Haploinsufficiency of the E3 ubiquitin-protein ligase geneTRIP12 causes intellectual disability with or withoutautism spectrum disorders speech delay and dysmorphic features

摘要

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 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 (CMA) 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 (LoF) mechanism. The shared clinical features include intellectual disability with or without autisticspectrum disorders, speech delay, and facial dysmorphism. Our findingsdemonstrate that E3 ubiquitin ligase TRIP12 plays an important role in nervoussystem development and function. The nine presented pathogenic variants furtherdocument that TRIP12 haploinsufficiency causes childhood-onsetneurodevelopmental disorder. Finally, our data enable expansion of thephenotypic spectrum of ubiquitin-proteasome dependent disorders.