Expanding the clinical spectrum of RNU4ATAC-opathies: more frequent and diverse than assumed

PURPOSE: Biallelic variants in the minor spliceosomal gene RNU4ATAC were successively identified in Taybi-Linder/MOPD1 (Microcephalic osteodysplastic primordial dwarfism type I), Roifman, and Lowry-Wood syndromes, characterized by variable microcephaly, short stature, neurodevelopmental impairment, skeletal dysplasia, and immunodeficiency. Two-thirds of the reported individuals present with Taybi-Linder syndrome, the first described and most severe form. METHODS: We collected clinical and molecular data from individuals with biallelic RNU4ATAC variants through various French and European networks and clinics, to refine the phenotypic spectrum of RNU4ATAC-opathies. RESULTS: We enrolled 69 participants and identified 18 new pathogenic variants. We report a significant proportion of attenuated/atypical presentations, novel rare symptoms, and, unexpectedly, a broad spectrum of autoimmune/inflammatory manifestations, affecting nearly half of the participants. Integrating our data with the 109 published cases, we propose a novel classification based on the main manifestations, immunodeficiency and microcephalic primordial dwarfism. Using computer-assisted facial analysis, we also demonstrated the existence of a specific dysmorphic pattern in RNU4ATAC-opathies, distinct between some sub-syndromes. CONCLUSION: We present a large cohort of individuals with RNU4ATAC-opathies and expand the phenotypic spectrum to pauci-symptomatic forms, indicating that these diseases are likely to remain underdiagnosed.