The neurodevelopmental and facial phenotype in individuals with a TRIP12 variant

Abstract

Haploinsufficiency of TRIP12 causes a neurodevelopmental disorder characterized by intellectual disability associated with epilepsy, autism spectrum disorder and dysmorphic features, also named Clark-Baraitser syndrome. Only a limited number of cases have been reported to date. We aimed to further delineate the TRIP12-associated phenotype and objectify characteristic facial traits through GestaltMatcher image analysis based on deep-learning algorithms in order to establish a TRIP12 gestalt. 38 individuals between 3 and 66 years (F = 20, M = 18) - 1 previously published and 37 novel individuals - were recruited through an ERN ITHACA call for collaboration. 35 TRIP12 variants were identified, including frameshift (n = 15) and nonsense (n = 6) variants, as well as missense (n = 5) and splice (n = 3) variants, intragenic deletions (n = 4) and two multigene deletions disrupting TRIP12. Though variable in severity, global developmental delay was noted in all individuals, with language deficit most pronounced. About half showed autistic features and susceptibility to obesity seemed inherent to this disorder. A more severe expression was noted in individuals with a missense variant. Facial analysis showed a clear gestalt including deep-set eyes with narrow palpebral fissures and fullness of the upper eyelids, downturned corners of the mouth and large, often low-set ears with prominent earlobes. We report the largest cohort to date of individuals with TRIP12 variants, further delineating the associated phenotype and introducing a facial gestalt. These findings will improve future counseling and patient guidance.

Fig. 1. Schematic overview of TRIP12 variants.

These include (A) 34 novel (top) and 20 previously reported [–8] (bottom) TRIP12 single-nucleotide variants or indels. Colors represent different variant types: missense (green), frameshift (blue), nonsense (red), small in-frame deletion (purple), splice (orange), translocation (grey) and (B) 5 novel (red) and 3 previously reported [7] (black) larger deletions affecting TRIP12.

Fig. 2. Schematic overview of cardinal TRIP12-associated phenotypic features.

Grey: total cohort (n = 38), light blue: proportion of assessed individuals, dark blue: proportion of affected individuals.

Fig. 3. Facial pictures of 21 TRIP12 individuals.

From left to right and top to bottom; subject 1 at 16 years, subject 2 at 1 year 7 months, subject 4 at 23 years 6 months, subject 10 at 5 years 8 months, subject 11 at 2 years 11 months, subject 12 at 18 years 5 months, subject 13 at 8 years 5 months, subject 14 at 5 years 9 months, subject 17 at 7 years, subject 18 at 4 years 3 months, subject 21 at 9 years, subject 23 at 65 years, subject 24 at 10 years, subject 26 at 7 years, subject 27 at 22 years, subject 28 at 14 years 8 months, subject 31 at 4 years 2 months, subject 34 at 19 years, subject 35 at 13 years 6 months, subject 37 at 2 years 10 months, subject 38 at 4 years 9 months. Recurrent facial features include deep-set eyes with narrow palpebral fissures, fullness of the upper eyelids, a broad nasal tip and wide mouth with prominent Cupid’s bow and downturned corners. Ears are often large and low-set with prominent earlobes.

Fig. 4. Average faces of healthy and TRIP12 individuals.

A Healthy average face based on 210–10 for each TRIP12 individual (n = 21) – UTKFace individuals matched for gender and age and (B) TRIP12 average face showing characteristic facial features, marked by deep-set eyes, full upper eyelids, a broad nasal tip and a wide mouth with prominent Cupid’s bow.

Fig. 5. Pairwise comparison of 21 TRIP12 pictures by GestaltMatcher.

Every column/row represents one TRIP12 subject (labeled with their subject number and corresponding variant type). TRIP12 pictures were matched in the GestaltMatcher gallery (4278 plus 20 TRIP12 pictures) and each TRIP12 picture was ranked based on the cosine distance, calculated in the CFPS. For example, when testing subject 34, subject 35 was at the 13^th rank and subject 12 at the 24^th rank. The red boxes highlight the two clusters of subjects with the highest facial similarities, but no correlation with the variant type is observed.