Oral-facial-digital syndromes (OFDS) are a group of clinically and genetically heterogeneous disorders characterized by defects in the development of the face and oral cavity along with digit anomalies. Pathogenic variants in over 20 genes encoding ciliary proteins have been found to cause OFDS through deleterious structural or functional impacts on primary cilia. We identified by exome sequencing bi-allelic missense variants in a novel disease-causing ciliary gene RAB34 in four individuals from three unrelated families. Affected individuals presented a novel form of OFDS (OFDS-RAB34) accompanied by cardiac, cerebral, skeletal and anorectal defects. RAB34 encodes a member of the Rab GTPase superfamily and was recently identified as a key mediator of ciliary membrane formation. Unlike many genes required for cilium assembly, RAB34 acts selectively in cell types that use the intracellular ciliogenesis pathway, in which nascent cilia begin to form in the cytoplasm. We find that the protein products of these pathogenic variants, which are clustered near the RAB34 C-terminus, exhibit a strong loss of function. Although some variants retain the ability to be recruited to the mother centriole, cells expressing mutant RAB34 exhibit a significant defect in cilium assembly. While many Rab proteins have been previously linked to ciliogenesis, our studies establish RAB34 as the first small GTPase involved in OFDS and reveal the distinct clinical manifestations caused by impairment of intracellular ciliogenesis.

Centre de Génétique et Centre de référence maladies rares 'Anomalies du Développement et Syndromes Malformatifs' FHU TRANSLAD Hôpital d'Enfants CHU Dijon Bourgogne 21079 Dijon France

Department of Clinical and Molecular Genetics Vall d'Hebron University Hospital 08035 Barcelona Spain

Department of Molecular Cellular and Developmental Biology Yale University New Haven CT 06511 USA

INSERM U1231 Génétique des Anomalies du Développement University Bourgogne Franche Comté 21070 Dijon France

Institute of Molecular and Clinical Pathology and Medical Genetics University Hospital Ostrava Ostrava 708 52 Czech Republic

Medical Genetics Group Vall d'Hebron Research Institute 08035 Barcelona Spain

Research Unit for Rare Diseases Department of Pediatrics and Inherited Metabolic Disorders 1st Faculty of Medicine Charles University and General University Hospital Prague Prague 128 08 Czech Republic

Unit of Embryo Fetal Pathology AP HP Antoine Béclère Hospital Paris Saclay University 92141 Clamart France

Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares Fédération Hospitalo Universitaire Médecine Translationnelle et Anomalies du Développement Dijon Bourgogne 21079 Dijon France

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