P 694. TRIP12 Variants as a Cause of Mental Disability with or without Autism

Background: Ubiquitin, which is found in all eukaryotic cells, reversibly binds to the function and biological half-life of a variety of proteins. Ubiquitin serves to control the quality of proteins, is part of signal transduction (e.g., NF-κB), and controls the cell cycle. Defects in the ubiquitin system have been implicated in various pathologies, including cancer, neurodegenerative diseases, or developmental disorders. Mutations in the thyroid hormone receptor interactor 12 gene (TRIP12), which encodes an E3 ligase in the ubiquitin pathway, are associated with mental retardation and autism spectrum disorder.

Aims: Recently, TRIP12 mutations have been identified as a possible cause of mild to moderate mental retardation (Zhang et al, 2017) in the form of language developmental disorder, autism spectrum disorder, and nonspecific dysmorphic signs. The purpose of this study is to raise awareness of this new genetic cause of mental disability.

Question: We contribute to the clinical phenotyping of the disease picture by investigating three patients with TRIP12 mutations.

Genetic Diagnostics: Case 1: Using molecular karyotyping, an approximately 1.6-Mb deletion was detected in the chromosomal region 2q36.3-q37.1, which in addition to eight other OMIM-listed genes contains the TRIP12 gene and thus leads to haploinsufficiency.

Case 2: Trio exome sequencing was used to detect a heterozygous stop mutation in the TRIP12 gene: c.5689C> T, p. (Gln1897 *) (de novo), which was classified as likely to be pathogenic.

Case 3: In the context of an exome sequencing, a probable pathogenic stop mutation c.4822C> T, p. (Arg1608 *) was detected in the TRIP12 gene (de novo).

Clinical Case Reports: Case 1: A 5-year-old female patient, fifth child of nonconsanguineous Syrian parents. Perinatal history: unremarkable, transmitted hypotrophic newborn (weight 2,500 g, length 50 cm, head circumference never measured); inconspicuous infant period. Global developmental disorder with expressive language development disorder, suspected mental retardation, autistic behavioral traits, axial hypotension. Nonspecific dysmorphic stigmata with prominent forehead, broad nasal root, hypertelorism, epicanthus, deep-seated ears. Somatic development unremarkable.

Case 2: A 7-year-old male patient, third child of nonconsanguineous German parents. Perinatal history: unremarkable, mature normotrophic newborn (weight 4,000 g, length 53 cm, head circumference 36 cm); inconspicuous infant period. Primary developmental disorder with absence of expressive language, moderate mental disability, discrete muscular hypotension, early childhood autism. Nonspecific dysmorphic signs with short nose and anteverted nares, small chin, and infraorbital swelling.

Case 3: An 8-year-old female patient, second child of nonconsanguineous German parents. Perinatal history: unremarkable, mature normotrophic newborn (weight 3,800 g, length 54 cm, head circumference 35 cm); inconspicuous infant period. Primary developmental disorder with emphasis on language deficits. Hyperkinetic behavioral disorder, mild to moderate mental retardation and incontinence. Nonspecific dysmorphic signs with broad nose and low standing columella, flat philtrum, narrow upper lip, prominent upper jaw region, and hypopigmentation on the abdomen. Somatic growth in the range P3–10.

Conclusion: In summary, heterozygous and mostly de novo mutations in the TRIP12 gene are the cause of nonsyndromal forms of mental disability with or without autism spectrum disorder. The dysmorphic signs are minor, but very variable, which makes a targeted diagnosis difficult. Since the number of cases is small, a genotype–phenotype correlation cannot be conclusively assessed. The investigation of larger cohorts with TRIP12 gene mutations is therefore warranted.