Abstract
Lowry-Wood syndrome (LWS) is a skeletal dysplasia characterized by multiple epiphyseal dysplasia associated with microcephaly, developmental delay and intellectual disability, and eye involvement. Pathogenic variants in RNU4ATAC, an RNA of the minor spliceosome important for the excision of U12-dependent introns, have been recently associated with LWS. This gene had previously also been associated with microcephalic osteodysplastic primordial dwarfism (MOPD) and Roifman syndrome (RS), two distinct conditions which share with LWS some skeletal and neurological anomalies. We performed exome sequencing in two individuals with Lowry-Wood syndrome. We report RNU4ATAC pathogenic variants in two further patients. Moreover, an analysis of all RNU4ATAC variants reported so far showed that FitCons scores for nucleotides mutated in the more severe MOPD are higher than RS or LWS and that they were more frequently located in the 5′ Stem–Loop of the RNA critical for the formation of the U4/U6.U5 tri-snRNP complex, whereas the variants are more dispersed in the other conditions. We are thus confirming that RNU4ATAC is the gene responsible for LWS and provide a genotype–phenotype correlation analysis.
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Acknowledgements
We thank the families for participating in the study and the Réseau de Médecine Génétique Appliqué du Québec for bioinformatics assistance. We acknowledge support from the Canadian Institutes of Health Research of Canada and the Fonds de Recherche Santé Québec to PMC. We thank the Galliera Genetic Biobank (Galliera Hospital), member of the Telethon Network of Genetic Biobanks (project n.GTB12001), for providing us with DNA sample of second patient. We dedicate the study to the memory of Dr. Giovanni Camera, the radiologist who contributed in reaching a clinical diagnosis for both patients.
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Shelihan, I., Ehresmann, S., Magnani, C. et al. Lowry-Wood syndrome: further evidence of association with RNU4ATAC, and correlation between genotype and phenotype. Hum Genet 137, 905–909 (2018). https://doi.org/10.1007/s00439-018-1950-8
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DOI: https://doi.org/10.1007/s00439-018-1950-8