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Human Genetics

, Volume 136, Issue 4, pp 377–386 | Cite as

Haploinsufficiency of the E3 ubiquitin-protein ligase gene TRIP12 causes intellectual disability with or without autism spectrum disorders, speech delay, and dysmorphic features

  • Jing Zhang
  • Tomasz Gambin
  • Bo Yuan
  • Przemyslaw Szafranski
  • Jill A. Rosenfeld
  • Mohammed Al Balwi
  • Abdulrahman Alswaid
  • Lihadh Al-Gazali
  • Aisha M. Al Shamsi
  • Makanko Komara
  • Bassam R. Ali
  • Elizabeth Roeder
  • Laura McAuley
  • Daniel S. Roy
  • David K. Manchester
  • Pilar Magoulas
  • Lauren E. King
  • Vickie Hannig
  • Dominique Bonneau
  • Anne-Sophie Denommé-Pichon
  • Majida Charif
  • Thomas Besnard
  • Stéphane Bézieau
  • Benjamin Cogné
  • Joris Andrieux
  • Wenmiao Zhu
  • Weimin He
  • Francesco Vetrini
  • Patricia A. Ward
  • Sau Wai Cheung
  • Weimin Bi
  • Christine M. Eng
  • James R. Lupski
  • Yaping Yang
  • Ankita Patel
  • Seema R. Lalani
  • Fan XiaEmail author
  • Paweł StankiewiczEmail author
Original Investigation

Abstract

Impairment of ubiquitin–proteasome system activity involving ubiquitin ligase genes UBE3A, UBE3B, and HUWE1 and deubiquitinating enzyme genes USP7 and USP9X has been reported in patients with neurodevelopmental delays. To date, only a handful of single-nucleotide variants (SNVs) and copy-number variants (CNVs) involving TRIP12, encoding a member of the HECT domain E3 ubiquitin ligases family on chromosome 2q36.3 have been reported. Using chromosomal microarray analysis and whole-exome sequencing (WES), we have identified, respectively, five deletion CNVs and four inactivating SNVs (two frameshifts, one missense, and one splicing) in TRIP12. Seven of these variants were found to be de novo; parental studies could not be completed in two families. Quantitative PCR analyses of the splicing mutation showed a dramatically decreased level of TRIP12 mRNA in the proband compared to the family controls, indicating a loss-of-function mechanism. The shared clinical features include intellectual disability with or without autistic spectrum disorders, speech delay, and facial dysmorphism. Our findings demonstrate that E3 ubiquitin ligase TRIP12 plays an important role in nervous system development and function. The nine presented pathogenic variants further document that TRIP12 haploinsufficiency causes a childhood-onset neurodevelopmental disorder. Finally, our data enable expansion of the phenotypic spectrum of ubiquitin–proteasome dependent disorders.

Keywords

Autism Spectrum Disorder Intellectual Disability Intellectual Disability Chromosomal Microarray Analysis Nonsense Mediate mRNA Decay 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

We are grateful to the families for participating in this study. We are most grateful to the Genomics platform of Nantes (Biogenouest Genomics) core facility for its technical support on performing exome for Subject 9 and his parents. We acknowledge HUGODIMS (Western France exome-based trio approach project to identify genes involved in intellectual disability). This study makes use of data generated by the DECIPHER community. A full list of centres who contributed to the generation of the data is available from http://decipher.sanger.ac.uk and via email from decipher@sanger.ac.uk. Funding for the project was provided by the Wellcome Trust. This work was supported in part by the National Human Genome Research Institute/National Heart Lung and Blood Institute grant to the Baylor-Hopkins Center for Mendelian Genomics [U54HG006542], and the NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director under Award Number U01HG007709, the National Institute of Neurological Disorders and Stroke R01 Grant [NS058529 to J.R.L.], and a grant from the French Ministry of Health and Poitou–Charentes Regional Health Agency (HUGODIMS, 2013, RC14_0107).

Compliance with ethical standards

Conflict of interest

JRL has stock ownership in 23andMe and Lasergen, is a paid consultant for Regeneron Pharmaceuticals, and is a co-inventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from the chromosomal microarray analysis and clinical exome sequencing offered by Baylor Genetics (http://bmgl.com/).

