The neurodevelopmental and facial phenotype in individuals with a TRIP12 variant.
Mio AerdenAnne Sophie Denommé-PichonDominique BonneauAnge-Line BruelJulian DelanneBénédicte GérardBenoit MazelChristophe PhilippeLucile PinsonClément ProuteauAudrey PutouxFrédéric Tran Mau ThemEleonore Viora-DupontAntonio VitobelloAlban ZieglerAmelie PitonBertrand IsidorChristine FrancannetPierre-Yves MaillardSophie JuliaAnais PhilippeElise SchaeferSaskia KoeneClaudia RuivenkampMariette J V HofferEric LegiusMiel TheunisBoris KerenJulien BurattiPerrine CharlesThomas CourtinMala Misra-IsrieMieke M van HaelstQuinten WaisfiszDagmar WieczorekAriane SchmetzTheresia HergetFanny KortümJasmin LisfeldFrançois-Guillaume DebrayNuria C BramswigIsis AtallahHeidi FodstadGuillaume JouretBerta AlmogueraSaoud Tahsin SwafiriFernando Santos-SimarroMaria Palomares-BraloVanesa López-GonzálezMaria KibaekPernille M TørringAlessandra RenieriLucia Pia BrunoKatrin ÕunapMonica WojcikTzung-Chien HsiehPeter KrawitzHilde Van EschPublished in: European journal of human genetics : EJHG (2023)
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.
Keyphrases
- intellectual disability
- autism spectrum disorder
- deep learning
- copy number
- type diabetes
- machine learning
- attention deficit hyperactivity disorder
- soft tissue
- poor prognosis
- metabolic syndrome
- dna methylation
- artificial intelligence
- systematic review
- weight gain
- genome wide
- randomized controlled trial
- body mass index
- physical activity
- adipose tissue
- hiv infected
- binding protein
- human immunodeficiency virus
- men who have sex with men