Biallelic pathogenic variants in TRMT1 disrupt tRNA modification and induce a syndromic neurodevelopmental disorder

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 the tRNA 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-rare TRMT1 variants that segregate with clinical pathology. We found that a subset of variants causes mis-splicing and loss of TRMT1 protein expression. Notably, patient cells with TRMT1 variants exhibit a deficiency in tRNA modifications catalyzed by TRMT1. Molecular analysis of TRMT1 variants 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 pathogenic TRMT1 variants. 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.