Deficiency of U4atac snRNA secondarily results in ciliary defects

In the human genome, about 700 genes contain usually one intron excised by the minor spliceosome. This spliceosome comprises its own set of snRNAs, among which U4atac. Its non-coding gene, RNU4ATAC, has been found mutated in Taybi-Linder (MOPD1/TALS), Roifman (RFMN) and Lowry-Wood syndromes (LWS). These rare developmental disorders, whose physiopathological mechanisms remain unsolved, associate ante- and post-natal growth retardation, microcephaly, skeletal dysplasia, intellectual disability, retinal dystrophy and immunodeficiency. Here, we report a homozygous RNU4ATAC mutation in the Stem II domain, n.16G>A, in two unrelated patients presenting with both typical traits of the Joubert syndrome (JBTS), a well-characterized ciliopathy, and of TALS/RFMN/LWS, thus widening the clinical spectrum of RNU4ATAC-associated disorders and indicating ciliary dysfunction as a mechanism downstream of minor splicing defects. This finding is supported by alterations of primary cilium function in TALS and JBTS/RFMN fibroblasts, as well as by u4atac zebrafish model, which exhibit ciliopathy-related phenotypes and ciliary defects. Altogether, our data indicate that alteration of cilium biogenesis is part of the physiopathological mechanisms of TALS/RFMN/LWS, secondarily to defects of minor intron splicing.

Spondylocostal Dysplasia and Brachydactyly: a case report

We report a preterm male neonate presenting with a skeletal dysplasia associated with multiple congenital anomalies. Radiologic findings and genetic studies are consistent with spondylocostal dysostosis (SCD) and autosomal dominant brachydactyly. This is the first case report of spondylocostal dysostosis and brachydactyly associated with TBX6 and IHH variants.