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

Abstract

Biallelic variants in the minor spliceosomal gene RNU4ATAC were successively identified in Taybi-Linder/Microcephalic osteodysplastic primordial dwarfism type I, Roifman, and Lowry-Wood syndromes, which are 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. 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. We enrolled 69 participants and identified 18 new pathogenic variants. We report a significant proportion of attenuated or atypical presentations, novel rare symptoms, and, unexpectedly, a broad spectrum of autoimmune or 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 that is distinct among some sub-syndromes. We present a large cohort of individuals with RNU4ATAC-opathies and expand the phenotypic spectrum to paucisymptomatic forms, indicating that these diseases are likely to remain underdiagnosed.