B‐cell immune deficiency in twin sisters expands the phenotype of MOPDI

Abstract

AbstractMicrocephalic osteodysplastic primordial dwarfism type I (MOPDI) is a very rare and severe autosomal recessive disorder characterized by marked intrauterine growth retardation, skeletal dysplasia, microcephaly and brain malformations. MOPDI is caused by biallelic mutations in RNU4ATAC, a non‐coding gene involved in U12‐type splicing of 1% of the introns in the genome, which are recognized by their specific splicing consensus sequences. Here, we describe a unique observation of immunodeficiency in twin sisters with mild MOPDI, who harbor a novel n.108_126del mutation, encompassing part of the U4atac snRNA 3′ stem‐loop and Sm protein binding site, and the previously reported n.111G>A mutation. Interestingly, both twin sisters show mild B‐cell anomalies, including low naive B‐cell counts and increased memory B‐cell and plasmablasts counts, suggesting partial and transitory blockage of B‐cell maturation and/or excessive activation of naive B‐cells. Hence, the localization of a mutation in stem II of U4atac snRNA, as observed in another RNU4ATAC‐opathy with immunodeficiency, that is, Roifman syndrome (RFMN), is not required for the occurrence of an immune deficiency. Finally, we emphasize the importance of considering immunodeficiency in MOPDI management to reduce the risk of serious infectious episodes.