Biallelic pathogenic variants in TRMT1 disrupt tRNA modification and induce a syndromic neurodevelopmental disorder
Authors: Efthymiou Stephanie , Leo Cailyn P , Deng Chenghong , Zhang Kejia , Lin Sheng-Jia , Maroofian Reza , Kaiyrzhanov Rauan , Lin Renee , Karagoz Irem , Scardamaglia Annarita , Owrang Daniel , Turchetti Valentina , Jahnke Friederike , Petree Cassidy , Derrick Anna V , Rees Mark I , Alvi Javeria Raza , Sultan Tipu , Li Chumei , Jacquemont Marie-Line , Tran-Mau-Them Frederic , Valenzuela-Palafoll Maria , Sidlow Rich , Yoon Grace , Morrow Michelle , Carere Alexis , O’Connor Mary , Fleischer Julie , Gerkes Erica H , Phornphutkul Chanika , Isidor Bertrand , Rivier-Ringenbach Clotilde , Philippe Christophe , Kurul Semra H , Soydemir Didem , Kara Bulent , Sunnetci-Akkoyunlu Deniz , Bothe Viktoria , Platzer Konrad , Wieczorek Dagmar , Koch-Hogrebe Margarete , Rahner Nils , Thuresson Ann-Charlotte , Matsson Hans , Frykholm Carina , Bozdoğan Sevcan Tuğ , Bişgin Atıl , Chatron Nicolas , Lesca Gaetan , Cabet Sara , Tümer Zeynep , Hjortshøj Tina D , Rønde Gitte , Marquardt Thorsten , Reunert Janine , Afzal Erum , Zamani Mina , Azizimalamiri Reza , Galehdari Hamid , Nourbakhshd Pardis , Chamanrou Niloofar , Chung Seo-Kyung , Suri Mohnish , Benke Paul J , Zaki Maha S , Gleeson Joseph G , Calame Daniel G , Pehlivan Davut , Yilmaz Halil I , Gezdirici Alper , Rad Aboulfazl , Abumansour Iman Sabri , Oprea Gabriela , Sidpra Jai , Mankad Kshitij , Vona Barbara , Fry Andrew E , Varshney Gaurav K , Houlden Henry , Fu Dragony 
Published: July 2024

The post-transcriptional modification of tRNAs plays a key role in tRNA folding and function to ensure proper levels of protein synthesis during growth and development. Pathogenic variants in tRNA modification enzymes have been implicated in diverse human neurodevelopmental and neurological disorders. However, the molecular basis for many of these disorders remains unknown, thereby limiting our understanding and potential treatment of pathologies linked to tRNA modification. Here, we describe an extensive cohort of 31 individuals from 24 unrelated families with bi-allelic variants in thetRNA methyltransferase 1(TRMT1) gene who present with a syndromic neurodevelopmental disorder universally characterized by intellectual disability in affected patients. Developmental delay, behavioral abnormalities and facial dysmorphisms represent additional core phenotypes of this syndrome. The variants include novel and ultra-rareTRMT1variants that segregate with clinical pathology. We found that a subset of variants causes mis-splicing and loss of TRMT1 protein expression. Notably, patient cells withTRMT1variants exhibit a deficiency in tRNA modifications catalyzed by TRMT1. Molecular analysis ofTRMT1variants reveal distinct regions of the TRMT1 protein required for tRNA modification activity and binding, including a TRMT1 subdomain critical for tRNA interaction. Importantly, depletion of TRMT1 in zebrafish is sufficient to induce developmental and behavioral phenotypes that recapitulate those observed in human patients with pathogenicTRMT1variants. Altogether, these findings demonstrate that loss of TRMT1-catalyzed tRNA modifications leads to a syndromic form of intellectual disability and elucidate the molecular underpinnings of tRNA modification deficiency caused by pathogenic TRMT1 variants.