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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.

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Fig. 1: Schematic overview of TRIP12 variants.
Fig. 2: Schematic overview of cardinal TRIP12-associated phenotypic features.
Fig. 3: Facial pictures of 21 TRIP12 individuals.
Fig. 4: Average faces of healthy and TRIP12 individuals.
Fig. 5: Pairwise comparison of 21 TRIP12 pictures by GestaltMatcher.

Data availability

All data generated or analysed during this study are either included in this published article or available from the corresponding author on reasonable request. All variants were uploaded in the DECIPHER database (DECIPHER Patient ID 489845-489882) [13].

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Acknowledgements

The authors would like to thank the patients and caregivers for their participation in this study. We are grateful to Caterina Lo Rizzo and Francesca Ariani for their contribution.

Funding

HVE is supported by a Senior Clinical Investigator fellowship of the Fonds voor Wetenschappelijk Onderzoek (FWO) Flanders. Almost all authors are members of the European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability ERN-ITHACA [EU Framework Partnership Agreement ID: 3HP-HP-FPA ERN-01-2016/739516]. K.Õ is supported by grant from the Estonian Research Council (grant PRG471). The Broad Center for Mendelian Genomics (UM1 HG008900) is funded by the National Human Genome Research Institute with supplemental funding provided by the National Heart, Lung, and Blood Institute under the Trans-Omics for Precision Medicine (TOPMed) program and the National Eye Institute.

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All authors were involved in the collection of clinical information, the genetic analyses/data interpretation and/or the preparation of the manuscript and all approved the final version.

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Correspondence to Mio Aerden or Hilde Van Esch.

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The authors declare no competing interests.

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This study was conducted according to the UZ Leuven ethical commission guidelines. Appropriate informed consent was obtained for each affected individual, in accordance with the respective local ethical committee. Written informed consent for the publication of pictures was obtained for 21 individuals.

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Aerden, M., Denommé-Pichon, AS., Bonneau, D. et al. The neurodevelopmental and facial phenotype in individuals with a TRIP12 variant. Eur J Hum Genet 31, 461–468 (2023). https://doi.org/10.1038/s41431-023-01307-x

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