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Original research
Pathogenic variants in TNRC6B cause a genetic disorder characterised by developmental delay/intellectual disability and a spectrum of neurobehavioural phenotypes including autism and ADHD
  1. Jorge Luis Granadillo1,
  2. Alexander P.A. Stegmann2,
  3. Hui Guo3,
  4. Kun Xia3,
  5. Brad Angle4,
  6. Kelly Bontempo4,
  7. Judith D Ranells5,
  8. Patricia Newkirk5,
  9. Carrie Costin6,
  10. Joleen Viront6,
  11. Constanze T Stumpel2,
  12. Margje Sinnema2,
  13. Bianca Panis7,
  14. Rolph Pfundt8,
  15. Ingrid P C Krapels9,
  16. Merel Klaassens10,
  17. Joost Nicolai11,
  18. Jinliang Li12,
  19. Yuwu Jiang12,
  20. Elysa Marco13,
  21. Ana Canton14,
  22. Ana Claudia Latronico14,
  23. Luciana Montenegro14,
  24. Bruno Leheup15,
  25. Celine Bonnet16,
  26. Shivarajan M. Amudhavalli17,
  27. Caitlin E Lawson17,
  28. Kirsty McWalter18,
  29. Aida Telegrafi18,
  30. Richard Pearson18,
  31. Malin Kvarnung19,
  32. Xia Wang20,
  33. Weimin Bi21,
  34. Jill Anne Rosenfeld20,21,
  35. Marwan Shinawi1
  1. 1 Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine in Saint Louis, Saint Louis, Missouri, USA
  2. 2 Department of Clinical Genetics and School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands
  3. 3 Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
  4. 4 Advocate Lutheran General Hospital, Park Ridge, Illinois, USA
  5. 5 Department of Pediatrics, University of South Florida, Tampa, Florida, USA
  6. 6 Akron Children's Hospital, Akron, Ohio, USA
  7. 7 Zuyderland Medical Centre Heerlen, Heerlen, The Netherlands
  8. 8 Department of Human Genetics, Radboud University Medical Centre, Nijmgen, The Netherlands
  9. 9 Department of Clinical Genetics, Maastricht University, Maastricht, The Netherlands
  10. 10 Department of Pediatrics, Maastricht University Medical Center, Maastricht, The Netherlands
  11. 11 Department of Neurology, Maastricht University Medical Center, Maastricht, Netherlands
  12. 12 Peking University First Hospital, Beijing, Beijing, China
  13. 13 UCSF Pediatric Brain Center, UCSF, San Francisco, California, USA
  14. 14 Unidade de Endocrinologia do Desenvolvimento, Laboratório de Hormônios e Genética Molecular, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
  15. 15 Service de Génétique clinique, Höpital Brabois, Centre Hospitalier Universitaire de Nancy, Nancy, Lorraine, France
  16. 16 Centre Hospitalier Universitaire de Nancy, Nancy, Lorraine, France
  17. 17 Children's Mercy Hospital, Kansas City, Missouri, USA
  18. 18 GeneDx, Gaithersburg, Maryland, USA
  19. 19 Department of Clinical Genetics & Department of Molecular Medicine and Surgery, Karolinska University Hospital & Karolinska Institute, Stockholm, Sweden
  20. 20 Baylor Genetics Laboratories, Houston, Texas, USA
  21. 21 Baylor College of Medicine Department of Molecular and Human Genetics, Houston, Texas, USA
  1. Correspondence to Dr Marwan Shinawi, Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine in Saint Louis, St. Louis, MO 63110, USA; Mshinawi{at}wustl.edu

Abstract

Background Rare variants in hundreds of genes have been implicated in developmental delay (DD), intellectual disability (ID) and neurobehavioural phenotypes. TNRC6B encodes a protein important for RNA silencing. Heterozygous truncating variants have been reported in three patients from large cohorts with autism, but no full phenotypic characterisation was described.

Methods Clinical and molecular characterisation was performed on 17 patients with TNRC6B variants. Clinical data were obtained by retrospective chart review, parent interviews, direct patient interaction with providers and formal neuropsychological evaluation.

Results Clinical findings included DD/ID (17/17) (speech delay in 94% (16/17), fine motor delay in 82% (14/17) and gross motor delay in 71% (12/17) of subjects), autism or autistic traits (13/17), attention deficit and hyperactivity disorder (ADHD) (11/17), other behavioural problems (7/17) and musculoskeletal findings (12/17). Other congenital malformations or clinical findings were occasionally documented. The majority of patients exhibited some dysmorphic features but no recognisable gestalt was identified. 17 heterozygous TNRC6B variants were identified in 12 male and five female unrelated subjects by exome sequencing (14), a targeted panel (2) and a chromosomal microarray (1). The variants were nonsense (7), frameshift (5), splice site (2), intragenic deletions (2) and missense (1).

Conclusions Variants in TNRC6B cause a novel genetic disorder characterised by recurrent neurocognitive and behavioural phenotypes featuring DD/ID, autism, ADHD and other behavioural abnormalities. Our data highly suggest that haploinsufficiency is the most likely pathogenic mechanism. TNRC6B should be added to the growing list of genes of the RNA-induced silencing complex associated with ID/DD, autism and ADHD.

  • ADHD
  • autism
  • autosomal dominant
  • De novo
  • developmental delay
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Footnotes

  • Twitter @marshinawi

  • JLG and AP.S contributed equally.

  • Contributors Study concept and design: JLG and MSH. Recruitment of patients and collection of clinical information: APAS, HG, KX, BA, KB, JR, PN, CC, JV, CTRMS, MS, BP, RPF, IPCK, MK, JN, JL, YJ, EM, AC, ACL, LM, BL, CB, AS, CEL, KM, AT, RP, MKv, XW, WB, JAR and MSH. Acquisition of data: JLG, APAS, HG, JL, LM, CB, KW, JAR and MSH. Analysis and interpretation of data: JLG and MSH. Drafting of the manuscript: JLG and MSH. Critical revision of the manuscript: JLG, APAS, HG, KB, JR, CTRMS, MS, IPCK, MK, JN, AC, BL, KM, AT, RP, WB, JAR and MSH. Study supervision: MSH.

  • Competing interests KM, AT and RP are employed by GeneDx, and XW, WB, JAR receive salary support from Baylor Genetics Laboratory. Both laboratories offer extensive genetic laboratory testing, including exome sequencing and derive revenue from this activity.

  • Patient consent for publication Parental/guardian consent obtained.

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

  • Data availability statement Data are available in a public, open access repository. All data relevant to the study are included in the article or uploaded as supplementary information. As indicated above, all data relevant to the study are included in the Supplementary Table.

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