Identification of new TRIP12 variants and detailed clinical evaluation of individuals with non-syndromic intellectual disability with or without autism

Abstract

The ubiquitin pathway is an enzymatic cascade including activating E1, conjugating E2, and ligating E3 enzymes, which governs protein degradation and sorting. It is crucial for many physiological processes. Compromised function of members of the ubiquitin pathway leads to a wide range of human diseases, such as cancer, neurodegenerative diseases, and neurodevelopmental disorders. Mutations in the thyroid hormone receptor interactor 12 (TRIP12) gene (OMIM 604506), which encodes an E3 ligase in the ubiquitin pathway, have been associated with autism spectrum disorder (ASD). In addition to autistic features, TRIP12 mutation carriers showed intellectual disability (ID). More recently, TRIP12 was postulated as a novel candidate gene for intellectual disability in a meta-analysis of published ID cohorts. However, detailed clinical information characterizing the phenotype of these individuals was not provided. In this study, we present seven novel individuals with private TRIP12 mutations including two splice site mutations, one nonsense mutation, three missense mutations, and one translocation case with a breakpoint in intron 1 of the TRIP12 gene and clinically review four previously published cases. The TRIP12 mutation-positive individuals presented with mild to moderate ID (10/11) or learning disability [intelligence quotient (IQ) 76 in one individual], ASD (8/11) and some of them with unspecific craniofacial dysmorphism and other anomalies. In this study, we provide detailed clinical information of 11 TRIP12 mutation-positive individuals and thereby expand the clinical spectrum of the TRIP12 gene in non-syndromic intellectual disability with or without ASD.

Fig. 1

Schematic illustration of TRIP12 indicating the WWE- and the catalytic HECT domain. The different isoforms of TRIP12 (A) and the localization of all TRIP12 mutations (B) are visualized. A The numbers above the rectangle depicting the protein indicate the number of amino acids. The amino acids (aa) lengths of the four major TRIP12 isoforms are 2040 aa (isoform a, first line NP_001271143.1 encoded by NM_001284214.1), 2025 aa (isoform b, second line NP_001271144.1 encoded by NM_0012824215.1), 1992 aa (isoform c, third line NP_004229.1 encoded by NM_004238.2) and 1722 aa (isoform d, fourth line NP_001271145.1 encoded by NM_001284216.1). All isoforms use the same translation start and stop signal, but differ in the usage of internal exons and the lengths of several used exons by in frame usage of alternative splice signals. They share the identical carboxy-terminal HECT domain but differ in the length of the predicted WWE domain. B We annotated the variants according to the predominant transcript NM_001284215.1 encoding TRIP12 isoform b (NP_001271144.1). The novel mutations are placed on the top, the previously published mutations on the bottom of the illustration. Individual 4 was previously published by Lelieved et al. (Lelieveld et al. 2016). Individuals 9, 10, and 11 were previously published by Iossifov et al. (2014), O’Roak et al. (2014)

Fig. 2

Clinical photographs of patients with mutations in TRIP12. A, B Individual 1 at the age of 11 4/12 years. He presents with hypertelorism, fullness of the upper eyelid, hypoplastic alae nasi, long and smooth philtrum and a wide mouth with a Cupid’s bow of the upper lip and a thin upper lip vermillion. C, D Individual 3 at the age of 76/12 years showing hypoplastic alae nasi and a U-shaped, thin upper lip. E, F Individual 5 at the age of 86/12 years displaying epicanthic folds, depressed nasal bridge, hypoplastic ale nasi, Cupid’s bow of the thin upper lip and large ear lobes. The ears of individuals 1, 3 and 5 (B, D, F) are small and posteriorly rotated. G, H Individual 6 at the age of 15 years. He shows a synophrys and a low columella

Fig. 3

Whole genome sequencing and breakpoint-PCR results in Individual 7 with a balanced reciprocal translocation, 46,X,t(X;2) (p11.3;q36.3). A Whole genome sequencing results are visualized using a Circos plot. The genomic breakpoint on chromosome 2 is located within TRIP12 and no genes were disrupted on chromosome X. B, C Breakpoint-PCR and Sanger sequencing show a one nucleotide microhomology on derivative chromosome 2 and a clean fusion without microhomology or any gain/loss of genetic material on derivative chromosome X