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.

中文翻译：

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Lowry-Wood综合征：与RNU4ATAC关联的进一步证据，以及基因型与表型之间的相关性。

Lowry-Wood综合征（LWS）是一种骨骼发育不良，其特征是多发性epi骨发育不良，伴有小头畸形，发育迟缓和智力残疾以及眼睛受累。最近，LNU4ATAC中的致病性变异体（一种对剪接U12的内含子很重要的小剪接体的RNA）已与LWS相关联。该基因以前也与小头畸形原发性侏儒症（MOPD）和Roifman综合征（RS）有关，这是与LWS共有的一些骨骼和神经异常的两种不同情况。我们对两名Lowry-Wood综合征患者进行了外显子组测序。我们在另外两名患者中报告了RNU4ATAC致病变异。此外，迄今对所有RNU4ATAC变体的分析表明，在更严重的MOPD中突变的核苷酸的FitCons得分高于RS或LWS，并且它们更频繁地位于RNA的5'Stem-Loop中，这对于形成SNP至关重要。 U4 / U6.U5 tri-snRNP复合体，而变体在其他条件下更分散。因此，我们证实RNU4ATAC是负责LWS的基因，并提供了基因型与表型的相关性分析。