Novel de novo TRIP12 mutation reveals variable phenotypic presentation while emphasizing core features of TRIP12 variations

Abstract

Intellectual disability (ID) is a complicated and multifactorial condition often with an unclear cause. Advancements in diagnostic techniques have identified genetic causes in a significant proportion. Pathogenic variants in TRIP12, encoding for an E3 ligand in the ubiquitin-protease pathway, have previously been identified as a cause of ID with autistic behavior and dysmorphic features. We report two unrelated patients with de novo mutations in TRIP12 and diagnoses of global developmental delay, autism spectrum disorder and dysmorphic features, as well as a range of other characteristics. Exome sequencing was utilized as part of an extensive genetic workup for both individuals. The genotypic and phenotypic data for both patients has been collated with previously reported data. Epilepsy was noted in about 20% published cases. One of our patents had epilepsy. These cases highlight the variable phenotypic presentations of TRIP12 variations while emphasizing the core features of ID and speech delay, with or without autistic features and epilepsy.

Novel Synonymous and Frameshift Variants in the TRIP12 Gene Identified in 2 Chinese Patients With Intellectual Disability

“…4,6 The majority of patients also present with motor delay (66%), autistic behaviors (71%), and other behavioral anomalies (75%). 8 Both of our patients also showed moderate ID, without autistic features, moderate to severe speech delay, motor delay, and distinct behavioral abnormalities. They both started walking at age 2 years, but patient 2 still had hypotonia, whereas no obvious muscular abnormalities were observed in patient 1.…”

“…5 Detailed characterization has been performed on a total of 24 patients with ID associated with TRIP12 variants. 4,[6][7][8] Almost 100 pathogenic variants, which include large fragment deletions, indels, and single nucleotide variations, have been documented in the Leiden Open Variation Database, ClinVar, or the Human Gene Mutation Database databases. Apart from the large fragment deletions that span the entire gene or a partial region of the gene, most pathogenic variations in the coding region of the TRIP12 gene are loss of function.…”

Graph Node Classification to Predict Autism Risk in Genes

“…These genes are ranked based on their confidence levels within their respective classes, offering insights into potential associations or relevance to syndromic and non-syndromic conditions. From the list of syndromic genes, many of them are associated with brain development or neuronal development syndromes (TRIP12 [44], NSD1 [45], CTNND2 [46], CADPS2 [47], MEF2C [48], SOX5 [49], and GRIP1 [50]). In contrast, most non-syndromic genes do not have a clear connection with the brain or neural development.…”

Genetic aetiologies for childhood speech disorder: novel pathways co-expressed during brain development

“…These findings expand the spectrum of phenotypes associated with these conditions. SETD1B has been previously associated with epilepsy, intellectual disability and language delay, and TRIP12 has been associated with non-syndromic intellectual disability 40 . Our data suggest that monogenic causes can underpin the less commonly occurring 'isolated' CAS phenotypes.…”