{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T03:19:58Z","timestamp":1783653598079,"version":"3.55.0"},"reference-count":50,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T00:00:00Z","timestamp":1757462400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Background and Clinical Significance: Neural tube defects (NTDs) represent a group of malformations, typically arising from a complex interplay between genetic susceptibility and environmental influences. Increasing evidence points to the contribution of rare pathogenic variants in genes involved in embryonic development in selected cases. To date, two families with NTDs carrying biallelic variants in TRIM36 and NUAK2 have been described. Specifically, germline homozygous pathogenic variants in NUAK2 were identified in three fetuses with anencephaly, thus implicating this gene as a critical regulator of neural tube closure. Case Presentation: We describe a family in which five individuals presented with sacral dimples, a subtle midline defect considered a minor malformation. Exome sequencing revealed a heterozygous missense variant, c.487G&gt;A in NUAK2, segregating with the phenotype. Although sacral dimples are often clinically silent and do not typically cause functional impairment, their presence in multiple relatives highlights a possible shared genetic etiology. Careful phenotypic recognition of such findings can therefore provide valuable insights into underlying molecular mechanisms. Conclusions: This report extends the clinical spectrum of NUAK2-related anomalies by demonstrating a novel genotype\u2013phenotype correlation. Our findings suggest that variants in this gene may follow a semi-dominant inheritance pattern, with heterozygous carriers manifesting milder phenotypes, such as sacral dimples, while biallelic pathogenic variants lead to severe NTDs. This observation reinforces the association between NUAK2 loss-of-function variants and NTDs and emphasizes the importance of genetic investigations in families where such dysmorphic traits recur. Ultimately, these results contribute to clarifying the molecular basis of NTDs and may inform both genetic counseling and risk stratification in affected families.<\/jats:p>","DOI":"10.3390\/diagnostics15182289","type":"journal-article","created":{"date-parts":[[2025,9,10]],"date-time":"2025-09-10T08:43:54Z","timestamp":1757493834000},"page":"2289","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["NUAK2 Pathogenic Variants Are Definitively Associated with Neural Tube Defects in Humans: New Genotype-Phenotype Correlation and Review of the Literature"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0788-1683","authenticated-orcid":false,"given":"Gioia","family":"Mastromoro","sequence":"first","affiliation":[{"name":"Department of Laboratory Science, Research and Development Division, Ospedale Isola Tiberina\u2014Gemelli Isola, 00186 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Dello Russo","sequence":"additional","affiliation":[{"name":"Department of Laboratory Science, Research and Development Division, Ospedale Isola Tiberina\u2014Gemelli Isola, 00186 Rome, Italy"},{"name":"Unit of Molecular Genetics, Center for Advanced Studies and Technology, \u2018G. d\u2019Annunzio\u2019 University of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Mariani","sequence":"additional","affiliation":[{"name":"Department of Laboratory Science, Research and Development Division, Ospedale Isola Tiberina\u2014Gemelli Isola, 00186 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serena","family":"Bucossi","sequence":"additional","affiliation":[{"name":"Department of Laboratory Science, Research and Development Division, Ospedale Isola Tiberina\u2014Gemelli Isola, 00186 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9590-7948","authenticated-orcid":false,"given":"Riccardo","family":"Riccardi","sequence":"additional","affiliation":[{"name":"Neonatology Unit, Ospedale Isola Tiberina\u2014Gemelli Isola, 00186 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9916-3309","authenticated-orcid":false,"given":"Amit","family":"Pal","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, AIIMS, Kalyani 741245,  India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5624-1140","authenticated-orcid":false,"given":"Rosanna","family":"Squitti","sequence":"additional","affiliation":[{"name":"Department of Laboratory Science, Research and Development Division, Ospedale Isola Tiberina\u2014Gemelli Isola, 00186 Rome, Italy"},{"name":"Department of Theoretical and Applied Sciences, eCampus University, 22100 Novedrate, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4783-1309","authenticated-orcid":false,"given":"Mehak","family":"Dangi","sequence":"additional","affiliation":[{"name":"Centre for Bioinformatics, Maharshi Dayanand University, Rohtak 124001, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Pizzuti","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauro Ciro Antonio","family":"Rongioletti","sequence":"additional","affiliation":[{"name":"Department of Laboratory Science, Research and Development Division, Ospedale Isola Tiberina\u2014Gemelli Isola, 00186 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1002\/ajmg.1320470528","article-title":"Evidence for multi-site closure of the neural tube in humans","volume":"47","author":"Kalousek","year":"1993","journal-title":"Am. 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