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

TitleHaploinsufficiency of the E3 ubiquitin-protein ligase gene TRIP12 causes intellectual disability with or without autism spectrum disorders, speech delay, and dysmorphic features.
Publication TypeJournal Article
Year of Publication2017
AuthorsZhang, J, Gambin, T, Yuan, B, Szafranski, P, Rosenfeld, JA, Balwi, MAl, Alswaid, A, Al-Gazali, L, Shamsi, AMAl, Komara, M, Ali, BR, Roeder, E, McAuley, L, Roy, DS, Manchester, DK, Magoulas, P, King, LE, Hannig, V, Bonneau, D, Denommé-Pichon, A-S, Charif, M, Besnard, T, Bézieau, S, Cogné, B, Andrieux, J, Zhu, W, He, W, Vetrini, F, Ward, PA, Cheung, SWai, Bi, W, Eng, CM, Lupski, JR, Yang, Y, Patel, A, Lalani, SR, Xia, F, Stankiewicz, P
JournalHum Genet
Volume136
Issue4
Pagination377-386
Date Published2017 Apr
ISSN1432-1203
KeywordsAdolescent, Autism Spectrum Disorder, Carrier Proteins, Child, Child, Preschool, Cohort Studies, DNA Copy Number Variations, Facies, Female, Haploinsufficiency, Humans, Infant, Intellectual Disability, Language Development Disorders, Male, Ubiquitin-Protein Ligases
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.

DOI10.1007/s00439-017-1763-1
Alternate JournalHum. Genet.
PubMed ID28251352
Grant ListUM1 HG006542 / HG / NHGRI NIH HHS / United States