International Multicenter Retrospective Study on UBTF -Related Neurodevelopmental Disorder

Background and Objectives UBTF encodes the upstream binding transcription factor (UBTF), a protein essential for rRNA synthesis. Dominantly acting pathogenic variants, either de novo or inherited, have been associated with a broad clinical childhood-onset neurodegenerative/neurodevelopmental spectrum whose genotype-phenotype correlation has not been accurately defined yet. This multicenter study aims to conduct a retrospective analysis of a large cohort of patients with pathogenic variants in the UBTF gene to refine diagnostic criteria and identify clinically relevant outcome measures for future trials. Methods Clinical centers provided clinical, molecular, and neuroimaging data on patients carrying pathogenic or predicted pathogenic UBTF variants, consistent with the clinical phenotype. Data were collected using an human phenotype ontology–based standardized electronic case report form and included unreported cases or updated information on patients reported in the literature from January 2017 to December 2024. Results A cohort of 49 patients (23 previously unreported) was included in the study. The disease typically presented at ≤3 years (89.6%) with neuroregression in 71.4% of cases, either in a child with preexisting neurodevelopmental delay (42.9%) or after previously normal psychomotor development (28.6%). Less frequently, neurodevelopmental delay occurred in isolation (26.5%). During disease progression, patients developed behavioral abnormalities (81.6%), movement disorders (78.3%), autonomic manifestations (50.0%), and epilepsy (34.7%). At the last follow-up (mean age 13 years and 6 months), only 2 patients were deceased (4.1%). The main neuroimaging findings included white matter hyperintensity (68.1%), cerebral (66.0%) and cerebellar (51.1%) atrophy, and thinning of the corpus callosum (38.3%). However, brain MRI findings were reported as normal in 21.3% of cases. We identified 7 novel UBTF variants (c.271G>C; c.349A>T; c.495C>A; c.517G>A; c.761A>G; c.1048-2A>G; and c.1625_1626+15del). Genotype-phenotype analysis led to the distinction of 2 allelic, clinically distinct disorders: a childhood-onset neurodegenerative disease due to gain-of-function variants, characterized by the triad of neuroregression, movement, and behavioral disorders, and a neurodevelopmental disorder with a milder clinical course associated with loss-of-function/hypomorphic variants. Discussion The results from our deep-phenotyping analysis suggest the classification of UBTF -related disease into 2 main clinical syndromes impacting the natural history of the disease with a different degree of severity and complexity. This novel observation should be considered in the management and prognosis of patients and will be fundamental in the design of targeted therapies.