering Developmental Disorders Study ¹⁷ , Kristine K Bachman ¹⁸ , Andrea H Seeley ¹⁸ , Alyson Krokosky ¹⁹ , Clesson Turner ¹⁹ , Luis Rohena ²⁰ , Maja Hempel ²¹ , Fanny Kortüm ²¹ , Davor Lessel ²¹ , Axel Neu ²² , Tim M Strom ²³ , Dagmar Wieczorek ²⁴ , Nuria Bramswig ²⁵ , Franco A Laccone ²⁶ , Jana Behunova ²⁶ , Helga Rehder ²⁶ , Christopher T Gordon ²⁷ , Marlène Rio ²⁸ , Serge Romana ²⁹ , Sha Tang ² , Dima El-Khechen ² , Megan T Cho ³⁰ , Kirsty McWalter ³⁰ , Ganka Douglas ³⁰ , Berivan Baskin ³⁰ , Amber Begtrup ³⁰ , Tara Funari ³⁰ , Kelly Schoch ⁷ , Alexander P A Stegmann ¹⁰ , Servi J C Stevens ¹⁰ , Dong-Er Zhang ³¹ , David Traver ³² , Xu Yao ³³ , Daniel G MacArthur ³⁴ , Han G Brunner ⁹ , Grazia M Mancini ³⁵ , Richard M Myers ³⁶ , Laurie B Owen ¹ , Ssang-Taek Lim ³⁷ , David L Stachura ⁵ , Lisenka E L M Vissers ³⁸ , Eun-Young Erin Ahn ³⁹

Affiliations

1. Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
2. Ambry Genetics, Aliso Viejo, CA 92656, USA.
3. Department of Human Genetics, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
4. Medical Genetics and Metabolism, Valley Children's Hospital, Madera, CA 93636, USA.
5. Department of Biological Sciences, California State University, Chico, Chico, CA 95929, USA.
6. Department of Biological Sciences, Wright State University, Dayton, OH 45435, USA.
7. Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710, USA.
8. Department of Medicine, University of Melbourne, Austin Hospital and Royal Melbourne Hospital, Parkville, VIC 3010, Australia; Institute for Genomic Medicine, Columbia University, New York, NY 10027, USA.
9. Department of Human Genetics, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands; Department of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht University Medical Center, 6202 AZ Maastricht, the Netherlands.
10. Department of Clinical Genetics and School for Oncology & Developmental Biology (GROW), Maastricht University Medical Center, 6202 AZ Maastricht, the Netherlands.
11. Department of Pediatrics, Radboudumc Amalia Children's Hospital, 6500 HB Nijmegen, the Netherlands.
12. Department of Neurology, Maastricht University Medical Center, 6299 HX Maastricht, the Netherlands.
13. Division of Genetics and Metabolism, Phoenix Children's Hospital, Phoenix, AZ 85016, USA.
14. Section on Medical Genetics, Department of Pediatrics, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
15. Nationwide Children's Hospital, Columbus, OH 43205, USA; Ohio State University College of Medicine, Columbus, OH 43210, USA.
16. West Midlands Regional Genetics Service, Birmingham Women's NHS Foundation Trust, Birmingham B15 2TG, UK.
17. Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
18. Geisinger Medical Center, Danville, PA 17822, USA.
19. Division of Genetics, Department of Pediatrics, Walter Reed National Military Medical Center, Bethesda, MD 20889, USA.
20. Division of Genetics, Department of Pediatrics, San Antonio Military Medical Center, Fort Sam Houston, TX 78234, USA; Department of Pediatrics, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
21. Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
22. Department of Pediatrics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
23. Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Human Genetics, Technical University of Munich, 81675 Munich, Germany.
24. Institute of Human Genetics, University Clinic Düsseldorf, Heinrich-Heine-University, 40225 Düsseldorf, Germany; Institute of Human Genetics, University Clinic Essen, University Duisburg-Essen, 45147 Essen, Germany.
25. Institute of Human Genetics, University Clinic Essen, University Duisburg-Essen, 45147 Essen, Germany.
26. Institute of Medical Genetics, Medical University of Vienna, Waehringer Strasse 10, 1090 Vienna, Austria.
27. Laboratory of Embryology and Genetics of Congenital Malformations, INSERM UMR 1163, Institut Imagine, 75015 Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France.
28. Département de Génétique, Hôpital Necker-Enfants Malades, 75015 Paris, France.
29. Service de Cytogénétique, Hôpital Necker-Enfants Malades, 75015 Paris, France; Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, 75015 Paris, France.
30. GeneDx Inc., 205 Perry Parkway, Gaithersburg, MD 20877, USA.
31. Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA; Department of Pathology, University of California, San Diego, La Jolla, CA 92093, USA; Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
32. Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
33. Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
34. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
35. Department of Clinical Genetics, Erasmus University Medical Center, 3015 CN Rotterdam, the Netherlands.
36. HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
37. Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA.
38. Department of Human Genetics, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands. Electronic address: [email protected].
39. Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA; Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA. Electronic address: [email protected].

Abstract

The overall understanding of the molecular etiologies of intellectual disability (ID) and developmental delay (DD) is increasing as next-generation Sequencing technologies identify genetic variants in individuals with such disorders. However, detailed analyses conclusively confirming these variants, as well as the underlying molecular mechanisms explaining the diseases, are often lacking. Here, we report on an ID syndrome caused by de novo heterozygous loss-of-function (LoF) mutations in SON. The syndrome is characterized by ID and/or DD, malformations of the cerebral cortex, epilepsy, vision problems, musculoskeletal abnormalities, and congenital malformations. Knockdown of son in zebrafish resulted in severe malformation of the spine, brain, and eyes. Importantly, analyses of RNA from affected individuals revealed that genes critical for neuronal migration and cortex organization (TUBG1, FLNA, PNKP, WDR62, PSMD3, and HDAC6) and metabolism (PCK2, PFKL, IDH2, ACY1, and ADA) are significantly downregulated because of the accumulation of mis-spliced transcripts resulting from erroneous SON-mediated RNA splicing. Our data highlight SON as a master regulator governing neurodevelopment and demonstrate the importance of SON-mediated RNA splicing in human development.