Clinical and genetic characterization of a progressive RBL2-associated neurodevelopmental disorder

Area of Science:

• Genetics and Developmental Biology
• Neuroscience
• Human Genetics

Background:

• Retinoblastoma (RB) proteins, including RBL2, are crucial transcriptional regulators in cell-cycle control and development.
• RBL2 dysfunction is associated with severe neurodevelopmental disorders, but clinical features are sparsely documented.
• Previous studies identified only a few individuals with biallelic predicted loss-of-function (pLOF) RBL2 variants.

Purpose of the Study:

• To comprehensively define the phenotypic spectrum of RBL2-associated neurodevelopmental disorder.
• To broaden the understanding of the molecular basis of RBL2-related conditions.
• To investigate the conserved function of the RBL2 orthologue in a model organism.

Main Methods:

• Clinical characterization of 35 patients from 20 families with RBL2 pLOF variants.
• Identification of 15 novel RBL2 variants, expanding the molecular spectrum.
• Utilizing Drosophila melanogaster to study the conserved Rbf orthologue's role in nervous system development and function.

Main Results:

• A broad spectrum of neurological and developmental abnormalities was observed in patients, including global developmental delay, intellectual disability, microcephaly, hypotonia, seizures, and behavioral issues.
• Neuroimaging revealed cerebral atrophy, white matter loss, corpus callosum hypoplasia, and cerebellar atrophy.
• Drosophila Rbf loss-of-function mutants exhibited phenotypes mirroring human conditions, including developmental delay, brain morphology alterations, locomotor defects, and sleep disturbances, with Rbf required in post-mitotic neurons for locomotion.

Conclusions:

• This study establishes genotype-phenotype correlations for RBL2-linked neurodevelopmental disorders.
• The findings highlight the conserved role of RBL2/Rbf in nervous system development and function across species.
• Gene therapy approaches targeting RBL2 restoration may offer potential therapeutic strategies for affected individuals.