Background: PURA-related neurodevelopmental disorder (
PURA-NDD; OMIM #616158) is a rare autosomal dominant condition caused by pathogenic variants in the
PURA gene encoding Purα, a multifunctional protein involved in DNA replication, transcriptional regulation, and RNA transport. Since its initial description in 2014,
PURA-NDD has been increasingly recognized as a distinct clinical entity with early onset and a broad phenotypic spectrum. The clinical presentation is characterized primarily by neonatal hypotonia, global developmental delay, intellectual disability, feeding difficulties, and epilepsy, along with additional features such as respiratory insufficiency, movement disorders, hypersomnolence, and variable dysmorphic traits. Despite a relatively recognizable core phenotype, marked inter-individual variability often limits the ability to establish a definitive clinical diagnosis based on phenotype alone. This underscores the essential role of molecular genetic testing in the differential diagnosis of rare neurodevelopmental disorders.
Patients and methods: We report a cohort of eight individuals (four males and four females) aged 17 months to 15.5 years with
PURA-related neurodevelopmental disorder (
PURA-NDD), evaluated using a genotype-first diagnostic strategy supported by comprehensive genomic testing, including next-generation sequencing (NGS) panels and whole-genome sequencing (WGS). Patients were referred for the evaluation of nonspecific neurodevelopmental features, including neonatal hypotonia, respiratory distress, and epilepsy, in the absence of a definitive clinical diagnosis.
Results: Molecular analysis identified eight heterozygous variants in
PURA, of which four (50%) were novel: c.311T>G p.(Met104Arg), c.406_407del p.(Gln136Glyfs64), c.515A>C p.(Gln172Pro), and c.885delinsGC p.(His296Profs21). The remaining variants included previously reported missense and frameshift changes associated with
PURA-NDD, as well as one variant previously reported in ClinVar.
Conclusions: Our findings not only confirm the core clinical features of
PURA-related neurodevelopmental disorder but also contribute to a more comprehensive delineation of its phenotypic spectrum. The detailed characterization of our cohort broadens the range of recognized clinical manifestations and further highlights the marked phenotypic heterogeneity of
PURA-NDD. In addition, the identification of both novel and previously reported pathogenic variants expands the mutational spectrum of
PURA and underscores the importance of integrating clinical, molecular, and bioinformatic data for accurate variant interpretation. Although genotype–phenotype correlations remain incompletely understood, emerging evidence suggests potential associations between variant type or location and clinical severity, warranting further investigation in larger cohorts. The recognition of characteristic neonatal features may facilitate earlier diagnosis and implementation of supportive multidisciplinary management. Overall, this study illustrates how genomic technologies not only improve diagnostic yield in rare disorders but also refine disease definition, enhance the understanding of underlying pathogenic mechanisms, and support the development of more precise genotype–phenotype correlations. Further studies involving larger cohorts and long-term follow-up are needed to better define the full clinical and molecular spectrum of
PURA-NDD.
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