{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:23:05Z","timestamp":1785410585391,"version":"3.56.0"},"reference-count":31,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:00:00Z","timestamp":1782777600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100023548","name":"CMHI","doi-asserted-by":"crossref","award":["S205\/2024"],"award-info":[{"award-number":["S205\/2024"]}],"id":[{"id":"10.13039\/501100023548","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100023548","name":"CMHI","doi-asserted-by":"crossref","award":["S182\/19"],"award-info":[{"award-number":["S182\/19"]}],"id":[{"id":"10.13039\/501100023548","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100023548","name":"CMHI","doi-asserted-by":"crossref","award":["MEiN 7071\/IB\/SN\/2020"],"award-info":[{"award-number":["MEiN 7071\/IB\/SN\/2020"]}],"id":[{"id":"10.13039\/501100023548","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100023548","name":"CMHI","doi-asserted-by":"crossref","award":["MEiN 7088\/II-KDM\/SN\/2020"],"award-info":[{"award-number":["MEiN 7088\/II-KDM\/SN\/2020"]}],"id":[{"id":"10.13039\/501100023548","id-type":"DOI","asserted-by":"crossref"}]},{"award":["S205\/2024"],"award-info":[{"award-number":["S205\/2024"]}],"id":[{"id":"https:\/\/ror.org\/020atbp69","id-type":"ROR","asserted-by":"publisher"}]},{"award":["S182\/19"],"award-info":[{"award-number":["S182\/19"]}],"id":[{"id":"https:\/\/ror.org\/020atbp69","id-type":"ROR","asserted-by":"publisher"}]},{"award":["MEiN 7071\/IB\/SN\/2020"],"award-info":[{"award-number":["MEiN 7071\/IB\/SN\/2020"]}],"id":[{"id":"https:\/\/ror.org\/020atbp69","id-type":"ROR","asserted-by":"publisher"}]},{"award":["MEiN 7088\/II-KDM\/SN\/2020"],"award-info":[{"award-number":["MEiN 7088\/II-KDM\/SN\/2020"]}],"id":[{"id":"https:\/\/ror.org\/020atbp69","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background:\u00a0PURA-related neurodevelopmental disorder (PURA-NDD; OMIM #616158) is a rare autosomal dominant condition caused by pathogenic variants in the PURA gene encoding Pur\u03b1, 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&gt;G p.(Met104Arg), c.406_407del p.(Gln136Glyfs64), c.515A&gt;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\u2013phenotype 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\u2013phenotype 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.<\/jats:p>","DOI":"10.3390\/genes17070765","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T03:06:34Z","timestamp":1782875194000},"page":"765","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["PURA-Related Neurodevelopmental Disorder: Insight from Eight New Cases"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-7671-2848","authenticated-orcid":false,"given":"Agnieszka","family":"Madej-Pilarczyk","sequence":"first","affiliation":[{"name":"Department of Medical Genetics, The Children\u2019s Memorial Health Institute, Member of the European Reference Network ITHACA, 04-730 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marzena","family":"Gawlik","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, The Children\u2019s Memorial Health Institute, Member of the European Reference Network ITHACA, 04-730 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-1782-8127","authenticated-orcid":false,"given":"Beata","family":"Cha\u0142upczy\u0144ska","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, The Children\u2019s Memorial Health Institute, Member of the European Reference Network ITHACA, 04-730 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jagoda","family":"B\u0142aszkiewicz","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, The Children\u2019s Memorial Health Institute, Member of the European Reference Network ITHACA, 04-730 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8360-0006","authenticated-orcid":false,"given":"Dorota","family":"Wicher","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, The Children\u2019s Memorial Health Institute, Member of the European Reference Network ITHACA, 04-730 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0603-7763","authenticated-orcid":false,"given":"Agata","family":"Cie\u015blikowska","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, The Children\u2019s Memorial Health Institute, Member of the European Reference Network ITHACA, 04-730 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anila","family":"Babameto-Laku","sequence":"additional","affiliation":[{"name":"Service of Genetics Laboratory, Faculty of Medicine, University Hospital Center \u201cMother Teresa\u201d, 1000 Tirana, Albania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3888-0624","authenticated-orcid":false,"given":"Krystyna","family":"Chrzanowska","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, The Children\u2019s Memorial Health Institute, Member of the European Reference Network ITHACA, 04-730 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1065-7968","authenticated-orcid":false,"given":"El\u017cbieta","family":"Ciara","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, The Children\u2019s Memorial Health Institute, Member of the European Reference Network ITHACA, 04-730 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.gene.2017.12.004","article-title":"PURA, the gene encoding Pur-alpha, member of an ancient nucleic acid-binding protein family with mammalian neurological functions","volume":"643","author":"Daniel","year":"2018","journal-title":"Gene"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1297","DOI":"10.1093\/nar\/gkac1237","article-title":"Depletion of the RNA-binding protein PURA triggers changes in posttranscriptional gene regulation and loss of P-bodies","volume":"51","author":"Molitor","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1016\/j.ajhg.2014.09.014","article-title":"Mutations in PURA cause profound neonatal hypotonia, seizures, and encephalopathy in 5q31.3 microdeletion syndrome","volume":"95","author":"Lalani","year":"2014","journal-title":"Am. 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