Clinical and neurogenetic characterisation of autosomal recessive RBL2-associated progressive neurodevelopmental disorder
Authors: Aughey Gabriel , Cali Elisa , Maroofian Reza , Zaki Maha S , Pagnamenta Alistair T , Rahman Fatima , Menzies Lara , Shafique Anum , Suri Mohnish , Roze Emmanuel , Aguennouz Mohammed , Ghizlane Zouiri , Saadi Saadia Maryam , Ali Zafar , Abdulllah Uzma , Cheema Huma Arshad , Anjum Muhammad Nadeem , Morel Godelieve , McFarland Robert , Altunoglu Umut , Kraus Verena , Shoukier Moneef , Murphy David , Flemming Kristina , Yttervik Hilde , Rhouda Hajar , Lesca Gaetan , Murtaza Bibi Nazia , Rehman Mujaddad Ur ,   SYNAPS Study Group, Consortium Genomics England , Seo Go Hun , Beetz Christian , Kayserili Hülya , Krioulie Yamna , Chung Wendy K , Naz Sadaf , Maqbool Shazia , Gleeson Joseph , Baig Shahid Mahmood , Efthymiou Stephanie , Taylor Jenny C , Severino Mariasavina , Jepson James EC , Houlden Henry 
Published: May 2024

Retinoblastoma (RB) proteins are highly conserved transcriptional regulators that play important roles during development by regulating cell-cycle gene expression. RBL2 dysfunction has been linked to a severe neurodevelopmental disorder. However, to date, clinical features have only been described in six individuals carrying five biallelic predicted loss of function (pLOF) variants. To define the phenotypic effects ofRBL2mutations in detail, we identified and clinically characterized a cohort of 28 patients from 18 families carrying LOF variants inRBL2, including fourteen new variants that substantially broaden the molecular spectrum. The clinical presentation of affected individuals is characterized by a range of neurological and developmental abnormalities. Global developmental delay and intellectual disability were uniformly observed, ranging from moderate to profound and involving lack of acquisition of key motor and speech milestones in most patients. Frequent features included postnatal microcephaly, infantile hypotonia, aggressive behaviour, stereotypic movements and non-specific dysmorphic features. Common neuroimaging features were cerebral atrophy, white matter volume loss, corpus callosum hypoplasia and cerebellar atrophy. In parallel, we used the fruit fly,Drosophila melanogaster, to investigate how disruption of the conserved RBL2 orthologueue Rbf impacts nervous system function and development. We found thatDrosophila RbfLOF mutants recapitulate several features of patients harboringRBL2variants, including alterations in the head and brain morphology reminiscent of microcephaly, and perturbed locomotor behaviour. Surprisingly, in addition to its known role in controlling tissue growth during development, we find that continuedRbfexpression is also required in fully differentiated post-mitotic neurons for normal locomotion inDrosophila, and that adult-stage neuronal re-expression ofRbfis sufficient to rescueRbfmutant locomotor defects. Taken together, this study provides a clinical and experimental basis to understand genotype-phenotype correlations in anRBL2-linked neurodevelopmental disorder and suggests that restoringRBL2expression through gene therapy approaches may ameliorate aspects ofRBL2LOF patient symptoms.