From Misdiagnosis to Discovery: Expanding the Spectrum of Spliceosomopathies

Background: Defining a genetic diagnosis is a challenging and stepwise process, often limited by current knowledge perspectives. Alterations in non-coding RNAs and in their modulating mechanisms are now emerging as one of the main possible explanations underpinning many unsolved cases of neurodevelopmental disorders. The latest description concerns the PUS7 gene, which encodes a pseudouridine synthase (PUS) enzyme, which has been causatively associated with an extremely rare recessive disease characterized by postnatal microcephaly, neurodevelopmental impairment, and minor dysmorphisms. Here, we report a novel case of this poorly known disorder, which was diagnosed in a young girl referred to our center following a misdiagnosis of Kleefstra Syndrome type 2. Methods: Whole-genome sequencing detected two composite heterozygous deletions in the PUS7 gene, which led us to dismiss the former diagnosis. Guided by the gestaltic evaluation of our case, we reviewed the current knowledge about the PUS7-related disorder and, driven by the biological role of this enzyme, investigated its similarities with a main spliceosomopathy, ReNU syndrome. Results: Data obtained from this exploratory analysis, together with the recent evidence from the literature, support the affinity between these conditions, suggesting that disorders of pseudouridylation might possibly be included among spliceosomopathies. Conclusions: Aside from expanding the current knowledge about the PUS7-related disorder and exploring its nosological classification, one of the main aims of our report is to raise awareness of the impact of genetic labelling and misdiagnoses. The use of whole-genome sequencing technologies requires the effective collaboration between laboratories and physicians to reach the correct diagnosis.