title: Haploinsufficiency of the E3 ubiquitin-protein ligase gene TRIP12 causes intellectual disability with or without autism spectrum disorders, speech delay, and dysmorphic features.
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.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.|Baylor Genetics, Houston, TX, 77021, USA.
authors.forename: Jing
authors.identifier: 0000-0002-6456-7490
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.|Institute of Computer Science, Warsaw University of Technology, Warsaw, 02-038, Poland.|Department of Medical Genetics, Institute of Mother and Child, Warsaw, 01-211, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Gambin
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.|Baylor Genetics, Houston, TX, 77021, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Yuan
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Szafranski
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Rosenfeld
authors.affiliation: Pathology and Laboratory Medicine, King Abdulaziz Medical City, Riyadh, 11246, Saudi Arabia.
authors.forename: Mohammed Al
authors.initials: MA
authors.lastname: Balwi
authors.affiliation: Department of Pediatrics, King Abdulaziz Medical City, Riyadh, Saudi Arabia.
authors.forename: Abdulrahman
authors.initials: A
authors.lastname: Alswaid
authors.affiliation: Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.
authors.forename: Lihadh
authors.initials: L
authors.lastname: Al-Gazali
authors.affiliation: Department of Pediatrics, Tawam Hospital, Al Ain, United Arab Emirates.
authors.forename: Aisha M Al
authors.initials: AMA
authors.lastname: Shamsi
authors.affiliation: Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.
authors.forename: Makanko
authors.initials: M
authors.lastname: Komara
authors.affiliation: Department of Pathology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.
authors.forename: Bassam R
authors.initials: BR
authors.lastname: Ali
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.|Departments of Pediatrics and Molecular and Human Genetics, Baylor College of Medicine, San Antonio, TX, 78230, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Roeder
authors.affiliation: UT Southwestern Medical Center, Children's Health Children's Medical Center, Dallas, TX, 75235, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: McAuley
authors.affiliation: Tripler Army Medical Center, Honolulu, 96859, USA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Roy
authors.affiliation: Genetics and Metabolism, Children's Hospital, Aurora, CO, 80045, USA.
authors.forename: David K
authors.initials: DK
authors.lastname: Manchester
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.
authors.forename: Pilar
authors.initials: P
authors.lastname: Magoulas
authors.affiliation: Vanderbilt Children's Hospital, Nashville, TN, 37232, USA.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: King
authors.affiliation: Vanderbilt Children's Hospital, Nashville, TN, 37232, USA.
authors.forename: Vickie
authors.initials: V
authors.lastname: Hannig
authors.affiliation: Department of Biochemistry and Genetics, University Hospital, 49933, Angers Cedex 9, France.|UMR CNRS 6015-INSERM 1083 and PREMMI, University of Angers, 49933, Angers Cedex 9, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Bonneau
authors.affiliation: Department of Biochemistry and Genetics, University Hospital, 49933, Angers Cedex 9, France.|UMR CNRS 6015-INSERM 1083 and PREMMI, University of Angers, 49933, Angers Cedex 9, France.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Denommé-Pichon
authors.affiliation: UMR CNRS 6015-INSERM 1083 and PREMMI, University of Angers, 49933, Angers Cedex 9, France.
authors.forename: Majida
authors.initials: M
authors.lastname: Charif
authors.affiliation: CHU Nantes, Service de Génétique Médicale, 9 quai Moncousu, 44093, Nantes Cedex 1, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Besnard
authors.affiliation: CHU Nantes, Service de Génétique Médicale, 9 quai Moncousu, 44093, Nantes Cedex 1, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Bézieau
authors.affiliation: CHU Nantes, Service de Génétique Médicale, 9 quai Moncousu, 44093, Nantes Cedex 1, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Cogné
authors.affiliation: Institute of Medical Genetics, Jeanne de Flandre Hospital, Lille University Hospital, Lille, 59800, France.
authors.forename: Joris
authors.initials: J
authors.lastname: Andrieux
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.|Baylor Genetics, Houston, TX, 77021, USA.
authors.forename: Wenmiao
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.|Baylor Genetics, Houston, TX, 77021, USA.
authors.forename: Weimin
authors.initials: W
authors.lastname: He
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.|Baylor Genetics, Houston, TX, 77021, USA.
authors.forename: Francesco
authors.initials: F
authors.lastname: Vetrini
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.|Baylor Genetics, Houston, TX, 77021, USA.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Ward
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.|Baylor Genetics, Houston, TX, 77021, USA.
authors.forename: Sau Wai
authors.initials: SW
authors.lastname: Cheung
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.|Baylor Genetics, Houston, TX, 77021, USA.
authors.forename: Weimin
authors.initials: W
authors.lastname: Bi
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.|Baylor Genetics, Houston, TX, 77021, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Eng
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.|Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA.|Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, 77030, USA.|Texas Children's Hospital, Houston, TX, 77030, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.|Baylor Genetics, Houston, TX, 77021, USA.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.|Baylor Genetics, Houston, TX, 77021, USA.
authors.forename: Ankita
authors.initials: A
authors.lastname: Patel
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.|Baylor Genetics, Houston, TX, 77021, USA.
authors.forename: Seema R
authors.initials: SR
authors.lastname: Lalani
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA. fxia@bcm.edu.|Baylor Genetics, Houston, TX, 77021, USA. fxia@bcm.edu.
authors.forename: Fan
authors.initials: F
authors.lastname: Xia
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA. pawels@bcm.edu.|Baylor Genetics, Houston, TX, 77021, USA. pawels@bcm.edu.
authors.forename: Paweł
authors.initials: P
authors.lastname: Stankiewicz
mesh_terms: D000293:Adolescent; D000067877:Autism Spectrum Disorder / Q000150:complications / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D056915:DNA Copy Number Variations; D019066:Facies; D005260:Female; D057895:Haploinsufficiency; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000150:complications / Q000235:genetics*; D007805:Language Development Disorders / Q000150:complications / Q000235:genetics*; D008297:Male; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; C530813:TRIP12 protein, human; D044767:Ubiquitin-Protein Ligases