UBR5-Associated Neurodevelopmental Disorder with Global Developmental Delay and Multi-Organ Involvement: A Case Report

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Background/Purpose: The number of known genetic neurodevelopmental disorders, which are often not only neurological but multi-system disorders, is continuously growing. A substantial percentage of the so far unsolved cases of suspected genetic neurodevelopmental disorder after exome, trio exome, or single genome analysis can be resolved by trio genome analysis of the child and its parents. Methods: We describe the clinical features, MRI, and genetic findings in a new case of UBR5-associated neurodevelopmental disorder in the context of the available literature after systematic searches in PubMed, MEDLINE, and Cochrane. Results: At the age of 2 years, a boy with a neurodevelopmental disorder of unknown cause presented in our center for rare neurological diseases. He has a primary global developmental delay and is microcephalic. Cerebral MRI shows a complex brain malformation, which is also the probable cause of epilepsy. Additionally, there are several other organ malformations, including dextrocardia, kidney dysplasia, iris and optic nerve colobomas, bilateral stenosis of the external auditory canal, and a micropenis. Eventually, facial and digital dysmorphisms indicated a syndromal disease. Prenatal chromosomal analysis and postnatal genetic testing, including trio exome analysis, had been inconspicuous. Trio genome analysis of the boy and his parents revealed a de novo probably pathogenic variant in the UBR5 gene. Just in January 2025, a new syndromic neurodevelopmental disorder due to variants in this gene was described. Conclusion: The precise description of the clinical phenotype, brain imaging, screening for organ malformations, and the use of trio genome analysis in case of a syndromic neurodevelopmental disorder help to identify de novo probably pathogenic or pathogenic variants in genes associated with very rare conditions or to unravel potential new disease-causing genes not yet associated with a clinical phenotype. Publication History Article published online: 26 September 2025 © 2025. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

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