Supplementary material

439_2017_1763_MOESM1_ESM.pdf (101 kb)
Supplementary material 1 (PDF 101 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Jing Zhang
    • 1
    • 2
  • Tomasz Gambin
    • 1
    • 3
    • 4
  • Bo Yuan
    • 1
    • 2
  • Przemyslaw Szafranski
    • 1
  • Jill A. Rosenfeld
    • 1
  • Mohammed Al Balwi
    • 5
  • Abdulrahman Alswaid
    • 6
  • Lihadh Al-Gazali
    • 7
  • Aisha M. Al Shamsi
    • 8
  • Makanko Komara
    • 9
  • Bassam R. Ali
    • 9
  • Elizabeth Roeder
    • 1
    • 10
  • Laura McAuley
    • 11
  • Daniel S. Roy
    • 12
  • David K. Manchester
    • 13
  • Pilar Magoulas
    • 1
  • Lauren E. King
    • 14
  • Vickie Hannig
    • 14
  • Dominique Bonneau
    • 15
    • 16
  • Anne-Sophie Denommé-Pichon
    • 15
    • 16
  • Majida Charif
    • 16
  • Thomas Besnard
    • 17
  • Stéphane Bézieau
    • 17
  • Benjamin Cogné
    • 17
  • Joris Andrieux
    • 18
  • Wenmiao Zhu
    • 1
    • 2
  • Weimin He
    • 1
    • 2
  • Francesco Vetrini
    • 1
    • 2
  • Patricia A. Ward
    • 1
    • 2
  • Sau Wai Cheung
    • 1
    • 2
  • Weimin Bi
    • 1
    • 2
  • Christine M. Eng
    • 1
    • 2
  • James R. Lupski
    • 1
    • 19
    • 20
    • 21
  • Yaping Yang
    • 1
    • 2
  • Ankita Patel
    • 1
    • 2
  • Seema R. Lalani
    • 1
    • 2
  • Fan Xia
    • 1
    • 2
    Email author
  • Paweł Stankiewicz
    • 1
    • 2
    Email author
  1. 1.Department of Molecular and Human GeneticsBaylor College of MedicineHoustonUSA
  2. 2.Baylor GeneticsHoustonUSA
  3. 3.Institute of Computer ScienceWarsaw University of TechnologyWarsawPoland
  4. 4.Department of Medical GeneticsInstitute of Mother and ChildWarsawPoland
  5. 5.Pathology and Laboratory Medicine, King Abdulaziz Medical CityRiyadhSaudi Arabia
  6. 6.Department of PediatricsKing Abdulaziz Medical CityRiyadhSaudi Arabia
  7. 7.Department of Pediatrics, College of Medicine and Health SciencesUnited Arab Emirates UniversityAl AinUnited Arab Emirates
  8. 8.Department of PediatricsTawam HospitalAl AinUnited Arab Emirates
  9. 9.Department of Pathology, College of Medicine and Health SciencesUnited Arab Emirates UniversityAl AinUnited Arab Emirates
  10. 10.Departments of Pediatrics and Molecular and Human GeneticsBaylor College of MedicineSan AntonioUSA
  11. 11.UT Southwestern Medical CenterChildren’s Health Children’s Medical CenterDallasUSA
  12. 12.Tripler Army Medical CenterHonoluluUSA
  13. 13.Genetics and MetabolismChildren’s HospitalAuroraUSA
  14. 14.Vanderbilt Children’s HospitalNashvilleUSA
  15. 15.Department of Biochemistry and GeneticsUniversity HospitalAngers Cedex 9France
  16. 16.UMR CNRS 6015-INSERM 1083 and PREMMIUniversity of AngersAngers Cedex 9France
  17. 17.CHU Nantes, Service de Génétique MédicaleNantes Cedex 1France
  18. 18.Institute of Medical Genetics, Jeanne de Flandre HospitalLille University HospitalLilleFrance
  19. 19.Department of PediatricsBaylor College of MedicineHoustonUSA
  20. 20.Human Genome Sequencing CenterBaylor College of MedicineHoustonUSA
  21. 21.Texas Children’s HospitalHoustonUSA

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