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Hum Genet. 2017 Apr;136(4):377-386. doi: 10.1007/s00439-017-1763-1. Epub 2017 Mar 1.

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

Author information

1
Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.
2
Baylor Genetics, Houston, TX, 77021, USA.
3
Institute of Computer Science, Warsaw University of Technology, Warsaw, 02-038, Poland.
4
Department of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland.
5
Pathology and Laboratory Medicine, King Abdulaziz Medical City, Riyadh, 11246, Saudi Arabia.
6
Department of Pediatrics, King Abdulaziz Medical City, Riyadh, Saudi Arabia.
7
Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.
8
Department of Pediatrics, Tawam Hospital, Al Ain, United Arab Emirates.
9
Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.
10
Departments of Pediatrics and Molecular and Human Genetics, Baylor College of Medicine, San Antonio, TX, 78230, USA.
11
UT Southwestern Medical Center, Children's Health Children's Medical Center, Dallas, TX, 75235, USA.
12
Tripler Army Medical Center, Honolulu, 96859, USA.
13
Genetics and Metabolism, Children's Hospital, Aurora, CO, 80045, USA.
14
Vanderbilt Children's Hospital, Nashville, TN, 37232, USA.
15
Department of Biochemistry and Genetics, University Hospital, 49933, Angers Cedex 9, France.
16
UMR CNRS 6015-INSERM 1083 and PREMMI, University of Angers, 49933, Angers Cedex 9, France.
17
CHU Nantes, Service de Génétique Médicale, 9 quai Moncousu, 44093, Nantes Cedex 1, France.
18
Institute of Medical Genetics, Jeanne de Flandre Hospital, Lille University Hospital, Lille, 59800, France.
19
Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA.
20
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA.
21
Texas Children's Hospital, Houston, TX, 77030, USA.
22
Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA. fxia@bcm.edu.
23
Baylor Genetics, Houston, TX, 77021, USA. fxia@bcm.edu.
24
Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA. pawels@bcm.edu.
25
Baylor Genetics, Houston, TX, 77021, USA. pawels@bcm.edu.

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.

PMID:
28251352
PMCID:
PMC5543723
DOI:
10.1007/s00439-017-1763-1
[Indexed for MEDLINE]
Free PMC Article

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